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Sample records for antigen hla matched

  1. Matching for Human Leukocyte Antigens (HLA) in corneal transplantation - to do or not to do.

    PubMed

    van Essen, T H; Roelen, D L; Williams, K A; Jager, M J

    2015-05-01

    As many patients with severe corneal disease are not even considered as candidates for a human graft due to their high risk of rejection, it is essential to find ways to reduce the chance of rejection. One of the options is proper matching of the cornea donor and recipient for the Human Leukocyte Antigens (HLA), a subject of much debate. Currently, patients receiving their first corneal allograft are hardly ever matched for HLA and even patients undergoing a regraft usually do not receive an HLA-matched graft. While anterior and posterior lamellar grafts are not immune to rejection, they are usually performed in low risk, non-vascularized cases. These are the cases in which the immune privilege due to the avascular status and active immune inhibition is still intact. Once broken due to infection, sensitization or trauma, rejection will occur. There is enough data to show that when proper DNA-based typing techniques are being used, even low risk perforating corneal transplantations benefit from matching for HLA Class I, and high risk cases from HLA Class I and probably Class II matching. Combining HLA class I and class II matching, or using the HLAMatchmaker could further improve the effect of HLA matching. However, new techniques could be applied to reduce the chance of rejection. Options are the local or systemic use of biologics, or gene therapy, aiming at preventing or suppressing immune responses. The goal of all these approaches should be to prevent a first rejection, as secondary grafts are usually at higher risk of complications including rejections than first grafts. PMID:25601193

  2. ONE ANTIGEN MISMATCHED RELATED VS. HLA-MATCHED UNRELATED DONOR HEMATOPOIETIC TRANSPLANTATION IN ADULTS WITH ACUTE LEUKEMIA: CIBMTR RESULTS IN THE ERA OF MOLECULAR HLA TYPING

    PubMed Central

    Valcárcel, David; Sierra, Jorge; Wang, Tao; Kan, Fangyu; Gupta, Vikas; Hale, Gregory A.; Marks, David I.; McCarthy, Philip L; Oudshoorn, Machteld; Petersdorf, Effie W; Ringdén, Olle; Setterholm, Michelle; Spellman, Stephen R; Waller, Edmund K.; Gajewski, James L; Marino, Susana R.; Senitzer, David; Lee, Stephanie J.

    2012-01-01

    Purpose Approximately 13% of patients lacking an HLA-identical sibling have a 1-antigen-mismatched related donor (MMRD). Historically, outcomes using a 1-antigen MMRD were considered equivalent to a matched unrelated donor (UD). Recent improvements in unrelated donor (UD) stem cell transplantation (SCT) due to better molecular HLA-matching justifies investigating if UD should be preferred to MMRD in adult patients with acute leukemia. Patients and Methods The outcomes of MMRD (n=89) and HLA-A, B, C, DRB1 allele matched UD (n=700) SCT reported to the CIBMTR between 1995 and 2005 were compared. Patients were transplanted for acute myeloid leukemia (AML) or acute lymphoid leukemia (ALL) in first or second complete remission. Results Donor type was not associated with hematological recovery. Univariate and multivariate comparisons of MMRD vs. HLA-matched UD transplants showed no statistically significant differences in overall survival, disease free survival, transplant related mortality, relapse, and 100-day grade III–IV acute graft-versus-host disease (GVHD). MMRD SCT was associated with a lower rate of chronic GVHD at 1-year, 35% vs 47% p=0.03, which was confirmed in multivariate analysis (RR 0.58, 95% CI 0.39-0.85, p<0.01). Conclusion HLA-matched UD and MMRD SCT are associated with comparable survival. Since less chronic GVHD was observed in MMRD, this option when available remains the first choice in acute leukemia patients without an HLA-identical sibling in need of allogeneic transplantation. PMID:20674756

  3. Effects of mismatching for Minor Histocompatibility Antigens on clinical outcomes in HLA-matched, unrelated hematopoietic stem cell transplants

    PubMed Central

    Spellman, Stephen; Warden, Melissa B.; Haagenson, Michael; Pietz, Bradley C.; Goulmy, Els; Warren, Edus H.; Wang, Tao; Ellis, Thomas M.

    2009-01-01

    Several studies in HLA-matched sibling hematopoietic stem cell transplantation (HSCT) have reported an association between mismatches in minor histocompatibility antigens (mHAg) and outcomes. We assessed whether single and multiple minor mHAg mismatches are associated with outcomes in 730 unrelated donor, HLA-A, B, C, DRB1, and DQB1 allele-matched hematopoietic stem cell transplants (HSCT) facilitated by the National Marrow Donor Program (NMDP) between 1996 and 2003. Patients had acute and chronic leukemia or myelodysplastic syndrome, received myeloablative conditioning regimens and calcineurin inhibitor-based graft-versus-host-disease (GvHD) prophylaxis, and most received bone marrow (85%). Donor and recipient DNA samples were genotyped for mHAg including: HA-1, HA-2, HA-3, HA-8, HB-1, CD31125/563. Primary outcomes included grades III–IV acute GvHD and survival; secondary outcomes included chronic GvHD, engraftment, and relapse. Single disparities at HA-1, HA-2, HA-3, HA-8, and HB-1 were not significantly associated with any of the outcomes analyzed. In HLA-A2 positive individuals, single CD31563 or multiple mHAg mismatches in the HvG vector were associated with lower risk of grades III–IV acute GVHD. Based on these data, we conclude that mHAg incompatibility at HA-1, HA-2, HA-3, HA-8, HB-1 and CD31 has no detectable effect on the outcome of HLA matched unrelated donor HSCT. PMID:19539218

  4. Effect of HLA-Matching Recipients to Donor Noninherited Maternal Antigens on Outcomes after Mismatched Umbilical Cord Blood Transplantation for Hematologic Malignancy

    PubMed Central

    Rocha, Vanderson; Spellman, Stephen; Zhang, Mei-Jie; Ruggeri, Annalisa; Purtill, Duncan; Brady, Colleen; Baxter-Lowe, Lee Ann; Baudoux, Etienne; Bergamaschi, Paola; Chow, Robert; Freed, Brian; Koegler, Gesine; Kurtzberg, Joanne; Larghero, Jerome; Lecchi, Lucilla; Nagler, Arnon; Navarrette, Cristina; Prasad, Vinod; Pouthier, Fabienne; Price, Thomas; Ratanatharathorn, Voravit; van Rood, Jon J.; Horowitz, Mary M.; Gluckman, Eliane; Eapen, Mary

    2013-01-01

    Transplantation-related mortality (TRM) is high after HLA-mismatched umbilical cord blood (UCB) transplantation (UCBT). In utero, exposure to noninherited maternal antigen (NIMA) is recognized by the fetus, which induces Tregulator cells to that haplotype. It is plausible that UCBTs in which recipients are matched to donor NIMAs may alleviate some of the excess mortality associated with this treatment. To explore this concept, we used marginal matched-pair Cox regression analysis to compare outcomes in 48 NIMA-matched UCBTs (ie, the NIMA of the donor UCB unit matched to the patient) and in 116 non–NIMA-matched UCBTs. All patients had a hematologic malignancy and received a single UCB unit. Cases and controls were matched on age, disease, disease status, transplantation-conditioning regimen, HLA match, and infused cell dose. TRM was lower after NIMA-matched UCBTs compared with NIMA-mismatched UCBTs (relative risk, 0.48; P=.05; 18% versus 32% at 5 years posttransplantation). Consequently, overall survival was higher after NIMA-matched UCBT. The 5-year probability of overall survival was 55% after NIMA-matched UCBTs versus 38% after NIMA-mismatched UCBTs (P=.04). When faced with the choice of multiple HLA-mismatched UCB units containing adequate cell doses, selecting an NIMA-matched UCB unit may improve survival after mismatched UCBT. PMID:22814031

  5. Effect of HLA-matching recipients to donor noninherited maternal antigens on outcomes after mismatched umbilical cord blood transplantation for hematologic malignancy.

    PubMed

    Rocha, Vanderson; Spellman, Stephen; Zhang, Mei-Jie; Ruggeri, Annalisa; Purtill, Duncan; Brady, Colleen; Baxter-Lowe, Lee Ann; Baudoux, Etienne; Bergamaschi, Paola; Chow, Robert; Freed, Brian; Koegler, Gesine; Kurtzberg, Joanne; Larghero, Jerome; Lecchi, Lucilla; Nagler, Arnon; Navarrette, Cristina; Prasad, Vinod; Pouthier, Fabienne; Price, Thomas; Ratanatharathorn, Voravit; van Rood, Jon J; Horowitz, Mary M; Gluckman, Eliane; Eapen, Mary

    2012-12-01

    Transplantation-related mortality (TRM) is high after HLA-mismatched umbilical cord blood (UCB) transplantation (UCBT). In utero, exposure to noninherited maternal antigen (NIMA) is recognized by the fetus, which induces T regulator cells to that haplotype. It is plausible that UCBTs in which recipients are matched to donor NIMAs may alleviate some of the excess mortality associated with this treatment. To explore this concept, we used marginal matched-pair Cox regression analysis to compare outcomes in 48 NIMA-matched UCBTs (ie, the NIMA of the donor UCB unit matched to the patient) and in 116 non-NIMA-matched UCBTs. All patients had a hematologic malignancy and received a single UCB unit. Cases and controls were matched on age, disease, disease status, transplantation-conditioning regimen, HLA match, and infused cell dose. TRM was lower after NIMA-matched UCBTs compared with NIMA-mismatched UCBTs (relative risk, 0.48; P = .05; 18% versus 32% at 5 years posttransplantation). Consequently, overall survival was higher after NIMA-matched UCBT. The 5-year probability of overall survival was 55% after NIMA-matched UCBTs versus 38% after NIMA-mismatched UCBTs (P = .04). When faced with the choice of multiple HLA-mismatched UCB units containing adequate cell doses, selecting an NIMA-matched UCB unit may improve survival after mismatched UCBT. PMID:22814031

  6. Evidence that matching for HLA antigens significantly increases transplant survival in 1001 renal transplants performed in the northwest region of England.

    PubMed

    Dyer, P A; Johnson, R W; Martin, S; Bakran, A; Gokal, R; Harris, R; Mallick, N P; Manos, J; Orr, W M; Pearson, R C

    1989-07-01

    In the 20-year period from March 1968 to March 1988, 860 patients received 1001 renal transplants in the Northwestern Regional Renal Transplant Unit at Manchester Royal Infirmary. Through a continuing policy of avoiding mismatches for HLA antigens and lymphocytotoxic antibody crossmatching, transplant survival rates were found to correlate with the degree of HLA-A and B antigen mismatching from 1968 to 1978 and with HLA-B and DR antigen mismatching from 1979 to 1988. Mismatching for HLA-B and DR antigens was also found to correlate with transplant survival in highly sensitized patients and in patients transplanted since 1981, the "cyclosporine era." Recipients who were HLA-DR1 positive were found to have the highest graft survival compared to recipients negative for this antigen. In contrast, HLA-DR3 positive recipients had the poorest outcome. Transplants from HLA-DRw6 positive donors showed higher transplant survival rates than donor kidneys positive for any other HLA-DR antigen. A correlation of transplant survival with HLA-B and DR mismatching was seen whether kidneys were collected within our region or received through the UK Transplant Service. We conclude that avoidance of mismatching for HLA-B and DR antigens confers high transplant survival rates (91.1% at 5 years for 0 HLA-B and DR mismatches), and in order to achieve this rate for most recipients exchange of donor kidneys between transplant centers will be essential. PMID:2665219

  7. Type 1 diabetes risk for human leukocyte antigen (HLA)-DR3 haplotypes depends on genotypic context: association of DPB1 and HLA class I loci among DR3- and DR4-matched Italian patients and controls.

    PubMed

    Noble, Janelle A; Martin, Adelle; Valdes, Ana M; Lane, Julie A; Galgani, Andrea; Petrone, Antonio; Lorini, Renata; Pozzilli, Paolo; Buzzetti, Raffaella; Erlich, Henry A

    2008-01-01

    Patients with high-risk human leukocyte antigen (HLA)-DR-DQ genotypes for type 1 diabetes (T1D) were compared with HLA-matched controls to evaluate T1D risk for other HLA loci, including HLA-A, -B, -Cw, and DPB1. Patients (n = 133) with high-risk genotypes (DR3/DR3, DR3/DR4, DR4/DR4) were selected from the Lazio (Rome) region of Italy. Screening of more than 9000 patients from the Lazio region and northern Italy yielded 162 controls with high-T1D-risk haplotypes. Although the overall distributions did not differ significantly, allele frequency differences were discovered between the controls from Lazio and controls from northern Italy for some alleles previously determined to affect T1D risk, such as A*3002, DPB1*0301, and DPB1*0402. Therefore, Lazio patient data were compared both with the Lazio subset of controls (n = 53) and with the entire group of controls for association analyses. Significant allele frequency differences between patients and DR-DQ-matched controls existed for specific alleles at all loci. Data for the DR3/DR3 subset of patients and controls demonstrated an increase of Cw*0702 in patients. Compared with controls, reduced patient frequencies were seen for several alleles, including A*0101, B*0801, and Cw*0701, all on the highly conserved, extended DR3 haplotype known as 8.1 in DR3/DR3, but not DR3/DR4, subgroup. DPB1*0101, often reported on 8.1 haplotypes, was also less frequent in DR3/DR3 patients than controls. Analysis of family-based data from the HBDI repository was consistent with the observed results from the Italian patients, indicating the presence of a T1D-protective locus at or near A*0101 and a second T1D-protective locus at or near DPB1*0101. These data indicate that T1D risk conferred by the 8.1 haplotype is genotype dependent. PMID:18486765

  8. Short tandem repeats haplotyping of the HLA region in preimplantation HLA matching.

    PubMed

    Fiorentino, Francesco; Kahraman, Semra; Karadayi, Hüseyin; Biricik, Anil; Sertyel, Semra; Karlikaya, Güvenc; Saglam, Yaman; Podini, Daniele; Nuccitelli, Andrea; Baldi, Marina

    2005-08-01

    Recently, preimplantation genetic diagnosis (PGD) has been considered for several indications beyond its original purpose, not only to test embryos for genetic disease but also to select embryos for a nondisease trait, such as specific human leukocyte antigen (HLA) genotypes, related to immune compatibility with an existing affected child in need of a haematopoetic stem cell (HSC) transplant. We have optimized an indirect single-cell HLA typing protocol based on a multiplex fluorescent polymerase chain reaction (PCR) of short tandem repeat (STR) markers scattered throughout the HLA complex. The assay was clinically applied in 60 cycles from 45 couples. A conclusive HLA-matching diagnosis was achieved in 483/530 (91.1%) of the embryos tested. In total, 74 (15.3%) embryos revealed an HLA match with the affected siblings, 55 (11.4%) of which resulted unaffected and 46 (9.5%) have been transferred to the patients. Nine pregnancies were achieved, five healthy HLA-matched children have already been delivered and cord blood HSCs, were transplanted to three affected siblings, resulting in a successful haematopoietic reconstruction. PMID:15886713

  9. HLA-B27 antigen

    MedlinePlus

    ... colitis Psoriatic arthritis (arthritis associated with psoriasis) Reactive arthritis Sacroiliitis (inflammation of the sacroiliac joint) Uveitis If there are symptoms or signs of an autoimmune disease, a positive HLA-B27 test may confirm the diagnosis. However, HLA-B27 ...

  10. HLA antigens in cardiomyopathic Chilean chagasics.

    PubMed Central

    Llop, E; Rothhammer, F; Acuña, M; Apt, W

    1988-01-01

    The distribution of HLA antigens in a sample of 124 Chagas serologically positive Chilean individuals was studied. The sample was subdivided according to the presence or absence of chagasic cardiomyopathy, in order to search for genetic differences associated with this pathological condition. The frequency of antigen B40 in the presence of antigen Cw3 was found to be significantly lower in subjects with cardiomyopathy. We tentatively suggest that the presence of these antigens among noncardiomyopathics is associated with a decreased susceptibility to develop chagasic cardiomyopathy in the Chilean population. PMID:3189340

  11. Class II HLA antigens in multiple sclerosis.

    PubMed Central

    Miller, D H; Hornabrook, R W; Dagger, J; Fong, R

    1989-01-01

    HLA typing in Wellington revealed a stronger association of multiple sclerosis with DR2 than with DQw1. The association with DQw1 appeared to be due to linkage disequilibrium of this antigen with DR2. These results, when considered in conjunction with other studies, are most easily explained by the hypothesis that susceptibility to multiple sclerosis is influenced by multiple risk factors, with DR2 being an important risk factor in Caucasoid populations. PMID:2732726

  12. HLA antigens in individuals with down syndrome and alopecia areata

    PubMed Central

    Estefan, Juliany L; Oliveira, Juliana C; Abad, Eliane D; Saintive, Simone B; Porto, Luis Cristóvão MS; Ribeiro, Marcia

    2014-01-01

    AIM: To describe human leukocyte antigen (HLA) alleles in individuals with Down syndrome and alopecia areata. METHODS: A cross-sectional study was conducted, which evaluated 109 individuals. Ten with down syndrome (DS) and alopecia areata (AA), ten with DS without AA and ten with AA without DS, and their families. The individuals were matched by gender and age. The following data were computed: gender, age, ethnic group, karyotype, clinical presentation and family history of alopecia areata. Descriptive analysis: measures of central tendency and frequency distribution. Inferential analysis: Fisher’s exact test to compare categorical data between the three groups and Kruskal-Wallis ANOVA test for numerical data. RESULTS: Seventy per cent of evaluated individuals in the DS and AA group were male; presented mean age of 18.6 (SD ± 7.2) years and 70% were Caucasian. We observed involvement of the scalp, with a single lesion in 10% and multiple in 90% of subjects. It was observed that there is no significant difference in the frequency distributions of the alleles HLA loci A, B, C, DRB1 and DQB1 of subjects studied. However, according to Fisher’s exact test, there is a trend (P = 0.089) of DS group to present higher proportions of HLA-A 36 and HLA-B 15 than the AA group and AA and DS group. CONCLUSION: There was a tendency for the DS group, to present proportion of HLA-A 36 and HLA-B 15 higher than the AA group and group of individuals with AA and DS. However, there was no significant difference in the frequency distribution of the alleles. PMID:25325065

  13. HLA-C Antigen mismatches are associated with worse outcomes in unrelated donor peripheral blood stem cell transplantation

    PubMed Central

    Woolfrey, Ann; Klein, John P.; Haagenson, Michael; Spellman, Stephen; Petersdorf, Effie; Oudshoorn, Machteld; Gajewski, James; Hale, Gregory A.; Horan, John; Battiwalla, Minoo; Marino, Susana R.; Setterholm, Michelle; Ringden, Olle; Hurley, Carolyn; Flomenberg, Neal; Anasetti, Claudio; Fernandez-Vina, Marcelo; Lee, Stephanie J.

    2010-01-01

    Purpose The association between human leukocyte antigen (HLA) matching and outcome in unrelated donor, peripheral blood stem cell (PBSC) transplantation has not been established. Patients and Methods 1933 unrelated donor-recipient pairs transplanted between 1999-2006 for AML, ALL, MDS or CML and who had high resolution HLA typing for HLA-A, B, C, DRB1, DQA1 and DQB1 were included in the analysis. Outcomes were compared between HLA-matched and HLA-mismatched pairs, adjusting for patient and transplant characteristics. Results Matching for HLA-A, -B, -C and DRB1 alleles [8/8 match] was associated with better survival at one year compared with 7/8 HLA-matched pairs (56% vs. 47%). Using 8/8 HLA-matched patients as the baseline (n=1243), HLA-C antigen mismatches (n=189) were statistically significantly associated with lower LFS (RR 1.36 [95% CI 1.13-1.64] p=0.0010), and increased risk for mortality (RR=1.41 [1.16-1.70], p=0.0005), treatment-related mortality (RR=1.61 [1.25-2.08], p=0.0002), and grades III-IV graft-versus-host disease (RR=1.98 [1.50-2.62], p<0.0001). HLA-B antigen or allele mismatching was associated with a higher risk for acute GVHD grades III-IV. No statistically significant differences in outcome were observed for HLA-C allele mismatch (n=61), nor for mismatches at HLA-A antigen/allele (n=136), HLA-DRB1 allele (n=39) or HLA-DQ antigen/allele (n=114) compared to 8/8 HLA-matched pairs. HLA mismatching was not associated with relapse or chronic GVHD. Conclusion HLA-C antigen mismatched unrelated PBSC donors are associated with worse outcomes compared with 8/8 HLA-matched donors. Limited power due to small sample sized prevents comment about other mismatches. PMID:20870028

  14. [The HLA antigen system in patients with pneumoconiosis].

    PubMed

    Kleĭner, A I; Makotchenko, V M; Nabrinskiĭ, S I; Prilipskaia, N I; Tkach, S I

    1992-01-01

    The antigenic HLA spectra, loci A, B and C, were explored in 102 patients suffering from pneumoconiosis of workers exposed to dust in machine building. Significant frequency differences were discovered in some antigens and their complexes (AI; A I B 8; Bw35 Cw4) between the patients and control group subjects (112 healthy persons). The patients with uncomplicated pneumoconiosis and coniotuberculosis manifested appreciable differences in the antigenic HLA spectra. The authors propose an algorithm of predicting risk at pneumoconiosis as well as risk at coniotuberculosis, resting on the results of the typing of the antigenic HLA spectra. PMID:1523545

  15. HLA antigen expression in enteropathy associated T cell lymphoma.

    PubMed Central

    Ashton-Key, M; Singh, N; Pan, L X; Smith, M E

    1996-01-01

    AIMS: To investigate the occurrence of abnormal patterns of HLA-ABC and HLA-DR expression in enteropathy associated T cell lymphoma and to relate such abnormalities to the Epstein Barr virus (EBV) status of the tumours. METHODS: Eleven enteropathy associated T cell lymphomas were immunostained with HC10 (HLA-ABC heavy chain) and TAL 1B5 (HLA-DR alpha chain) monoclonal antibodies and polyclonal anti-beta 2 microglobulin (beta 2m, the HLA-ABC light chain) antibodies. In situ hybridisation for EBV using EBER probes was performed on all cases. RESULTS: Tumour cells of two of 11 patients were EBER positive. One of these showed partial, and the other, complete loss of beta 2m. HLA-DR expression was undetectable in both patients. Of the remaining nine EBER negative tumours, two were HLA-ABC heavy chain negative or showed only occasional positive cells and five of nine showed partial or complete loss of the HLA-ABC light chain, beta 2m. Seven of the nine cases were either negative for HLA-DR or showed weak expression in a proportion of tumour cells. CONCLUSIONS: These data show that low or absent HLA-ABC and HLA-DR antigen expression occurs commonly in enteropathy associated T cell lymphoma. These abnormal patterns of HLA expression may be associated with escape from immune attack which, in a minority of patients, could be directed against EBV antigens. Images PMID:8813950

  16. Rapid assessment of the antigenic integrity of tetrameric HLA complexes by human monoclonal HLA antibodies.

    PubMed

    Eijsink, Chantal; Kester, Michel G D; Franke, Marry E I; Franken, Kees L M C; Heemskerk, Mirjam H M; Claas, Frans H J; Mulder, Arend

    2006-08-31

    The ability of tetrameric major histocompatibility complex (MHC) class I-peptide complexes (tetramers) to detect antigen-specific T lymphocyte responses has yielded significant information about the generation of in vivo immunity in numerous antigenic systems. Here we present a novel method for rapid validation of tetrameric HLA molecules based on the presence of allodeterminants. Human monoclonal antibodies (mAbs) recognizing polymorphic determinants on HLA class I were immobilized on polystyrene microparticles and used to probe the structural integrity of tetrameric HLA class I molecules by flow cytometry. A total of 22 tetramers, based on HLA-A1, A2, A3, A24, B7 and B8 were reactive with their counterpart mAbs, thus confirming their antigenic integrity. A positive outcome of this mAb test ensures that tetrameric HLA class I can be used with greater confidence in subsequent functional assays. PMID:16973172

  17. Impact of allele-level HLA matching on outcomes after myeloablative single unit umbilical cord blood transplantation for hematologic malignancy

    PubMed Central

    Klein, John P.; Ruggeri, Annalisa; Spellman, Stephen; Lee, Stephanie J.; Anasetti, Claudio; Arcese, William; Barker, Juliet N.; Baxter-Lowe, Lee Ann; Brown, Maria; Fernandez-Vina, Marcelo A.; Freeman, John; He, Wensheng; Iori, Anna Paola; Horowitz, Mary M.; Locatelli, Franco; Marino, Susana; Maiers, Martin; Michel, Gerard; Sanz, Guillermo F.; Gluckman, Eliane; Rocha, Vanderson

    2014-01-01

    We studied the effect of allele-level matching at human leukocyte antigen (HLA)-A, -B, -C, and -DRB1 in 1568 single umbilical cord blood (UCB) transplantations for hematologic malignancy. The primary end point was nonrelapse mortality (NRM). Only 7% of units were allele matched at HLA-A, -B, -C, and -DRB1; 15% were mismatched at 1, 26% at 2, 30% at 3, 16% at 4, and 5% at 5 alleles. In a subset, allele-level HLA match was assigned using imputation; concordance between HLA-match assignment and outcome correlation was confirmed between the actual and imputed HLA-match groups. Compared with HLA-matched units, neutrophil recovery was lower with mismatches at 3, 4, or 5, but not 1 or 2 alleles. NRM was higher with units mismatched at 1, 2, 3, 4, or 5 alleles compared with HLA-matched units. The observed effects are independent of cell dose and patient age. These data support allele-level HLA matching in the selection of single UCB units. PMID:24141369

  18. Risk associations between HLA-DPB1 T-cell epitope matching and outcome of unrelated hematopoietic cell transplantation are independent of HLA-DPA1.

    PubMed

    Fleischhauer, K; Fernandez-Viña, M A; Wang, T; Haagenson, M; Battiwalla, M; Baxter-Lowe, L A; Ciceri, F; Dehn, J; Gajewski, J; Hale, G A; Heemskerk, M B A; Marino, S R; McCarthy, P L; Miklos, D; Oudshoorn, M; Pollack, M S; Reddy, V; Senitzer, D; Shaw, B E; Waller, E K; Lee, S J; Spellman, S R

    2014-09-01

    HLA-DP antigens are beta-alpha heterodimers encoded by polymorphic HLA-DPB1 and -DPA1 alleles, respectively, in strong linkage disequilibrium (LD) with each other. Non-permissive unrelated donor (UD)-recipient HLA-DPB1 mismatches across three different T-cell epitope (TCE) groups are associated with increased mortality after hematopoietic SCT (HCT), but the role of HLA-DPA1 is unclear. We studied 1281 onco-hematologic patients after 10/10 HLA-matched UD-HCT facilitated by the National Marrow Donor Program. Non-permissive mismatches defined solely by HLA-DPB1 TCE groups were associated with significantly higher risks of TRM compared to permissive mismatches (hazard ratio (HR) 1.30, confidence interval (CI) 1.06-1.53; P=0.009) or allele matches. Moreover, non-permissive HLA-DPB1 TCE group mismatches in the graft versus host (GvH) direction significantly decreased the risk of relapse compared to permissive mismatches (HR 0.55, CI 0.37-0.80; P=0.002) or allele matches. Splitting each group into HLA-DPA1*02:01 positive or negative, in frequent LD with HLA-DPB1 alleles from two of the three TCE groups, or into HLA-DPA1 matched or mismatched, did not significantly alter the observed risk associations. Our findings suggest that the effects of clinically non-permissive HLA-DPB1 TCE group mismatches are independent of HLA-DPA1, and that selection of donors with non-permissive DPB1 TCE mismatches in GvH direction might provide some protection from disease recurrence. PMID:24955785

  19. Risk-associations between HLA-DPB1 T cell epitope matching and outcome of unrelated hematopoietic cell transplantation are independent from HLA-DPA1

    PubMed Central

    Fleischhauer, Katharina; Fernandez-Viña, Marcelo A.; Wang, Tao; Haagenson, Michael; Battiwalla, Minoo; Baxter-Lowe, Lee Ann; Ciceri, Fabio; Dehn, Jason; Gajewski, James; Hale, Gregory A.; Heemskerk, Martin BA; Marino, Susana R.; McCarthy, Philip L.; Miklos, David; Oudshoorn, Machteld; Pollack, Marilyn S.; Reddy, Vijay; Senitzer, David; Shaw, Bronwen E.; Waller, Edmund K.; Lee, Stephanie J.; Spellman, Stephen R.

    2014-01-01

    HLA-DP antigens are beta-alpha heterodimers encoded by polymorphic HLA-DPB1 and -DPA1 alleles, respectively, in strong linkage disequilibrium (LD) with each other. Non-permissive unrelated donor (UD)-recipient HLA-DPB1 mismatches across three different T cell epitope (TCE) groups are associated with increased mortality after hematopoietic cell transplantation (HCT), but the role of HLA-DPA1 is unclear. We studied 1281 onco-hematologic patients after 10/10 HLA-matched UD-HCT facilitated by the National Marrow Donor Program. Non-permissive mismatches defined solely by HLA-DPB1 TCE groups were associated with significantly higher risks of treatment-related mortality compared to permissive mismatches (HR 1.30, CI 1.06–1.53; p=0.009) or allele matches. Moreover, non-permissive HLA-DPB1 TCE group mismatches in the graft versus host (GvH) direction significantly decreased the risk of relapse compared to permissive mismatches (HR 0.55, CI 0.37–0.80; p=0.002) or allele matches. Splitting each group into HLA-DPA1*02:01 positive or negative, in frequent LD with HLA-DPB1 alleles from two of the three TCE groups, or into HLA-DPA1 matched or mismatched, did not significantly alter the observed risk associations. Our findings suggest that the effects of clinically non-permissive HLA-DPB1 TCE group mismatches are independent of HLA-DPA1, and that selection of donors with non-permissive DPB1 TCE mismatches in GvH direction might provide some protection from disease recurrence. PMID:24955785

  20. [HLA and keloids: antigenic frequency and therapeutic response].

    PubMed

    Rossi, A; Bozzi, M

    1989-01-01

    Twenty keloid subjects were typed for class 1 (HLA-A, B and C) and class 2 (HLA-DR and DQ) histocompatibility antigens. Their frequencies were compared to those found in control populations. Of all the antigens belonging to class 1, B 21 was more prevalent in patients. The findings regarding class 2 antigens were noteworthy: in keloid patients there was a significant prevalence of DR 5 (RR = 3.54 and 7.93 respectively for the two control groups) and DQw 3 (RR = 16.8). The patients typed for HLA-antigens were treated with corticosteroid infiltrations. The responses to the treatments were no related to the histocompatibility antigens. PMID:2628278

  1. Alloantibody Responses After Renal Transplant Failure Can Be Better Predicted by Donor-Recipient HLA Amino Acid Sequence and Physicochemical Disparities Than Conventional HLA Matching.

    PubMed

    Kosmoliaptsis, V; Mallon, D H; Chen, Y; Bolton, E M; Bradley, J A; Taylor, C J

    2016-07-01

    We have assessed whether HLA immunogenicity as defined by differences in donor-recipient HLA amino-acid sequence (amino-acid mismatch score, AMS; and eplet mismatch score, EpMS) and physicochemical properties (electrostatic mismatch score, EMS) enables prediction of allosensitization to HLA, and also prediction of the risk of an individual donor-recipient HLA mismatch to induce donor-specific antibody (DSA). HLA antibody screening was undertaken using single-antigen beads in 131 kidney transplant recipients returning to the transplant waiting list following first graft failure. The effect of AMS, EpMS, and EMS on the development of allosensitization (calculated reaction frequency [cRF]) and DSA was determined. Multivariate analyses, adjusting for time on the waiting list, maintenance on immunosuppression after transplant failure, and graft nephrectomy, showed that AMS (odds ratio [OR]: 1.44 per 10 units, 95% CI: 1.02-2.10, p = 0.04) and EMS (OR: 1.27 per 10 units, 95% CI: 1.02-1.62, p = 0.04) were independently associated with the risk of developing sensitization to HLA (cRF > 15%). AMS, EpMS, and EMS were independently associated with the development of HLA-DR and HLA-DQ DSA, but only EMS correlated with the risk of HLA-A and -B DSA development. Differences in donor-recipient HLA amino-acid sequence and physicochemical properties enable better assessment of the risk of HLA-specific sensitization than conventional HLA matching. PMID:26755448

  2. HLA antigens and insulin dependent diabetes mellitus. A family study.

    PubMed

    Savi, M; Neri, T M; Zavaroni, I; Coscelli, I

    1977-12-01

    Sixteen insulin dependent diabetic patients (age at onset less than 35 years) and their families were tissue typed for HLA antigens. Glucose tolerance of relatives was also tested. Among diabetic patients two HLA antigens were found with increased frequency: B8 (31 percent, control 15 percent) and Bw35 (38 percent, control 23 percent). Among normal relatives B8 and Bw35 had the same frequency as the control group. Bw15 frequency was not increased in either group. In relatives, no correlation between HLA antigens (B8 or Bw35) and abnormal glucose tolerance, obesity and over-weight at birth was found. Present data confirm previous reports of high B8 frequency in early onset diabetic patients, but fail to demonstrate a raised frequency of abnormal glucose tolerance among relatives bearing B8 (or, in our cases, Bw35). B8 may be considered a genetic indicator for susceptibility to juvenile diabetes. On the basis of present results in families, however non genetic factors clearly also play a determinant role. Furthermore, that diabetogenesis arises from a link between Ir-genes and HLA-B8 antigen should only be considered a suggestive hypothesis. PMID:413751

  3. Comparable survival after HLA-well-matched unrelated or matched sibling donor transplantation for acute myeloid leukemia in first remission with unfavorable cytogenetics at diagnosis

    PubMed Central

    Gupta, Vikas; Tallman, Martin S.; He, Wensheng; Logan, Brent R.; Copelan, Edward; Gale, Robert Peter; Khoury, Hanna J.; Klumpp, Thomas; Koreth, John; Lazarus, Hillard M.; Marks, David I.; Martino, Rodrigo; Rizzieri, David A.; Rowe, Jacob M.; Sabloff, Mitchell; Waller, Edmund K.; DiPersio, John F.; Bunjes, Donald W.

    2010-01-01

    We compared the outcomes of unrelated donor (URD, n = 358) with human leukocyte antigen (HLA)–matched sibling donor (MSD, n = 226) transplantations in patients with acute myeloid leukemia (AML) in first complete remission (CR1) having unfavorable cytogenetics at diagnosis. Unfavorable cytogenetic abnormalities were: complex (≥ 3 abnormalities), 32%; and noncomplex involving chromosome 7, 25%; chromosome 5, 9%; 11q or MLL rearrangements, 18%; t(6;9), 5%; and other noncomplex, 10%. URDs were HLA-well-matched (n = 254; 71%) or partially-matched (n = 104; 29%). Three-year leukemia-free survival (LFS) for MSD was 42% (95% confidence interval [CI], 35%-48%) compared with 34% (95% CI, 28%-41%) for HLA-well-matched URD and 29% (95% CI, 20%-39%) for partially-matched URD (P = .08). In multivariate analysis, HLA-well-matched URD and MSD yielded similar LFS (relative risk [RR] = 1.1, 95% CI, 0.86-1.40, P = .44) and overall survival (OS; RR = 1.06, 95% CI, 0.83-1.37, P = .63). LFS and OS were significantly inferior for HLA-partially-matched URD recipients, those with prior myelodysplastic syndrome, and those older than 50 years. All cytogenetic cohorts had similar outcomes. Patients with chronic graft-versus-host disease had a significantly lower risk of relapse (RR = 0.68, 95% CI, 0.47-0.99, P = .05). Hematopoietic cell transplantation (HCT) using HLA-well-matched URD and MSD resulted in similar LFS and OS in AML patients in CR1 with unfavorable cytogenetics. Outcomes of HCT from HLA-partially- matched URD were inferior. PMID:20538804

  4. A Novel Cancer Vaccine Strategy Based on HLA-A*0201 Matched Allogeneic Plasmacytoid Dendritic Cells

    PubMed Central

    Aspord, Caroline; Charles, Julie; Leccia, Marie-Therese; Laurin, David; Richard, Marie-Jeanne; Chaperot, Laurence; Plumas, Joel

    2010-01-01

    Background The development of effective cancer vaccines still remains a challenge. Despite the crucial role of plasmacytoid dendritic cells (pDCs) in anti-tumor responses, their therapeutic potential has not yet been worked out. We explored the relevance of HLA-A*0201 matched allogeneic pDCs as vectors for immunotherapy. Methods and Findings Stimulation of PBMC from HLA-A*0201+ donors by HLA-A*0201 matched allogeneic pDCs pulsed with tumor-derived peptides triggered high levels of antigen-specific and functional cytotoxic T cell responses (up to 98% tetramer+ CD8 T cells). The pDC vaccine demonstrated strong anti-tumor therapeutic in vivo efficacy as shown by the inhibition of tumor growth in a humanized mouse model. It also elicited highly functional tumor-specific T cells ex-vivo from PBMC and TIL of stage I-IV melanoma patients. Responses against MelA, GP100, tyrosinase and MAGE-3 antigens reached tetramer levels up to 62%, 24%, 85% and 4.3% respectively. pDC vaccine-primed T cells specifically killed patients' own autologous melanoma tumor cells. This semi-allogeneic pDC vaccine was more effective than conventional myeloid DC-based vaccines. Furthermore, the pDC vaccine design endows it with a strong potential for clinical application in cancer treatment. Conclusions These findings highlight HLA-A*0201 matched allogeneic pDCs as potent inducers of tumor immunity and provide a promising immunotherapeutic strategy to fight cancer. PMID:20454561

  5. Presentation of human minor histocompatibility antigens by HLA-B35 and HLA-B38 molecules.

    PubMed Central

    Yamamoto, J; Kariyone, A; Akiyama, N; Kano, K; Takiguchi, M

    1990-01-01

    Cytotoxic T lymphocyte (CTL) clones specific for human minor histocompatibility antigens (hmHAs) were produced from a patient who had been grafted with the kidneys from his mother and two HLA-identical sisters. Of eight CTL clones generated, four recognized an hmHA (hmHA-1) expressed on cells from the mother and sister 3 (second donor); two recognized another antigen (hmHA-2) on cells from the father, sister 2 (third donor), and sister 3; and the remaining two clones recognized still another antigen (hmHA-3) on cells from the father and sister 3. Panel studies revealed that CTL recognition of hmHA-1 was restricted by HLA-B35 and that of hmHA-2 and hmHA-3 was restricted by HLA-B38. The HLA-B35 restriction of the hmHA-1-specific CTL clones was substantiated by the fact that they killed HLA-A null/HLA-B null Hmy2CIR targets transfected with HLA-B35 but not HLA-B51, -Bw52, or -Bw53 transfected Hmy2CIR targets. These data demonstrated that the five amino acids substitutions on the alpha 1 domain between HLA-B35 and -Bw53, which are associated with Bw4/Bw6 epitopes, play a critical role in the relationship of hmHA-1 to HLA-B35 molecules. The fact that the hmHA-1-specific CTLs failed to kill Hmy2CIR cells expressing HLA-B35/51 chimeric molecules composed of the alpha 1 domain of HLA-B35 and other domains of HLA-B51 indicated that eight residues on the alpha 2 domain also affect the interaction of hmHA-1 and the HLA-B35 molecules. PMID:2157206

  6. ALTERNATIVE DONORS EXTEND TRANSPLANTATION FOR PATIENTS WITH LYMPHOMA WHO LACK AN HLA MATCHED DONOR

    PubMed Central

    Bachanova, Veronika; Burns, Linda J.; Wang, Tao; Carreras, Jeanette; Gale, Robert Peter; Wiernik, Peter H.; Ballen, Karen K.; Wirk, Baldeep; Munker, Reinhold; Rizzieri, David A.; Chen, Yi-Bin; Gibson, John; Akpek, Görgün; Costa, Luciano J.; Kamble, Rammurti T.; Aljurf, Mahmoud D.; Hsu, Jack W.; Cairo, Mitchell S.; Schouten, Harry C.; Bacher, Ulrike; Savani, Bipin N.; Wingard, John R.; Lazarus, Hillard M.; Laport, Ginna G.; Montoto, Silvia; Maloney, David G.; Smith, Sonali M.; Brunstein, Claudio; Saber, Wael

    2015-01-01

    Alternative donor transplantation is increasingly used for high risk lymphoma patients. We analyzed 1593 transplant recipients (2000 to 2010) and compared transplant outcomes in recipients of 8/8 allele human leukocyte antigen (HLA)-A, -B, -C, and DRB1 matched unrelated donors (MUD; n=1176), 7/8 allele HLA-matched unrelated donors (MMUD; n=275) and umbilical cord blood donors (1 or 2 units UCB; n=142). Adjusted 3-year non-relapse mortality of MMUD (44%) was higher as compared to MUD (35%; p=0.004), but similar to UCB recipients (37%; p=0.19), although UCB had lower rates of neutrophil and platelet recovery compared to unrelated donor groups. With a median follow-up of 55 months, 3-year adjusted cumulative incidence of relapse was lower after MMUD compared with MUD (25% vs 33%, p=0.003) but similar between UCB and MUD (30% vs 33%; p=0.48). In multivariate analysis UCB recipients had lower risks of acute and chronic graft versus host disease compared with adult donor groups (UCB vs MUD: HR=0.68, p=0.05; HR=0.35; p<0.001). Adjusted 3-year overall survival was comparable (43% MUD, 37% MMUD and 41% UCB). Data highlight that patients with lymphoma have acceptable survival after alternative donor transplantation. MMUD and UCB can expand the curative potential of allotransplant to patients who lack suitable HLA-matched sibling or MUD. PMID:25402415

  7. Interplay between Immune responses to HLA and Non-HLA self-antigens in allograft rejection

    PubMed Central

    Angaswamy, Nataraju; Tiriveedhi, Venkataswarup; Sarma, Nayan J; Subramanian, Vijay; Klein, Christina; Wellen, Jason; Shenoy, Surendra; Chapman, William C; Mohanakumar, T.

    2013-01-01

    Recent studies strongly suggest an increasing role for immune responses against self-antigens (Ags) which are not encoded by the major histocompatibility complex in the immunopathogenesis of allograft rejection. Although, improved surgical techniques coupled with improved methods to detect and avoid sensitization against donor human leukocyte antigen (HLA) have improved the immediate and short term function of transplanted organs. However, acute and chronic rejection still remains a vexing problem for the long term function of the transplanted organ. Immediately following organ transplantation, several factors both immune and non immune mechanisms lead to the development of local inflammatory milieu which sets the stage for allograft rejection. Traditionally, development of antibodies (Abs) against mismatched donor HLA have been implicated in the development of Ab mediated rejection. However, recent studies from our laboratory and others have demonstrated that development of humoral and cellular immune responses against non-HLA self-Ags may contribute in the pathogenesis of allograft rejection. There are reports demonstrating that immune responses to self-Ags especially Abs to the self-Ags as well as cellular immune responses especially through IL17 has significant pro-fibrotic properties leading to chronic allograft failure. This review summarizes recent studies demonstrating the role for immune responses to self-Ags in allograft immunity leading to rejection as well as present recent evidence suggesting there is interplay between allo- and autoimmunity leading to allograft dysfunction. PMID:23876679

  8. [Histocompatibility HLA system of man. Considerations in the light of current concepts. IV. Soluble HLA class I antigens (sHLA-I)].

    PubMed

    Kedzierska, A; Turowski, G

    2001-01-01

    Soluble class I human leukocyte antigens (sHLA) have been detected in serum, sweat, lymphatic fluid, urine and cerebrospinal fluid. The levels vary among different individuals and are significantly affected by inflammatory diseases and organ rejection. This article discusses the clinical significance of levels of serum HLA class I antigens, both in patients with viral diseases and following organ transplantation, as well as the potential involvement of such antigens in the immune response. The potential use of sHLA in clinical medicine is far-reaching. sHLA-peptide complexes may find wide application, particularly for the treatment recipients. Although further in vivo studies are required, available data show the efficacy of sHLA to regulate T-cell function. PMID:11868249

  9. Selective elution of HLA antigens and beta 2-microglobulin from human platelets by chloroquine diphosphate

    SciTech Connect

    Kao, K.J.

    1988-01-01

    To determine whether chloroquine can specifically elute HLA antigens and beta 2-microglobulin (beta 2-M) from the platelet surface, quantitative immunofluorescence flow cytometry and monoclonal antibodies were used to show that HLA antigens and beta 2-M were proportionally eluted from the platelet surface without affecting the membrane glycoproteins IIb and IIIa. Second, an autoradiogram of electrophoresed I-125-labeled platelets showed that only beta 2-M but not other I-125-labeled membrane proteins could be eluted. Although HLA antigens were poorly labeled by I-125 and could not be detected on the autoradiogram, the eluted HLA antigens could be detected by anti-HLA monoclonal antibody and immunoblotting techniques. No loss of plasma membrane integrity was observed by transmission electron microscopy after chloroquine treatment of platelets. The results indicate that chloroquine selectively elutes HLA antigens and their noncovalently associated beta 2-M without affecting other integral platelet membrane proteins.

  10. A simple and safe method for single HLA-antigen-typing by a solid phase assay.

    PubMed

    Häcker-Shahin, B; Giannitsis, D J

    1991-01-01

    A rapid solid phase assay for detection of single HLA-antigens on platelets was developed. The platelets were attached to the surface of polystyrene microtitre plate wells by means of a sodium carbonate buffer and centrifugation. Uncovered areas were blocked by a gelatin blocking buffer. After incubation with commercially available anti-HLA-sera the bound anti-HLA-specific antibodies directed against HLA-antigens present on the platelets were made visible by anti-IgG-coated indicator red cells and a brief centrifugation. A positive result, meaning the presence of an HLA-antigen, was indicated by a slight red cell adherence over the reaction surface. In the absence of the HLA-antigen no binding occurred and the indicator red cells formed a small red disc-like pellet. PMID:1954783

  11. HLA antigens in Japanese patients with myasthenia gravis.

    PubMed Central

    Matsuki, K; Juji, T; Tokunaga, K; Takamizawa, M; Maeda, H; Soda, M; Nomura, Y; Segawa, M

    1990-01-01

    HLA antigens in 104 Japanese patients and 41 families with myasthenia gravis (MG) were investigated. The frequencies of DR9 and DRw13 were significantly increased in the patients who developed MG before 3 yr of age. The DQw3 antigen was positive for all the patients that developed MG before 15 yr with only one exception. All the examined cases that developed MG before 3 yr (including this DQw3 negative patient) had the same DQA and DQB DNA restriction fragments. These HLA frequencies decreased as the age of onset increased, and no significant association was observed in adult-onset MG. No patients had B8, DR3, and DQw2. The relative risk was higher for the DR9/DRw13 heterozygotes (37.4) than for DR9 (16.4) or DRw13 (7.1) in the childhood-onset MG. Statistical analysis suggested that DR9 and DRw13 (or DQw1 and DQw3) act synergistically in the disease development. Family study revealed diverse DR9 haplotypes. The most frequent DRw13 haplotype was Bw44-BFF-C4A3B1-DRw13-DQw1, which may be evolutionarily related to the caucasian B8-DR3-DQw2 haplotype. These results showed that MG in early childhood in Japanese individuals is genetically different from that in adulthood and that in caucasians. Images PMID:1974553

  12. Human Leukocyte Antigen (HLA) Class I Restricted Epitope Discovery in Yellow Fewer and Dengue Viruses: Importance of HLA Binding Strength

    PubMed Central

    Lund, Ole; Nascimento, Eduardo J. M.; Maciel, Milton; Nielsen, Morten; Voldby Larsen, Mette; Lundegaard, Claus; Harndahl, Mikkel; Lamberth, Kasper; Buus, Søren; Salmon, Jérôme; August, Thomas J.; Marques, Ernesto T. A.

    2011-01-01

    Epitopes from all available full-length sequences of yellow fever virus (YFV) and dengue fever virus (DENV) restricted by Human Leukocyte Antigen class I (HLA-I) alleles covering 12 HLA-I supertypes were predicted using the NetCTL algorithm. A subset of 179 predicted YFV and 158 predicted DENV epitopes were selected using the EpiSelect algorithm to allow for optimal coverage of viral strains. The selected predicted epitopes were synthesized and approximately 75% were found to bind the predicted restricting HLA molecule with an affinity, KD, stronger than 500 nM. The immunogenicity of 25 HLA-A*02:01, 28 HLA-A*24:02 and 28 HLA-B*07:02 binding peptides was tested in three HLA-transgenic mice models and led to the identification of 17 HLA-A*02:01, 4 HLA-A*2402 and 4 HLA-B*07:02 immunogenic peptides. The immunogenic peptides bound HLA significantly stronger than the non-immunogenic peptides. All except one of the immunogenic peptides had KD below 100 nM and the peptides with KD below 5 nM were more likely to be immunogenic. In addition, all the immunogenic peptides that were identified as having a high functional avidity had KD below 20 nM. A*02:01 transgenic mice were also inoculated twice with the 17DD YFV vaccine strain. Three of the YFV A*02:01 restricted peptides activated T-cells from the infected mice in vitro. All three peptides that elicited responses had an HLA binding affinity of 2 nM or less. The results indicate the importance of the strength of HLA binding in shaping the immune response. PMID:22039500

  13. HLA antigen changes in malignant cells: epigenetic mechanisms and biologic significance

    PubMed Central

    Campoli, Michael; Ferrone, Soldano

    2009-01-01

    Changes in classical and non-classical HLA class I as well as HLA class II antigens have been identified in malignant lesions. These changes which are described in this paper are believed to play a major role in the clinical course of the disease since both HLA class I and class II antigens are critical to the interaction between tumor cells and components of both innate and adaptive immune system. Abnormalities in HLA antigen expression in malignant cells, which range in frequency from 0-90%, are caused by distinct mechanisms. They include defects in β2-microglobulin (β2m) synthesis, loss of the gene(s) encoding HLA antigen heavy chain(s), mutations which inhibit HLA antigen heavy chain transcription or translation, defects in the regulatory mechanisms which control HLA antigen expression and/or abnormalities in one or more of the antigen processing machinery (APM) components. More recently, epigenetic events associated with tumor development and progression have been found to underlie changes in HLA antigen, APM component, co-stimulatory molecule and TA expression in malignant cells. The types of epigenetic modifications that may occur in normal and malignant cells as well as their role underlying changes in HLA expression by malignant cells have been reviewed. The epigenetic events associated with alterations in HLA antigen expression may be clinically relevant since, in some case, they have been shown to impair the recognition of tumor cells by components of the adaptive immune system. The functional relevance and potential clinical significance of these epigenetic alterations have been addressed. Lastly, unlike genetic alterations, epigenetic modifications can, in some cases, be reversed with pharmacologic agents that induce DNA hypomethylation or inhibit histone deacetylation. Therefore strategies to overcome epigenetic modifications underlying changes in HLA expression in malignant cells have been discussed. PMID:18836468

  14. Submit and disulfide structure of monomeric and dimeric forms of detergent-soluble HLA antigens.

    PubMed

    Springer, T A; Robb, R J; Terhorst, C; Strominger, J L

    1977-07-10

    The structure of monomeric and disulfide-bonded dimeric forms of HLA antigens has been studied. Detergent-soluble HLA antigen heavy chains contain one or two easily reduced sulfhydryl groups not found in papain-solubilized HLA antigens, as demonstrated by amino acid analysis (Springer, T. A., and Strominger, J.L. (1976) Proc. Natl. Acad. Sci. U.S.A. 73, 2481-2485, and Terhorst, C., Parham, P., Mann, D.L., and Strominger, J.L. (1976) Proc. Natl. Acad. Sci. U.S.A. 73, 910-914) and by labeling with iodo[3H]acetate. Dimer formation occurred during purification, since it was prevented by pretreatment of membranes containing HLA antigen with iodoacetamide. Cross-linking studies showed that the non-disulfide-bonded form of HLA antigens contains one subunit each of the Mr = 44,000 heavy chain and the Mr = 12,000 light chain (beta2-microglobulin). PMID:873911

  15. HLA Class II Antigen Expression in Colorectal Carcinoma Tumors as a Favorable Prognostic Marker12

    PubMed Central

    Sconocchia, Giuseppe; Eppenberger-Castori, Serenella; Zlobec, Inti; Karamitopoulou, Eva; Arriga, Roberto; Coppola, Andrea; Caratelli, Sara; Spagnoli, Giulio Cesare; Lauro, Davide; Lugli, Alessandro; Han, Junyi; Iezzi, Giandomenica; Ferrone, Cristina; Ferlosio, Amedeo; Tornillo, Luigi; Droeser, Raoul; Rossi, Piero; Attanasio, Antonio; Ferrone, Soldano; Terracciano, Luigi

    2014-01-01

    The goal of this study was to determine the frequency of HLA class II antigen expression in colorectal carcinoma (CRC) tumors, its association with the clinical course of the disease, and the underlying mechanism(s). Two tissue microarrays constructed with 220 and 778 CRC tumors were stained with HLA-DR, DQ, and DP antigen-specific monoclonal antibody LGII-612.14, using the immunoperoxidase staining technique. The immunohistochemical staining results were correlated with the clinical course of the disease. The functional role of HLA class II antigens expressed on CRC cells was analyzed by investigating their in vitro interactions with immune cells. HLA class II antigens were expressed in about 25% of the 220 and 21% of the 778 tumors analyzed with an overall frequency of 23%. HLA class II antigens were detected in 19% of colorectal adenomas. Importantly, the percentage of stained cells and the staining intensity were significantly lower than those detected in CRC tumors. However, HLA class II antigen staining was weakly detected only in 5.4% of 37 normal mucosa tissues. HLA class II antigen expression was associated with a favorable clinical course of the disease. In vitro stimulation with interferon gamma (IFNγ) induced HLA class II antigen expression on two of the four CRC cell lines tested. HLA class II antigen expression on CRC cells triggered interleukin-1β (IL-1β) production by resting monocytes. HLA class II antigen expression in CRC tumors is a favorable prognostic marker. This association may reflect stimulation of IL-1β production by monocytes. PMID:24563618

  16. Biological significance of HLA locus matching in unrelated donor bone marrow transplantation

    PubMed Central

    Kashiwase, Koichi; Matsuo, Keitaro; Azuma, Fumihiro; Morishima, Satoko; Onizuka, Makoto; Yabe, Toshio; Murata, Makoto; Doki, Noriko; Eto, Tetsuya; Mori, Takehiko; Miyamura, Koichi; Sao, Hiroshi; Ichinohe, Tatsuo; Saji, Hiroo; Kato, Shunichi; Atsuta, Yoshiko; Kawa, Keisei; Kodera, Yoshihisa; Sasazuki, Takehiko

    2015-01-01

    We hypothesized that the compatibility of each HLA loci between donor and patient induced divergent transplant-related immunologic responses, which attributed to the individualized manifestation of clinical outcomes. Here, we analyzed 7898 Japanese pairs transplanted with T-cell–replete marrow from an unrelated donor with complete HLA allele typing data. Multivariable competing risk regression analyses were conducted to evaluate the relative risk (RR) of clinical outcomes after transplantation. A significant RR of HLA allele mismatch compared with match was seen with HLA-A, -B, -C, and -DPB1 for grade III-IV acute graft-versus-host disease (GVHD), and HLA-C for chronic GVHD. Of note, only HLA-C and HLA-DPB1 mismatch reduced leukemia relapse, and this graft-versus-leukemia effect of HLA-DPB1 was independent of chronic GVHD. HLA-DRB1 and HLA-DQB1 double (DRB1_DQB1) mismatch was revealed to be a significant RR for acute GVHD and mortality, whereas single mismatch was not. Thus, the number of HLA-A, -B, -C, -DPB1, and DRB1_DQB1 mismatches showed a clear-cut risk difference for acute GVHD, whereas the number of mismatches for HLA-A, -B, -C, and DRB1_DQB1 showed the same for mortality. In conclusion, we determined the biological response to HLA locus mismatch in transplant-related immunologic events, and provide a rationale for use of a personalized algorithm for unrelated donor selection. PMID:25519752

  17. HLA antigens in Bali (Indonesia) with a special reference to an isolated community.

    PubMed

    Breguet, G; Wolnizer, C M; Doran, T; Bashir, H; Jeannet, M; Benzonana, G; Ney, R; Adiputra, N; Scherz, R; Blake, N M

    1982-10-01

    One hundred eighty-two Balinese were typed for HLA-A and -B locus antigens. From these, 103 were also typed for HLA-C, 51 for HLA-DR, 172 for Bf and 173 for GLO. These results and the significant phenotypic associations are situated with respect to other South-East Asian populations. In addition to this first study, 175 individuals from an isolated Balinese village typed for HLA-A, -B, -DR, Bf and GLO are presented. The effect of isolation on haplotype (HLA-A/-B/Bf/-DR) variability is discussed. PMID:6815824

  18. HLA-B27-restricted antigen presentation in the absence of tapasin reveals polymorphism in mechanisms of HLA class I peptide loading.

    PubMed

    Peh, C A; Burrows, S R; Barnden, M; Khanna, R; Cresswell, P; Moss, D J; McCluskey, J

    1998-05-01

    Tapasin is a resident ER protein believed to be critical for antigen presentation by HLA class I molecules. We demonstrate that allelic variation in MHC class I molecules influences their dependence on tapasin for peptide loading and antigen presentation. HLA-B*2705 molecules achieve high levels of surface expression and present specific viral peptides in the absence of tapasin. In contrast, HLA-B*4402 molecules are highly dependent upon human tapasin for these functions, while HLA-B8 molecules are intermediate in this regard. Significantly, HLA-B*2705 like HLA-B*4402, requires tapasin to associate efficiently with TAP (transporters associated with antigen processing). The unusual ability of HLA-B*2705 to form peptide complexes without associating with TAP or tapasin confers flexibility in the repertoire of peptides presented by this molecule. We speculate that these properties might contribute to the role of HLA-B27 in conferring susceptibility to inflammatory spondyloarthropathies. PMID:9620674

  19. Human leukocyte antigen (HLA)-binding epitopes dataset for the newly identified T-cell antigens of Mycobacterium immunogenum.

    PubMed

    Chandra, Harish; Yadav, Jagjit S

    2016-09-01

    The dataset described herein is related to our article entitled "T-cell antigens of Mycobacterium immunogenum (MI), an etiological agent of occupational hypersensitivity pneumonitis'' (Chandra and Yadav, 2016) [1]. The data include in silico-predicted T-cell epitopes of the T-cell antigens AgA and AgD of MI predicted to bind to HLA-I or HLA-II alleles. Data on two reference T-cell antigens ESAT-6 and CFP-10 of Mycobacterium tuberculosis H37Rv are included for comparison. The data for each antigen include the predicted epitope׳s amino acid sequence, its first amino acid position, and its ability to bind HLA-I or HLA-II allele(s). PMID:27508266

  20. Comparison of Class II HLA antigen expression in normal and carcinomatous human breast cells

    SciTech Connect

    Bernard, D.J.; Maurizis, J.C.; Chassagne, J.; Chollet, P.; Plagne, R.

    1985-03-01

    Class II HLA antigen expression in breast carcinoma and normal breast gland cells was compared using a method more accurate than immunofluorescence. This new method involves labeling membrane proteins with /sup 131/I and the anti-Class II HLA monoclonal antibody with /sup 125/I. The isolation and purification of the doubly labeled (/sup 125/I-/sup 131/I) immune complex was performed by affinity chromatography and chromatofocusing successively. When the specific activity of glycoproteins is known, the amount of glycoprotein which bind specifically to the anti-Class II HLA monoclonal antibody can be deduced. In breast carcinoma cells, 1.5 to 2% of the purified glycoproteins bind specifically to the monoclonal antibody, whereas less than 0.3% of normal breast gland cells binds. In contrast, leukemic cells, of which 80 to 90% possess Class II HLA antigens, 2 to 3% of Class II HLA glycoproteins bind specifically with the anti-Class II HLA monoclonal antibody.

  1. Soluble HL-A antigens in serum. I. Isolation and purification.

    PubMed

    Oh, S K; Pellegrino, M A; Ferrone, S; Sevier, E D; Reisfeld, R A

    1975-03-01

    A new method was developed which utilizes fractional salting out, gel filtration, ion exchange chromatography and polyacrylamide gel electrophoresis for the isolation and purification of soluble HL-A antigens from serum. The method produced purified antigens possessing HL-A 5,9 specificities with yield up to 60% of that detected in the original serum. Up to 150-fold increase in specific HL-A antigenic activity above that in the starting material could be achieved as measured by the ability of the purified antigens to specifically inhibit the cytotoxic activity of HL-A alloantisera against selected target cells. Electrophoretically purified HL-A antigens with different specificities appear to have a similar molecular size, i.e. 33 000, but differ in their electric charge properties, beta2-microglobulin (beta2m) seems to be noncovalently associated with HL-A antigens present in serum, but during purification beta2m in progressively lost until at the final purification by polyacrylamide gel electrophoresis, the material is completely devoid of beta2m. PMID:789087

  2. Impact of donor-recipient HLA-matching at HLA-A, -B, -C and –DRB1 on outcomes after umbilical cord blood transplantation for leukemia and myelodysplastic syndrome: a retrospective analysis

    PubMed Central

    Eapen, Mary; Klein, John P.; Sanz, Guillermo F.; Spellman, Stephen; Ruggeri, Annalisa; Anasetti, Claudio; Brown, Maria; Champlin, Richard E.; Garcia-Lopez, Joan; Hattersely, Gareth; GesineKoegler; Laughlin, Mary J.; Michel, Gerard; Nabhan, Samir K.; Smith, Franklin O.; Horowitz, Mary M.; Gluckman, Eliane; Rocha, Vanderson

    2011-01-01

    Background The importance of matching at the human leukocyte antigen (HLA) C locus has not been well defined for unrelated umbilical cord blood transplantation. The selection algorithm for umbilical cord blood units generally considers intermediate resolution HLA typing at A and B, and allele-level at DRB1. We aimed to determine the relative importance of matching at HLA-C in addition to current selection criteria. Methods We used Cox regression to retrospectively examine for the effect of donor-recipient HLA matching on outcomes of 803 single umbilical cord blood transplantations for leukemia (N=727) and myelodysplastic syndrome (N=76). The primary endpoint was transplant-related mortality. HLA typing was performed using molecular techniques with a minimum of intermediate resolution for HLA-A, -B and -C and allele-level for DRB1. Findings Compared to transplantations matched at HLA-A, -B, -C, -DRB1 (N=69; HR 1.00), transplant-related mortality risks were higher after transplantations matched at HLA-A, -B, -DRB1 and mismatched at HLA-C (N=23;HR 3.97, 95% CI 1.27 – 12.40, p=0.018). Transplant-related mortality risk were also higher after transplantations with a single mismatch at HLA-A or -B, or -DRB1 and mismatched at HLA-C (N=234; HR 1.70 95% CI 1.06 – 2.74, p=0.029) compared to transplantations matched at HLA-C with a single mismatch at HLA-A, -B, or -DRB1 (N=127; HR 1.00). Examining for an overall effect of HLA disparity on transplant-related mortality, risks were higher with units mismatched at two (N=259; HR 3.27 95% CI 1.42 – 7.54, p=0.006), three (N=253; HR 3.34 95% CI 1.45 – 7.71, p=0.005) or four (N=75; HR 3.51 95% CI 1.44 – 8.58, p=0.006) loci compared to matched units (N=69; HR 1.00). Interpretation These data suggest that we re-evaluate the current strategy for umbilical cord blood unit selection, by considering matching at HLA-C for units that are matched at HLA-A, -B, -DRB1 or in the presence of a single locus mismatch at HLA-A, -B or DRB1

  3. A comparative reference study for the validation of HLA-matching algorithms in the search for allogeneic hematopoietic stem cell donors and cord blood units.

    PubMed

    Bochtler, W; Gragert, L; Patel, Z I; Robinson, J; Steiner, D; Hofmann, J A; Pingel, J; Baouz, A; Melis, A; Schneider, J; Eberhard, H-P; Oudshoorn, M; Marsh, S G E; Maiers, M; Müller, C R

    2016-06-01

    The accuracy of human leukocyte antigen (HLA)-matching algorithms is a prerequisite for the correct and efficient identification of optimal unrelated donors for patients requiring hematopoietic stem cell transplantation. The goal of this World Marrow Donor Association study was to validate established matching algorithms from different international donor registries by challenging them with simulated input data and subsequently comparing the output. This experiment addressed three specific aspects of HLA matching using different data sets for tasks of increasing complexity. The first two tasks targeted the traditional matching approach identifying discrepancies between patient and donor HLA genotypes by counting antigen and allele differences. Contemporary matching procedures predicting the probability for HLA identity using haplotype frequencies were addressed by the third task. In each task, the identified disparities between the results of the participating computer programs were analyzed, classified and quantified. This study led to a deep understanding of the algorithms participating and finally produced virtually identical results. The unresolved discrepancies total to less than 1%, 4% and 2% for the three tasks and are mostly because of individual decisions in the design of the programs. Based on these findings, reference results for the three input data sets were compiled that can be used to validate future matching algorithms and thus improve the quality of the global donor search process. PMID:27219013

  4. Role of HLA antigens in Rh (D) alloimmunized pregnant women from Mumbai, Maharashtra, India.

    PubMed

    Kumar, U Shankar; Ghosh, K; Gupte, S S; Gupte, S C; Mohanty, D

    2002-03-01

    Immunogenetic studies in various diseases provide potential genetic markers. We have studied the incidence of HLA A, B, C, DR and DQ loci antigen in Rh (D) antigen isoimmunized mothers compared to those nonimmunized isoimmunized Rh negative mothers. Seventy six mothers who were immunized to Rh (D) antigen due to pregnancy (responders) and fifty four mothers who did not develop Rh (D) isoimmunization despite positive pregnancies (nonresponders) were selected for the study. Standard methods of serological HLA typing, ABO and Rh (D) groups, and screening for Rh D antibodies were used. 392 unrelated individuals from the population were compared as controls. In addition 45 unrelated individuals from the same population were typed for HLA DRB and DQB gene using PCR-SSP kits. The genotype frequencies of HLA A2, A3, A28, B13, B17, B35, B52, B60, Cw2, Cw6, DR4, and DQ3 were significantly increased, while the frequencies of the HLA A11, A29, A31, B7, B37, B51, Cw1 and DR9 were decreased in the responder women when compared to the non-responder women. HLA A30 (19) split antigen was not identified in immunized women while HLA A23 (9) split antigen was not identified in non immunized women. HLA A3, B17, Cw2 and DR4 showed a significant relative risk among the immunized responder women. When compared with Rh immunized women (responders) reported from USA, England and Hungary the phenotype frequencies of HLA A11, A24, A28, B5, B17, B40, DR2 and DR5 were increased while HLA A23, B8, B18, and DR6 were decreased in the Indian Rh immunized women. Two locus haplotype frequency analysis observed among the responders women revealed that among the significant haplotypes expressed A2-B5, B7-Cw1, DR2-DQ1 were highly significant haplotypes in positive linkage, while A1-B5, and A1-B7 were in significant negative linkage disequilibrium. The haplotype frequencies were

  5. Successful haematopoietic stem cell transplantation in 44 children from healthy siblings conceived after preimplantation HLA matching.

    PubMed

    Kahraman, Semra; Beyazyurek, Cagri; Yesilipek, Mehmet Akif; Ozturk, Gulyuz; Ertem, Mehmet; Anak, Sema; Kansoy, Savas; Aksoylar, Serap; Kuşkonmaz, Barış; Oniz, Haldun; Slavin, Shimon; Karakas, Zeynep; Tac, Huseyin Avni; Gulum, Nese; Ekmekci, Gokhan Cumhur

    2014-09-01

    Haematopoietic stem cell transplantation (HSCT) remains the best therapeutic option for many acquired and inherited paediatric haematological disorders. Unfortunately, the probability of finding an HLA matched donor is limited. An alternative technique is PGD combined with HLA matching, which offers the possibility of selecting unaffected embryos that are HLA compatible with the sick child, with the aim of possible use of stem cells from the resulting baby in future. Since the first successful report for Fanconi anaemia a decade ago, the therapeutic success of this technique was reported in a few cases and for a limited number of disorders. Here, we report full recovery of 44 sick children who received HSCT from healthy infants conceived after pre-implantation HLA matching for the following 10 indications; beta-thalassaemia, Wiskott-Aldrich syndrome, Fanconi anaemia, sickle cell anaemia, acute myeloid leukaemia, acute lymphoblastic leukaemia, Glanzmann's thrombasthaenia, Diamond-Blackfan anaemia, X-linked adrenoleukodystrophy and mucopolysaccharidosis type I. No serious complications were observed among recipients and donors. Graft failure occurred in four children with beta-thalassaemia where a second HSCT was planned. Preimplantation HLA matching is a reliable technique and provides a realistic option for couples seeking treatment for an affected child when no HLA-matched donor is available. PMID:25066893

  6. Autoinflammation and HLA-B27: Beyond Antigen Presentation.

    PubMed

    Sibley, Cailin H

    2016-08-01

    HLA-B27 associated disorders comprise a group of inflammatory conditions which have in common an association with the HLA class I molecule, HLA-B27. Given this association, these diseases are classically considered disorders of adaptive immunity. However, mounting data are challenging this assumption and confirming that innate immunity plays a more prominent role in pathogenesis than previously suspected. In this review, the concept of autoinflammation is discussed and evidence is presented from human and animal models to support a key role for innate immunity in HLA-B27 associated disorders. PMID:27229619

  7. HLA-B51 and haplotypic diversity of B-Cw associations: implications for matching in unrelated hematopoietic stem cell transplantation.

    PubMed

    Bettens, F; Nicoloso de Faveri, G; Tiercy, J-M

    2009-04-01

    In unrelated hematopoietic stem cell transplantation (HSCT), human leukocyte antigen (HLA)-C locus incompatibilities occur frequently and are associated with increased risk of posttransplant complications. Because HLA-B51 is associated with a high rate of Cw disparities, we performed a comprehensive four-digit typing analysis of 140 ABCDRB1 B51 genotypes proven by pedigree analysis and 311 unrelated donors selected for 75 B51-positive patients. In addition, 145 A1/Ax-B8/B51-DR3/DRx donors were HLA typed at a high-resolution level and tested for three microsatellite (Msat) polymorphisms located in the HLA class I and III regions. Based on these data sets, 182 different ABCDR haplotypes with 14 different B-Cw associations were detected. Rates of Cw mismatches were shown to be highly correlated with the ABDRB1 haplotypes. We have computed 21 B51 haplotypes that disclose a high probability of HLA-C allele matching and 30 haplotypes with a low (<25%) probability. The HLA-C allele frequency profiles were quite different in these two groups, with a more heterogeneous distribution in the low matching probability group. HLA-Cw*1502 was inversely correlated with the likelihood to identify a Cw-mismatched donor: it was present in 61% of the high vs 18% of the low probability group (P < 0.0001). The analysis of three Msats in the class I and III regions showed a higher allelic diversity in B51-positive haplotypes compared with the conserved A1-B8-DR3 haplotype. HLA-B51 haplotypes therefore exhibit a high diversity at the level of B-Cw associations and of non-HLA polymorphisms in the class I and III regions. Such heterogeneity negatively impacts on overall matching in HSCT. PMID:19317740

  8. HLA class I-restricted human cytotoxic T cells recognize endogenously synthesized hepatitis B virus nucleocapsid antigen.

    PubMed Central

    Bertoletti, A; Ferrari, C; Fiaccadori, F; Penna, A; Margolskee, R; Schlicht, H J; Fowler, P; Guilhot, S; Chisari, F V

    1991-01-01

    Knowledge of the immune effector mechanisms responsible for clearance of hepatitis B virus (HBV)-infected cells has been severely limited by the absence of reproducible systems to selectively expand and to characterize HBV-specific cytotoxic T lymphocytes (CTLs) in the peripheral blood of patients with viral hepatitis. By using a strategy involving sequential stimulation with HBV nucleocapsid synthetic peptides followed by autologous, or HLA class I-matched, HBV nucleocapsid transfectants, we now report the existence of CTLs able to lyse target cells that express endogenously synthesized HBV nucleocapsid antigen in the peripheral blood of patients with acute viral hepatitis B. The CTL response is HLA-A2 restricted, mediated by CD8-positive T cells, and specific for a single epitope, located between amino acid residues 11 and 27 of HBV core protein; these residues are shared with the secretable precore-derived hepatitis B e antigen. Equivalent lysis of target cells that express each of these proteins suggests that their intracellular trafficking pathways may intersect. The current report provides definitive evidence that HLA class I-restricted, CD8-positive CTLs that recognize endogenously synthesized HBV nucleocapsid antigen are induced during acute HBV infection in humans and establishes a strategy that should permit a detailed analysis of the role played by HBV-specific CTLs in the immunopathogenesis of viral hepatitis. PMID:1660137

  9. Serum antibodies to human leucocyte antigen (HLA)-E, HLA-F and HLA-G in patients with systemic lupus erythematosus (SLE) during disease flares: Clinical relevance of HLA-F autoantibodies.

    PubMed

    Jucaud, V; Ravindranath, M H; Terasaki, P I; Morales-Buenrostro, L E; Hiepe, F; Rose, T; Biesen, R

    2016-03-01

    T lymphocyte hyperactivity and progressive inflammation in systemic lupus erythematosus (SLE) patients results in over-expression of human leucocyte antigen (HLA)-Ib on the surface of lymphocytes. These are shed into the circulation upon inflammation, and may augment production of antibodies promoting pathogenicity of the disease. The objective was to evaluate the association of HLA-Ib (HLA-E, HLA-F and HLA-G) antibodies to the disease activity of SLE. The immunoglobulin (Ig)G/IgM reactivity to HLA-Ib and β2m in the sera of 69 German, 29 Mexican female SLE patients and 17 German female controls was measured by multiplex Luminex(®)-based flow cytometry. The values were expressed as mean flourescence intensity (MFI). Only the German SLE cohort was analysed in relation to the clinical disease activity. In the controls, anti-HLA-G IgG predominated over other HLA-Ib antibodies, whereas SLE patients had a preponderance of anti-HLA-F IgG over the other HLA-Ib antibodies. The disease activity index, Systemic Lupus Erythematosus Disease Activity Index (SLEDAI)-2000, was reflected only in the levels of anti-HLA-F IgG. Anti-HLA-F IgG with MFI level of 500-1999 was associated with active SLE, whereas inactive SLE revealed higher MFI (>2000). When anti-HLA-F IgG were cross-reactive with other HLA-Ib alleles, their reactivity was reflected in the levels of anti-HLA-E and -G IgG. The prevalence of HLA-F-monospecific antibodies in SLE patients was also associated with the clinical disease activity. Anti-HLA-F IgG is possibly involved in the clearance of HLA-F shed from lymphocytes and inflamed tissues to lessen the disease's severity, and thus emerges as a beneficial immune biomarker. Therefore, anti-HLA-Ib IgG should be considered as a biomarker in standard SLE diagnostics. PMID:26440212

  10. Cell surface properties of HLA antigens on Epstein-Barr virus-transformed cell lines.

    PubMed Central

    Smith, L M; Petty, H R; Parham, P; McConnell, H M

    1982-01-01

    A number of monoclonal antibodies have been used to investigate the distributions and rates of lateral motion of the HLA-A,B, and-DR antigens on several Epstein--Barr virus-transformed B-cell lines. The lateral diffusion coefficients (D) of fluorescein conjugates of the monoclonal antibodies bound to the cell surface were determined by fluorescence recovery after pattern photobleaching. Ds of HLA-A and-B were found to be comparable and of the order of 10(-9) to 10(-10) cm2/sec for each of the seven monoclonal antibodies and four cell lines examined. The HLA antigens appear to be monomeric on the cell surface based on experiments using mixtures of arsanilic acid-conjugated and fluorescein-conjugated antibodies. Four monoclonal antibodies against DR antigens were examined. Two of these, Genox 3.53 and L243, labeled the cell surface uniformly and gave Ds comparable to those obtained for the HLA-A and -B antigens. The other two, DA2 and 2.06, rapidly patched on the cell surface and were immobile. The DA2, L243, and Genox 3.53 antibodies bound outside of the caps formed with the arsanilic acid-conjugated 2.06 antibody and a second-step rhodamine-conjugated rabbit anti-arsanilate antibody. This is consistent with recent biochemical evidence that there are multiple distinct antigens coded for by the HLA-DR region. Images PMID:6281776

  11. The impact of human leukocyte antigen (HLA) micropolymorphism on ligand specificity within the HLA-B*41 allotypic family

    SciTech Connect

    Bade-Döding, Christina; Theodossis, Alex; Gras, Stephanie; Kjer-Nielsen, Lars; Eiz-Vesper, Britta; Seltsam, Axel; Huyton, Trevor; Rossjohn, Jamie; McCluskey, James; Blasczyk, Rainer

    2011-09-28

    Polymorphic differences between human leukocyte antigen (HLA) molecules affect the specificity and conformation of their bound peptides and lead to differential selection of the T-cell repertoire. Mismatching during allogeneic transplantation can, therefore, lead to immunological reactions. We investigated the structure-function relationships of six members of the HLA-B*41 allelic group that differ by six polymorphic amino acids, including positions 80, 95, 97 and 114 within the antigen-binding cleft. Peptide-binding motifs for B*41:01, *41:02, *41:03, *41:04, *41:05 and *41:06 were determined by sequencing self-peptides from recombinant B*41 molecules by electrospray ionization tandem mass spectrometry. The crystal structures of HLA-B*41:03 bound to a natural 16-mer self-ligand (AEMYGSVTEHPSPSPL) and HLA-B*41:04 bound to a natural 11-mer self-ligand (HEEAVSVDRVL) were solved. Peptide analysis revealed that all B*41 alleles have an identical anchor motif at peptide position 2 (glutamic acid), but differ in their choice of C-terminal p{Omega} anchor (proline, valine, leucine). Additionally, B*41:04 displayed a greater preference for long peptides (>10 residues) when compared to the other B*41 allomorphs, while the longest peptide to be eluted from the allelic group (a 16mer) was obtained from B*41:03. The crystal structures of HLA-B*41:03 and HLA-B*41:04 revealed that both alleles interact in a highly conserved manner with the terminal regions of their respective ligands, while micropolymorphism-induced changes in the steric and electrostatic properties of the antigen-binding cleft account for differences in peptide repertoire and auxiliary anchoring. Differences in peptide repertoire, and peptide length specificity reflect the significant functional evolution of these closely related allotypes and signal their importance in allogeneic transplantation, especially B*41:03 and B*41:04, which accommodate longer peptides, creating structurally distinct peptide-HLA

  12. Association of HLA antigens and BCR-ABL transcripts in leukemia patients with the Philadelphia chromosome

    PubMed Central

    de Carvalho, Daiana Landenberger; Barbosa, Cristian Dias; de Carvalho, André Luiz; Beck, Sandra Trevisan

    2012-01-01

    Objective This study aimed to verify the association between human leukocyte antigens and the bcr-abl fusion protein resulting from t(9;22)(q34;q11) in chronic leukemia myeloid and acute lymphoblastic leukemia patients. Methods Forty-seven bcr-abl positive individuals were evaluated. Typing was performed bymicrolymphocytotoxicity and molecular biological methods (human leukocyte antigens Class I and Class II). A control group was obtained from the data of potential bone marrow donors registered in the Brazilian Bone Marrow Donor Registry (REDOME). Results Positive associations with HLA-A25 and HLA-B18 were found for the b2a2 transcript, as well as a tendency towards a positive association with HLA-B40 and a negative association with HLA-A68. The b3a2 transcript showed positive associations with HLA-B40 and HLA-DRB1*3. Conclusion The negative association between human leukocyte antigens and the BCR-ABL transcript suggests that binding and presentation of peptides derived from the chimeric protein are effective to increase a cytotoxic T lymphocyte response appropriate for the destruction of leukemic cells. PMID:23049441

  13. Unrelated Donor Hematopoietic Cell Transplantation: Factors Associated with a Better HLA Match

    PubMed Central

    Dehn, Jason; Arora, Mukta; Spellman, Stephen; Setterholm, Michelle; Horowitz, Mary; Confer, Dennis; Weisdorf, Daniel

    2012-01-01

    Background The impact of non-HLA patient factors on the match of the selected unrelated donor (URD) for hematopoietic cell transplantation (HCT) has not been fully evaluated. National Marrow Donor Program (NMDP) data for 7486 transplants using peripheral blood stem cells (PBSC) or bone marrow from years 2000–2005 were evaluated using multivariate logistic regression to identify independent non-HLA patient factors associated with completing a more closely matched URD transplant. Results Advanced (intermediate and late stage) disease was significantly associated with an increased likelihood of transplant using a less-matched (partially-matched or mismatched) donor. Additionally, Black patients were 2.83 times, Asian 2.05 times, and Hispanic 1.73 times more likely to have a less-matched HCT donor than Caucasian patients. Younger patients, HCT at lower volume centers and in earlier years had significantly higher likelihood of having a less HLA matched URD transplant. Conclusion Our analysis provides encouraging evidence of HLA matching improvement in recent years. Initiating a patient’s URD search early in the disease process, especially for patients from non-Caucasian racial and ethnic groups, will provide the best likelihood for identifying the best available donor and making informed transplant decisions. PMID:19041054

  14. HLA-DR3 antigen in the resistance to idiopathic dilated cardiomyopathy

    PubMed Central

    Jin, B.; Wu, B.W.; Wen, Z.C.; Shi, H.M.; Zhu, J.

    2016-01-01

    Idiopathic dilated cardiomyopathy (IDC) has been hypothesized as a multifactorial disorder initiated by an environment trigger in individuals with predisposing human leukocyte antigen (HLA) alleles. Published data on the association between HLA-DR3 antigen and IDC risk are inconclusive. To derive a more precise estimation of the relationship, a meta-analysis was performed. Studies were identified by searching the PUBMED and Embase database (starting from June 2015). A total of 19 case-control studies including 1378 cases and 10383 controls provided data on the association between HLA-DR3 antigen and genetic susceptibility to IDC. Overall, significantly decreased frequency of HLA-DR3 allele (OR=0.72; 95%CI=0.58-0.90; P=0.004) was found in patients with IDC compared with controls. When stratified by myocardial biopsy or non-biopsy cases, statistically decreased risk was found for IDC in myocardial biopsy cases (OR=0.69; 95%CI=0.57-0.84; P=0.0003). In the subgroup analysis by ethnicity, borderline statistically significantly decreased risk was found among Europeans from 12 case-control studies (OR=0.76; 95%CI=0.58-1.00; P=0.05). In conclusion, our results suggest that individuals with HLA-DR3 antigen may have a protective effect against IDC. PMID:27007655

  15. Clinical correlates of human leucocyte antigen (HLA)-G in systemic sclerosis1

    PubMed Central

    Favoino, E; Favia, I E; Vettori, S; Vicenti, C; Prete, M; Valentini, G; Perosa, F

    2015-01-01

    Human leucocyte antigen (HLA)-G has a tolerogenic function and could play a role in the pathogenesis of immune-mediated diseases, including systemic sclerosis (SSc). The aim of this study was to evaluate HLA-G serum expression (sHLA-G) and the HLA-G gene 14 base pairs (bp) insertion/deletion (del−/del+) polymorphism in patients with Ssc, to search for possible associations with clinical and laboratory variables. sHLA-G was measured by enzyme-linked immunosorbent assay (ELISA) in sera from 77 patients with SSc and 32 healthy donors (HD); the 14 bp del−/del+ polymorphism was evaluated by polymerase chain reaction (PCR) amplification of peripheral blood mononuclear cells (PBMC) genomic DNA. Receiver operating characteristics (ROC) analysis identified the HLA-G cut-off that best discriminated dichotomized clinical and serological variables, that was subsequently employed to subdivide SSc patients into HLA-G high (HLA-G+) and low (HLA-G−) profile groups. sHLA-G were not statistically different between SSc patients and HD, nor between distinct SSc autoantibody subsets. Subdividing SSc patients by HLA-G positivity or negativity yielded significant differences for the modified Rodnan skin score (mRss) (P = 0·032), ‘general’ (P = 0·031) and ‘kidney’ (P = 0·028) Medsger severity scores (MSS) and disease activity index, and especially Δ heart/lung (P = 0·005). A worse ‘general’ MSS (P = 0·002) and Δ heart/lung (P = 0·011) were more frequent in the low sHLA-G group. These two variables and mRss were associated with sHLA-G levels at logistic regression analysis. Treatment had no influence on sHLA-G. Moreover, a higher frequency of scleredema was detected in the del+/del+ than the del-/del+ group (P = 0.04). These data suggest modulatory effects of sHLA-G on SSc. Prospective studies are needed to investigate a role in predicting the disease course. PMID:25847615

  16. Prevalence of HLA-B27 antigen in patients with juvenile idiopathic arthritis

    PubMed Central

    Turowska-Heydel, Dorota; Sobczyk, Małgorzata; Chudek, Jerzy

    2015-01-01

    Introduction Human leukocyte antigen B27 (HLA-B27) is considered as a risk factor for development of juvenile idiopathic arthritis (JIA). The aim of this study was to analyse the prevalence of HLA-B27 antigen in JIA categories and its influence on disease onset and response to conventional therapy. Material and methods The retrospective analysis included 461 unselected children with JIA hospitalized in a single reference rheumatology centre between July 2007 and June 2012. The diagnosis was based on criteria by the International League of Association for Rheumatology. HLA-B27 was determined in 387 of all patients (84%) by hybridization of the amplified, labelled product to immobilize it on the microarray probe. Results HLA-B27 antigen was found in 104 of 383 affected children (27.2%), 48 of 206 girls (23.3%), and 56 of 177 boys (31.6%) – most frequently in patients with enthesitis-related arthritis (71%), psoriatic arthritis (50%) and unclassified cases (86.7%). The age of JIA onset was slightly (by 1 year) but significantly different in patients with and without HLA-B27 antigen [11 (8.5–14) vs. 10 (5–13.5) years.; p < 0.001]. The use of disease-modifying antirheumatic drugs (DMARDs) and corticosteroids was more frequently clinically ineffective in HLA-B27 positive than negative patients (23.1% vs. 15.2%; p = 0.09). Patients with polyarthritis, systemic, and psoriatic arthritis more frequently received biological therapy. HLA-B27 positive patients with enthesitis-related arthritis received biological therapy more frequently than HLA-B27 negative ones (20.4% vs. 0, respectively; p = 0.09). Conclusions HLA-B27 antigen is a strong risk factor for the development of enthesitis-related arthritis, and to a lesser extent for psoriatic arthritis and extended course of oligoarthritis. The presence of this antigen does not affect the disease onset but seems to predict resistance to therapy with disease-modifying drugs and corticosteroids.

  17. Is rheumatoid arthritis in Indians associated with HLA antigens sharing a DR beta 1 epitope?

    PubMed Central

    Ollier, W E; Stephens, C; Awad, J; Carthy, D; Gupta, A; Perry, D; Jawad, A; Festenstein, H

    1991-01-01

    HLA class II antigens were identified in a group of 44 patients with rheumatoid arthritis (RA) originating largely from the north or northeast of the Indian subcontinent and resident now in east London. Compared with 67 locally typed east London Asian controls, the prevalence of three HLA-DR antigens was raised in the patients: DR1 18.2% v 6.0% chi 2 = 3.99, DR4 20.5% v 11.9% chi 2 = 1.48, and DRw10 27.3% v 8.9% chi 2 = 6.56. These differences were also found when the patients with RA were compared with a larger control group of 110 northern Indians: DR1 18.2% v 7.2% chi 2 = 4.02, DR4 20.5% v 7.2% chi 2 = 5.56, and DRw10 27.3% v 8.1% chi 2 = 9.7. Twenty five (57%) of the patients expressed at least one of these antigens. All patients were also characterised for HLA-Dw types by mixed lymphocyte culture typing. The prevalence of the HLA-DR4 associated Dw types in the patients was: Dw4 2.3%, Dw10 0%, Dw14 11.4%, and Dw15 6.8%. The DR beta 1 chains of DR1 and DRw10 together with the Dw types of DR4 other than Dw10 share amino acid residues in a region of the third hypervariable region considered to be critical in antigen presentation. It is concluded that RA in Indians is associated with these HLA antigens, and data from this study support the hypothesis of a cross reactive epitope common to HLA specificities associated with RA. PMID:1710441

  18. The role of HLA-DR antigens in PPD-stimulated lymphocyte-monocyte interactions.

    PubMed

    Haar, D; Heron, I

    1982-11-01

    Autologous monocytes are required for an optimal lymphocyte proliferative response to purified protein derivate of tuberculin (PPD) in vitro and for a mixed lymphocyte culture induced by alloantigens. In the proliferative response to PPD we found that autologous monocytes could be replaced with HLA-DR-compatible monocytes and partly with HLA-DR semi-identical. In spite of a statistically significant difference between autologous and HLA-DR disparate monocytes in their cooperative capacity with PPD-stimulated lymphocytes, replacement in nearly one third of the cases was possible. These findings were supported by more detailed studies in which increasing numbers of allogenic and autologous monocytes were added to the isolated lymphocytes in the presence of PPD. It is concluded that the serologically defined HLA-DR antigens alone give insufficient information of the restriction elements controlling the PPD-stimulated lymphocyte-monocyte interactions. PMID:6184773

  19. Suppression of allo-human leucocyte antigen (HLA) antibodies secreted by B memory cells in vitro: intravenous immunoglobulin (IVIg) versus a monoclonal anti-HLA-E IgG that mimics HLA-I reactivities of IVIg

    PubMed Central

    Zhu, D; Ravindranath, M H; Terasaki, P I; Miyazaki, T; Pham, T; Jucaud, V

    2014-01-01

    B memory cells remain in circulation and secrete alloantibodies without antigen exposure > 20 years after alloimmunization postpartum or by transplantation. These long-lived B cells are resistant to cytostatic drugs. Therapeutically, intravenous immunoglobulin (IVIg) is administered to reduce allo-human leucocyte antigen (HLA) antibodies pre- and post-transplantation, but the mechanism of reduction remains unclear. Recently, we reported that IVIg reacts with several HLA-I alleles and the HLA reactivity of IVIg is lost after its HLA-E reactivity is adsorbed out. Therefore, we have generated an anti-HLA-E monoclonal antibody that mimics the HLA-reactivity of IVIg to investigate whether this antibody suppresses IgG secretion, as does IVIg. B cells were purified from the blood of a woman in whose blood the B memory cells remained without antigen exposure > 20 years after postpartum alloimmunization. The B cells were stimulated with cytokines using a well-defined culture system. The anti-HLA-E monoclonal antibody (mAb) significantly suppressed the allo-HLA class-II IgG produced by the B cells, and that this suppression was far superior to that by IVIg. These findings were confirmed with HLA-I antibody secreted by the immortalized B cell line, developed from the blood of another alloimmunized woman. The binding affinity of the anti-HLA-E mAb for peptide sequences shared (i.e. shared epitopes) between HLA-E and other β2-microglobulin-free HLA heavy chains (open conformers) on the cell surface of B cells may act as a ligand and signal suppression of IgG production of activated B memory cells. We propose that anti-HLA-E monoclonal antibody may also be useful to suppress allo-HLA IgG production in vivo. PMID:24611451

  20. The contribution of HLA class I antigens in immune status following two doses of rubella vaccination.

    PubMed

    Ovsyannikova, Inna G; Jacobson, Robert M; Vierkant, Robert A; Jacobsen, Steven J; Pankratz, V Shane; Poland, Gregory A

    2004-12-01

    The variability of humoral and cellular immune responses modulated by human leukocyte antigen (HLA) genes is a significant factor in the protective effect of rubella vaccines. We performed HLA class I typing in a group of 346 healthy schoolchildren and young adults who previously received two doses of measles-mumps-rubella-II vaccine. Rubella virus-specific humoral (serum antibody) immunity and cell-mediated immunity (lymphocyte proliferation) were assessed. Median values for antibody levels and stimulation indices (SI) were 38.63 IU/ml and 2.29 IU/ml, respectively. The alleles that provided suggestive, but not conclusive, evidence of HLA association with rubella seropositivity were HLA-B*2705 (median, 24.68 IU/ml; p = 0.160), B*4501 (median, 61.22 IU/ml; p = 0.098), Cw*0303 (median, 30.34 IU/ml; p = 0.102) and Cw*0704 (median, 26.58 IU/ml; p = 0.144). These alleles approach, but do not achieve, statistical significance. Of all the alleles analyzed, HLA-B*3503 (median SI, 3.00; p = 0.031) and HLA-Cw*1502 (median SI, 3.19; p = 0.035) were positively associated with lymphoproliferative responses to rubella virus antigens, whereas the HLA-B*3901 (SI, 1.34; p = 0.066) allele was negatively associated. This suggests that class I HLA alleles may have limited associations with humoral and cellular immune responses to rubella vaccine. These data may facilitate our understanding of immune response variation in a genetically outbred heterogeneous population. PMID:15603879

  1. Identification of 4 novel HLA-B*40:01 restricted minor histocompatibility antigens and their potential as targets for graft-versus-leukemia reactivity

    PubMed Central

    Griffioen, Marieke; Honders, M. Willy; van der Meijden, Edith D.; van Luxemburg-Heijs, Simone A.P.; Lurvink, Ellie G.A.; Kester, Michel G.D.; van Bergen, Cornelis A.M.; Falkenburg, J.H. Frederik

    2012-01-01

    Background Patients with hematologic malignancies can be successfully treated with donor lymphocyte infusion after HLA-matched allogeneic hematopoietic stem cell transplantation. The effect of donor lymphocyte infusion is mediated by donor T cells recognizing minor histocompatibility antigens. T cells recognizing hematopoietic restricted minor histocompatibility antigens may induce selective graft-versus-leukemia reactivity, whereas broadly-expressed antigens may be targeted in graft-versus-host disease. Design and Methods We analyzed in detail CD8+ T-cell immunity in a patient with relapsed chronic myelogenous leukemia who responded to donor lymphocyte infusion with minimal graft-versus-host disease of the skin. CD8+ T-cell clones specific for 4 HLA-B*40:01 restricted minor histocompatibility antigens were isolated which were identified by screening a plasmid cDNA library and whole genome association scanning. Detailed T-cell reactivity and monitoring experiments were performed to estimate the clinical and therapeutic relevance of the novel antigens. Results Three antigens were demonstrated to be expressed on primary leukemic cells of various origins as well as subtypes of non-malignant hematopoietic cells, whereas one antigen was selectively recognized on malignant hematopoietic cells with antigen presenting cell phenotype. Skin derived fibroblasts were only recognized after pre-treatment with IFN-γ by two T-cell clones. Conclusions Our data show evidence for different roles of the HLA-B*40:01 restricted minor histocompatibility antigens in the onset and execution of the anti-tumor response. All antigens may have contributed to a graft-versus-leukemia effect, and one minor histocompatibility antigen (LB-SWAP70-1Q) has specific therapeutic value based on its in vivo immunodominance and strong presentation on leukemic cells of various origins, but absence of expression on cytokine-treated fibroblasts. PMID:22419570

  2. BSHI Guideline: HLA matching and donor selection for haematopoietic progenitor cell transplantation.

    PubMed

    Little, A-M; Green, A; Harvey, J; Hemmatpour, S; Latham, K; Marsh, S G E; Poulton, K; Sage, D

    2016-10-01

    A review of the British Society for Histocompatibility and Immunogenetics (BSHI) "Guideline for selection and HLA matching of related, adult unrelated donors and umbilical cord units for haematopoietic progenitor cell transplantation" was undertaken by a BSHI appointed writing committee. Literature searches were performed, and the data extracted were presented as recommendations according to the GRADE nomenclature. PMID:27503599

  3. Human fibroblasts in idiopathic retroperitoneal fibrosis express HLA-DR antigens.

    PubMed

    Lee, I

    1991-09-01

    Idiopathic retroperitoneal fibrosis (IRF) is a rare human disease characterized by non-neoplastic fibroblastic proliferation associated with chronic inflammatory cells; its pathogenesis is obscure. We undertook an immunohistochemical study for the expression of HLA-DR antigens and other immune-related markers by retroperitoneal proliferating fibroblasts and inflammatory cells from 2 IRF patients. Patterns of immunoreactivity were compared with those expressed by human nodular fasciitis (NF) and granulation tissue. In IRF, most fibroblasts immunostained strongly for HLA-DR antigens, whereas fibroblasts in NF and granulation tissue did, not immunostain at all. The fibroblasts did not immunostain for interleukin 2 receptor, C3b receptor, CD-4, CD-8, or Leu-M1 in any of the tissue studied. Most macrophages and lymphocytes in IRF and NF immunostained Strangly for HLA-DR antigens. In IRF, the CD-4 and CD-8 immunostained T-lymphocytes appeared equally distributed. The expression of HLA-DR antigens by fibroblasts in IRF indicates that this rare disease may indeed be an immune-associated hypersensitivity disorder. PMID:1777134

  4. Use of HLA peptidomics and whole exome sequencing to identify human immunogenic neo-antigens.

    PubMed

    Kalaora, Shelly; Barnea, Eilon; Merhavi-Shoham, Efrat; Qutob, Nouar; Teer, Jamie K; Shimony, Nilly; Schachter, Jacob; Rosenberg, Steven A; Besser, Michal J; Admon, Arie; Samuels, Yardena

    2016-02-01

    The antigenicity of cells is demarcated by the peptides bound by their Human Leucocyte Antigen (HLA) molecules. Through this antigen presentation, T cell specificity response is controlled. As a fraction of the expressed mutated peptides is presented on the HLA, these neo-epitopes could be immunogenic. Such neo-antigens have recently been identified through screening for predicted mutated peptides, using synthetic peptides or ones expressed from minigenes, combined with screening of patient tumor-infiltrating lymphocytes (TILs). Here we present a time and cost-effective method that combines whole-exome sequencing analysis with HLA peptidome mass spectrometry, to identify neo-antigens in a melanoma patient. Of the 1,019 amino acid changes identified through exome sequencing, two were confirmed by mass spectrometry to be presented by the cells. We then synthesized peptides and evaluated the two mutated neo-antigens for reactivity with autologous bulk TILs, and found that one yielded mutant-specific T-cell response. Our results demonstrate that this method can be used for immune response prediction and promise to provide an alternative approach for identifying immunogenic neo-epitopes in cancer. PMID:26819371

  5. Tumor-specific up-regulation of the nonclassical class I HLA-G antigen expression in renal carcinoma.

    PubMed

    Ibrahim, E C; Guerra, N; Lacombe, M J; Angevin, E; Chouaib, S; Carosella, E D; Caignard, A; Paul, P

    2001-09-15

    HLA-G is a nonclassical class I antigen mainly expressed at the maternofetal interface during pregnancy where it is thought to down-modulate maternal immune response against the semiallogeneic fetus. Recent studies indicate that ectopic up-regulation of HLA-G expression on melanoma cells may also favor their escape from antitumor immune response. HLA-G expression was here investigated on paraffin-embedded tumor and adjacent normal renal tissues of 18 renal cell carcinoma (RCC) patients. We provide evidence that HLA-G antigen is differentially expressed in carcinoma and normal renal cells and that up-regulation of this antigen in the tumor cells is more frequent than alterations of other MHC class I or class II antigens. We also demonstrated that HLA-G cell surface expression and secretion is maintained in a tumor cell line (DM) established from an HLA-G-positive RCC lesion. Furthermore, we show that type I (alpha and beta) and, in particular, type II (gamma) IFN treatment enhances steady-state mRNA levels and cell surface expression of HLA-G in the DM cell line. As several studies suggest that HLA-G displays various functional features that allow down-modulation of immune response in vitro, we propose that selective in vivo expression of HLA-G may participate in the impairment of antitumor immunity in RCC. PMID:11559559

  6. Use of HLA peptidomics and whole exome sequencing to identify human immunogenic neo-antigens

    PubMed Central

    Kalaora, Shelly; Qutob, Nouar; Teer, Jamie K.; Shimony, Nilly; Schachter, Jacob; Rosenberg, Steven A.; Samuels, Yardena

    2016-01-01

    The antigenicity of cells is demarcated by the peptides bound by their Human Leucocyte Antigen (HLA) molecules. Through this antigen presentation, T cell specificity response is controlled. As a fraction of the expressed mutated peptides is presented on the HLA, these neo-epitopes could be immunogenic. Such neoantigens have recently been identified through screening for predicted mutated peptides, using synthetic peptides or ones expressed from minigenes, combined with screening of patient tumor-infiltrating lymphocytes (TILs). Here we present a time and cost-effective method that combines whole-exome sequencing analysis with HLA peptidome mass spectrometry, to identify neo-antigens in a melanoma patient. Of the 1,019 amino acid changes identified through exome sequencing, two were confirmed by mass spectrometry to be presented by the cells. We then synthesized peptides and evaluated the two mutated neo-antigens for reactivity with autologous bulk TILs, and found that one yielded mutant-specific T-cell response. Our results demonstrate that this method can be used for immune response prediction and promise to provide an alternative approach for identifying immunogenic neo-epitopes in cancer. PMID:26819371

  7. Genotyping of human leukocyte antigen (HLA) ancestral haplotypes as prognostic marker in cancer using PCR analysis.

    PubMed

    Villabona, Lisa; Andersson, Emilia; Marchesi, Maddalena; Masucci, Giuseppe V

    2014-01-01

    The major histocompatibility complex (MHC) comprises a set of genes that are essential to immunity and surveillance against neoplastic transformation. MHC antigens not only regulate antitumor immune responses in experimental animal models but also directly correlate with survival and prognosis of patients with various types of cancers. Effective recognition of tumor cells by effector T cells may be affected by the genotype and the extent of expression of human leukocyte antigen (HLA)-peptide complexes. Therefore, MHC antigens may serve as potential biomarkers for prognosis and allow selection of cancer patients for specific therapy. We describe PCR-based method to determine the HLA genotype in healthy individuals and patients using blood and tumor tissue as DNA source. PMID:24258987

  8. Approach for Identifying Human Leukocyte Antigen (HLA)-DR Bound Peptides from Scarce Clinical Samples.

    PubMed

    Heyder, Tina; Kohler, Maxie; Tarasova, Nataliya K; Haag, Sabrina; Rutishauser, Dorothea; Rivera, Natalia V; Sandin, Charlotta; Mia, Sohel; Malmström, Vivianne; Wheelock, Åsa M; Wahlström, Jan; Holmdahl, Rikard; Eklund, Anders; Zubarev, Roman A; Grunewald, Johan; Ytterberg, A Jimmy

    2016-09-01

    Immune-mediated diseases strongly associating with human leukocyte antigen (HLA) alleles are likely linked to specific antigens. These antigens are presented to T cells in the form of peptides bound to HLA molecules on antigen presenting cells, e.g. dendritic cells, macrophages or B cells. The identification of HLA-DR-bound peptides presents a valuable tool to investigate the human immunopeptidome. The lung is likely a key player in the activation of potentially auto-aggressive T cells prior to entering target tissues and inducing autoimmune disease. This makes the lung of exceptional interest and presents an ideal paradigm to study the human immunopeptidome and to identify antigenic peptides.Our previous investigation of HLA-DR peptide presentation in the lung required high numbers of cells (800 × 10(6) bronchoalveolar lavage (BAL) cells). Because BAL from healthy nonsmokers typically contains 10-15 × 10(6) cells, there is a need for a highly sensitive approach to study immunopeptides in the lungs of individual patients and controls.In this work, we analyzed the HLA-DR immunopeptidome in the lung by an optimized methodology to identify HLA-DR-bound peptides from low cell numbers. We used an Epstein-Barr Virus (EBV) immortalized B cell line and bronchoalveolar lavage (BAL) cells obtained from patients with sarcoidosis, an inflammatory T cell driven disease mainly occurring in the lung. Specifically, membrane complexes were isolated prior to immunoprecipitation, eluted peptides were identified by nanoLC-MS/MS and processed using the in-house developed ClusterMHCII software. With the optimized procedure we were able to identify peptides from 10 × 10(6) cells, which on average correspond to 10.9 peptides/million cells in EBV-B cells and 9.4 peptides/million cells in BAL cells. This work presents an optimized approach designed to identify HLA-DR-bound peptides from low numbers of cells, enabling the investigation of the BAL immunopeptidome from individual patients

  9. Is there any impact of HLA-DPB1 disparity in 10/10 HLA-matched unrelated hematopoietic SCT? Results of a French multicentric retrospective study.

    PubMed

    Gagne, K; Loiseau, P; Dubois, V; Dufossé, F; Perrier, P; Dormoy, A; Jollet, I; Renac, V; Masson, D; Picard, C; Lafarge, X; Hanau, D; Quainon, F; Delbos, F; Coeffic, B; Absi, Léna; Eliaou, J-F; Moalic, V; Fort, M; de Matteis, M; Theodorou, I; Hau, F; Batho, A; Pedron, B; Caillat-Zucman, S; Marry, E; Raus, N; Yakoub-Agha, I; Cesbron, A

    2015-02-01

    We retrospectively analyzed the impact of HLA-DPB1 mismatches in a large cohort of 1342 French patients who underwent 10/10 HLA-matched unrelated HSCT. A significant impact of HLA-DPB1 allelic mismatches (2 vs 0) was observed in severe acute GVHD (aGVHDIII-IV) (risk ratio (RR)=1.73, confidence interval (CI) 95% 1.09-2.73, P=0.019) without impact on OS, TRM, relapse and chronic GVHD (cGVHD). According to the T-cell epitope 3 (TCE3)/TCE4 HLA-DPB1 disparity algorithm, 37.6% and 58.4% pairs had nonpermissive HLA-DPB1, respectively. TCE3 and TCE4 disparities had no statistical impact on OS, TRM, relapse, aGVHD and cGVHD. When TCE3/TCE4 disparities were analyzed in the graft-vs-host or host-vs-graft (HVG) direction, only a significant impact of TCE4 nonpermissive disparities in the HVG direction was observed on relapse (RR=1.34, CI 95% 1.00-1.80, P=0.048). In conclusion, this French retrospective study shows an adverse prognosis of HLA-DPB1 mismatches (2 vs 0) on severe aGVHD and of nonpermissive TCE4 HVG disparities on relapse after HLA-matched 10/10 unrelated HSCT. PMID:25365066

  10. Complex preimplantation genetic diagnosis for beta-thalassaemia, sideroblastic anaemia, and human leukocyte antigen (HLA)-typing.

    PubMed

    Kakourou, Georgia; Vrettou, Christina; Kattamis, Antonis; Destouni, Aspasia; Poulou, Myrto; Moutafi, Maria; Kokkali, Georgia; Pantos, Konstantinos; Davies, Stephen; Kitsiou-Tzeli, Sophia; Kanavakis, Emmanuel; Traeger-Synodinos, Joanne

    2016-01-01

    Preimplantation genetic diagnosis (PGD) to select histocompatible siblings to facilitate curative haematopoeitic stem-cell transplantation (HSCT) is now an acceptable option in the absence of an available human leukocyte antigen (HLA) compatible donor. We describe a case where the couple who requested HLA-PGD, were both carriers of two serious haematological diseases, beta-thalassaemia and sideroblastic anaemia. Their daughter, affected with sideroblastic anaemia, was programmed to have HSCT. A multiplex-fluorescent-touchdown-PCR protocol was optimized for the simultaneous amplification of: the two HBB-gene mutated regions (c.118C> T, c.25-26delAA), four short tandem repeats (STRs) in chr11p15.5 linked to the HBB gene, the SLC25A38 gene mutation (c.726C > T), two STRs in chr3p22.1 linked to the SLC25A38 gene, plus eleven informative STRs for HLA-haplotyping (chr6p22.1-21.3). This was followed by real-time nested PCR and high-resolution melting analysis (HRMA) for the detection of HBB and SLC25A38 gene mutations, as well as the analysis of all STRs on an automatic genetic analyzer (sequencer). The couple completed four clinical in vitro fertilization (IVF)/PGD cycles. At least one matched unaffected embryo was identified and transferred in each cycle. A twin pregnancy was established in the fourth PGD cycle and genotyping results at all loci were confirmed by prenatal diagnosis. Two healthy baby girls were delivered at week 38 of pregnancy. The need to exclude two familial disorders for HLA-PGD is rarely encountered. The methodological approach described here is fast, accurate, clinically-validated, and of relatively low cost. PMID:26636621

  11. Combined effect of total nucleated cell dose and HLA match on transplantation outcome in 1061 cord blood recipients with hematologic malignancies

    PubMed Central

    Scaradavou, Andromachi; Stevens, Cladd E.

    2010-01-01

    Both total nucleated cell (TNC) dose and human leukocyte antigen (HLA)–match affect the outcome of cord blood (CB) transplantation. However, how to prioritize these characteristics in unit selection is not established. Therefore, we analyzed the outcomes of 1061 patients who received single-unit myeloablative CB transplantation for leukemia or myelodysplasia. TNC dose and HLA-match each affected survival via their effect on transplant-related mortality (TRM); neither was associated with relapse. Therefore, TRM was the focus of multivariate analyses combining dose and HLA-match. Compared with our 1 HLA-mismatch (MM) reference group with TNC 2.5 to 4.9 × 107/kg, recipients of 0 MM units had the lowest TRM regardless of dose (relative risk [RR] = 0.4, P = .019). TRM for recipients of 1- or 2-MM units with TNC 5.0 × 107/kg or greater was similar to the reference group (RR = 0.8, P = .391 and RR = 1.0, P = .847) despite their greater dose. Recipients of 2 MM units with TNC 2.5 to 4.9 × 107/kg had a greater TRM (RR = 1.5, P = .014), and those with 1 or 2 MM and TNC less than 2.5 × 107/kg or 3 MM did substantially worse. These findings support new unit selection criteria that take into account both TNC dose and HLA-match and have important implications for the size of the global CB inventory needed to find an optimum CB graft. PMID:20029048

  12. Defining the HLA class I-associated viral antigen repertoire from HIV-1-infected human cells.

    PubMed

    Ternette, Nicola; Yang, Hongbing; Partridge, Thomas; Llano, Anuska; Cedeño, Samandhy; Fischer, Roman; Charles, Philip D; Dudek, Nadine L; Mothe, Beatriz; Crespo, Manuel; Fischer, William M; Korber, Bette T M; Nielsen, Morten; Borrow, Persephone; Purcell, Anthony W; Brander, Christian; Dorrell, Lucy; Kessler, Benedikt M; Hanke, Tomáš

    2016-01-01

    Recognition and eradication of infected cells by cytotoxic T lymphocytes is a key defense mechanism against intracellular pathogens. High-throughput definition of HLA class I-associated immunopeptidomes by mass spectrometry is an increasingly important analytical tool to advance our understanding of the induction of T-cell responses against pathogens such as HIV-1. We utilized a liquid chromatography tandem mass spectrometry workflow including de novo-assisted database searching to define the HLA class I-associated immunopeptidome of HIV-1-infected human cells. We here report for the first time the identification of 75 HIV-1-derived peptides bound to HLA class I complexes that were purified directly from HIV-1-infected human primary CD4(+) T cells and the C8166 human T-cell line. Importantly, one-third of eluted HIV-1 peptides had not been previously known to be presented by HLA class I. Over 82% of the identified sequences originated from viral protein regions for which T-cell responses have previously been reported but for which the precise HLA class I-binding sequences have not yet been defined. These results validate and expand the current knowledge of virus-specific antigenic peptide presentation during HIV-1 infection and provide novel targets for T-cell vaccine development. PMID:26467324

  13. First successful bone marrow transplantation for X-linked chronic granulomatous disease by using preimplantation female gender typing and HLA matching.

    PubMed

    Reichenbach, Janine; Van de Velde, Hilde; De Rycke, Martine; Staessen, Cathérine; Platteau, Peter; Baetens, Patricia; Güngör, Tayfun; Ozsahin, Hulya; Scherer, Franziska; Siler, Ulrich; Seger, Reinhard A; Liebaers, Inge

    2008-09-01

    Allogeneic hematopoietic stem cell transplantation from an human leukocyte antigen (HLA)-identical donor is currently the only proven curative treatment for chronic granulomatous disease. Hematopoietic stem cell transplantation with alternative donors is associated with higher morbidity and mortality. Therefore, we performed in vitro fertilization and preimplantation HLA matching combined with female sexing for hematopoietic stem cell transplantation in chronic granulomatous disease. Ethical and psychological issues were considered carefully. We used in vitro fertilization with X-enriched spermatozoa followed by preimplantation genetic diagnosis to identify female HLA-genoidentical embryos in a family in need of a suitable donor for their boy affected with severe X-linked chronic granulomatous disease. Two preimplantation genetic diagnosis cycles were performed in the family. In the second cycle, 2 HLA-genoidentical female embryos were transferred and a singleton pregnancy was obtained, resulting in the birth of an unaffected girl at term. Because of insufficient cell numbers in the cord-blood source, conventional hematopoietic stem cell transplantation had to be performed at 12 months of age of the donor and 5 years of age of the recipient and resulted in complete stable donor chimerism and immunologic reconstitution up to 25 months post-hematopoietic stem cell transplantation. Hematopoietic stem cell transplantation after in vitro fertilization and combined female sexing and HLA matching offers a new and relatively rapid therapeutic option for patients with X-linked primary immunodeficiency such as chronic granulomatous disease who need hematopoietic stem cell transplantation but lack an HLA-genoidentical donor. PMID:18762514

  14. HLA-A, -B, -C, -DR, and -DQ Matching in Pancreas Transplantation: Effect on Graft Rejection and Survival.

    PubMed

    Rudolph, E N; Dunn, T B; Mauer, D; Noreen, H; Sutherland, D E R; Kandaswamy, R; Finger, E B

    2016-08-01

    To enhance selection of appropriate deceased donors for pancreas transplants, we sought to determine whether HLA matching improved posttransplantation outcomes. In this single-center study of 1219 pancreas transplants, we correlated posttransplantation outcomes with HLA-A, -B, -C, -DR, and -DQ matches and mismatches. Rejection was linearly correlated with the number of mismatches. The individual number of HLA mismatches reached significance at four or more with a 2.3- to 2.9-fold increase in rejection. The effect was most predominant with HLA-B (1.8-fold with one mismatch and 2.0-fold with two mismatches) and -DR (1.9-fold with two mismatches) loci, whereas HLA-A, -C, and -DQ matches or mismatches did not independently predict acute rejection. The affect was strongest in solitary pancreas transplants, with little impact for simultaneous pancreas and kidney (SPK). In contrast, HLA matching did not affect graft or patient survival rates but was associated with a reduced risk of opportunistic infection. Avoidance of acute rejection saved an estimated $32 000 for solitary pancreas recipients and $52 000 for SPK recipients in hospital costs. Our data do not support the use of HLA matching for predicting pancreas graft survival but do support its significance for the reduction of acute rejection, particularly for solitary pancreas recipients. PMID:26814363

  15. Uptake of HLA Alloantigens via CD89 and CD206 Does Not Enhance Antigen Presentation by Indirect Allorecognition

    PubMed Central

    Breman, Eytan; Ruben, Jurjen M.; Franken, Kees L.; Heemskerk, Mirjam H. M.; Roelen, Dave L.; Claas, Frans H.

    2016-01-01

    In organ transplantation, alloantigens are taken up by antigen presenting cells and presented via the indirect pathway to T-cells which in turn can induce allograft rejection. Monitoring of these T-cells is of major importance; however no reliable assay is available to routinely monitor indirect allorecognition. Recently we showed that HLA monomers can be successfully used to monitor indirect allorecognition. Targeting antigens to endocytic receptors on antigen presenting cells may further enhance the presentation of antigens via HLA class II and improve the efficiency of this assay. In the current study we explored targeting of HLA monomers to either CD89 expressing monocytes or mannose receptor expressing dendritic cells. Monomer-antibody complexes were generated using biotin-labeled monomers and avidin labeling of the antibodies. We demonstrate that targeting the complexes to these receptors resulted in a dose-dependent HLA class II mediated presentation to a T-cell clone. The immune-complexes were efficiently taken up and presented to T-cells. However, the level of T-cell reactivity was similar to that when only exogenous antigen was added. We conclude that HLA-A2 monomers targeted for presentation through CD89 on monocytes or mannose receptor on dendritic cells lead to proper antigen presentation but do not enhance indirect allorecognition via HLA-DR. PMID:27413760

  16. HLA-DR, DQ and T cell antigen receptor constant beta genes in Japanese patients with ulcerative colitis.

    PubMed Central

    Kobayashi, K; Atoh, M; Konoeda, Y; Yagita, A; Inoko, H; Sekiguchi, S

    1990-01-01

    We studied the T cell antigen receptor (TcR) constant beta chain genes on HLA typed Japanese patients with ulcerative colitis (UC). A TcR constant beta EcoRI 6.0-kb fragment was present in all Japanese UC patients (n = 17) but completely absent in the controls (n = 35) (chi2 = 47.6, P less than 0.001). The frequency of HLA-DR2 antigen was significantly higher in UC patients (85% versus 28% in controls, P less than 0.001). Furthermore, HLA-DQw1 antigen was also increased in UC patients (96% versus 60% in controls, P less than 0.001). However, HLA-DR4 antigen was significantly decreased in UC patients (12% versus 37%, P = 0.02). HLA-DR1 antigen was not found in UC patients and was present in only 15% of the controls. These results suggest that TcR beta chain and HLA-DQw1 antigen may be important in the pathogenesis of Japanese UC. Images Fig. 1 PMID:1973647

  17. Immunological and clinical significance of HLA class I antigen processing machinery component defects in malignant cells.

    PubMed

    Concha-Benavente, Fernando; Srivastava, Raghvendra; Ferrone, Soldano; Ferris, Robert L

    2016-07-01

    Experimental as well as clinical studies demonstrate that the immune system plays a major role in controlling generation and progression of tumors. The cancer immunoediting theory supports the notion that tumor cell immunogenicity is dynamically shaped by the immune system, as it eliminates immunogenic tumor cells in the early stage of the disease and then edits their antigenicity. The end result is the generation of a tumor cell population able to escape from immune recognition and elimination by tumor infiltrating lymphocytes. Two major mechanisms, which affect the target cells and the effector phase of the immune response, play a crucial role in the editing process. One is represented by the downregulation of tumor antigen (TA) processing and presentation because of abnormalities in the HLA class I antigen processing machinery (APM). The other one is represented by the anergy of effector immune infiltrates in the tumor microenvironment caused by aberrant inhibitory signals triggered by immune checkpoint receptor (ICR) ligands, such as programmed death ligand-1 (PD-L1). In this review, we will focus on tumor immune escape mechanisms caused by defects in HLA class I APM component expression and/or function in different types of cancer, with emphasis on head and neck cancer (HNC). We will also discuss the immunological implications and clinical relevance of these HLA class I APM abnormalities. Finally, we will describe strategies to counteract defective TA presentation with the expectation that they will enhance tumor recognition and elimination by tumor infiltrating effector T cells. PMID:27264839

  18. Soluble HLA class I antigen secretion by normal lymphocytes: relationship with cell activation and effect of interferon-gamma.

    PubMed Central

    Brieva, J A; Villar, L M; Leoro, G; Alvarez-Cermeño, J C; Roldán, E; Gonzalez-Porqué, P

    1990-01-01

    HLA class I antigens are thought to be integral membrane proteins. However, soluble forms of these molecules have been detected. Our laboratory has recently shown that the predominant form of these soluble proteins present in human serum, spleen tissue and culture supernatant of activated lymphocytes exhibits molecular weight and structure similar to classical HLA class I antigens, but lacks HLA A or B polymorphic determinants. In the present study, the secretion of such soluble proteins by lymphocytes has been further explored. Phytohaemagglutinin-stimulated normal lymphocytes secrete considerable quantities of soluble HLA (sHLA) class I proteins. This secretion seems to be a general property of lymphocytes, since activation of T as well as B cells by appropriate mitogens equally induce sHLA I secretion. Lymphocytes require RNA and protein synthesis, but not DNA synthesis, for the secretion to occur. Kinetic studies reveal that maximal sHLA I secretion precedes the peak of DNA synthesis by 24 h. In vitro stimulation with antigens or alloantigens also provokes sHLA I secretion. Moreover, this phenomenon has also been detected for in vivo-activated lymphocytes, as enhanced spontaneous sHLA I secretion was observed in cultures of low-density blastic B and T cells, and of blood lymphocytes obtained from normal subjects who had received a booster immunization 5 days earlier. Interferon-gamma (IFN-gamma) increases the expression of membrane-bound class I antigens but does not induce any sHLA I secretion, suggesting that both molecules are under different regulatory mechanisms. Our results indicate that human lymphocytes, upon stimulation, actively secrete considerable amounts of a soluble form of these biologically relevant proteins. PMID:2122936

  19. TH1 and TH2 responses are influenced by HLA antigens in healthy neonates vaccinated with recombinant hepatitis B vaccine.

    PubMed

    Jafarzadeh, Abdollah; Shokri, Fazel

    2012-12-01

    The immune response to hepatitis B surface antigen (HBsAg) is influenced by several factors, of which HLA antigens and balanced secretion of Th1/Th2 cytokines play important roles. The aim of this study was to evaluate the influence of HLA antigens on cytokine secretion by HBsAg-stimulated peripheral blood mononuclear cells (PBMC) from healthy neonates vaccinated with recombinant HBsAg. PBMCs were isolated from 48 Iranian neonates vaccinated with a recombinant HBV vaccine. The cells were stimulated in vitro with rHBsAg and the concentration of IL-4, IL-10, IL-12 and IFN-γ were quantitated in culture supernatant by sandwich ELISA. HLA typing was performed by microlymphocytotoxicity method. Significant diminished secretion of both Th1 (IFN-γ) and Th2 (IL-4, IL-10) cytokines was observed in HBsAg-stimulated PBMC from vaccinees expressing the HLA-DR7 compared to DR7 negative vaccinees. Similarly, lower production of these cytokines was also observed in vaccinees with DR7-DR53-DQ2, B7-DR7-DR53-DQ2 and A2-DR7-DR53-DQ2 haplotypes (p<0.05, p <0.005). While HBsAg-stimulated PBMC of DR13+ subjects produced lower levels of Th2-type cytokines (IL-4 and IL-10), those of HLA-B8+ or HLA-A9+ subjects produced higher levels of Th2-type cytokines. Cytokine secretion in response to PHA mitogen was not associated with a given HLA antigen or haplotype and was similarly represented in all groups of subjects irrespective of their HLA complex. These results indicate that HLA antigens may differentially influence cytokine secretion by HBsAg-specific T-cells of healthy neonates vaccinated with recombinant HB vaccine. This phenomenon may have an important implication for control of the immune response to HBsAg vaccine. PMID:23264407

  20. CD94-NKG2A Recognition of Human Leukocyte Antigen (HLA)-E Bound to an HLA Class I Leader Sequence

    SciTech Connect

    Petrie,E.; Clements, C.; Lin, J.; Sullivan, L.; Johnson, D.; Huyton, T.; Heroux, A.; Hoare, H.; Beddoe, T.; et al

    2008-01-01

    The recognition of human leukocyte antigen (HLA)-E by the heterodimeric CD94-NKG2 natural killer (NK) receptor family is a central innate mechanism by which NK cells monitor the expression of other HLA molecules, yet the structural basis of this highly specific interaction is unclear. Here, we describe the crystal structure of CD94-NKG2A in complex with HLA-E bound to a peptide derived from the leader sequence of HLA-G. The CD94 subunit dominated the interaction with HLA-E, whereas the NKG2A subunit was more peripheral to the interface. Moreover, the invariant CD94 subunit dominated the peptide-mediated contacts, albeit with poor surface and chemical complementarity. This unusual binding mode was consistent with mutagenesis data at the CD94-NKG2A-HLA-E interface. There were few conformational changes in either CD94-NKG2A or HLA-E upon ligation, and such a 'lock and key' interaction is typical of innate receptor-ligand interactions. Nevertheless, the structure also provided insight into how this interaction can be modulated by subtle changes in the peptide ligand or by the pairing of CD94 with other members of the NKG2 family. Differences in the docking strategies used by the NKG2D and CD94-NKG2A receptors provided a basis for understanding the promiscuous nature of ligand recognition by NKG2D compared with the fidelity of the CD94-NKG2 receptors.

  1. Mixed enzyme-linked immunosorbent assay (MELISA) for HLA class I antigen: a plasma membrane marker.

    PubMed

    Bjerrum, O W; Borregaard, N

    1990-03-01

    This study introduces a simple, reproducible assay for HLA class I antigen using antibodies against beta 2-microglobulin and the heavy chain on HLA. The sandwich technique was named mixed enzyme-linked immunosorbent assay (MELISA), and was designed for identification of plasma membranes in neutrophil subcellular fractions. The subcellular localization of HLA was identical to that of other plasma membrane markers, [3H]concanavalin A and detergent-independent alkaline phosphatase, and was unchanged by stimulation of cells by weak and strong secretagogues. In addition to the presence as part of the HLA complex in the plasma membrane uncomplexed beta 2-microglobulin is present in the specific granules of neutrophils. However, the release of beta 2-microglobulin from intact neutrophils stimulated with formyl-methionylleucylphenylalanine was much higher than could be explained by exocytosis of specific granules. Subcellular fractionation studies demonstrated that beta 2-microglobulin is localized in fractions characterized by latent alkaline phosphatase and released from this novel secretory compartment in response to stimulation with formyl-methionylleucylphenylalanine. PMID:2181625

  2. Reduced Human Leukocyte Antigen (HLA) Protection in Gulf War Illness (GWI)

    PubMed Central

    Georgopoulos, Apostolos P.; James, Lisa M.; Mahan, Margaret Y.; Joseph, Jasmine; Georgopoulos, Angeliki; Engdahl, Brian E.

    2015-01-01

    Background Gulf War Illness (GWI) is a disease of unknown etiology with symptoms suggesting the involvement of an immune process. Here we tested the hypothesis that Human Leukocyte Antigen (HLA) composition might differ between veterans with and without GWI. Methods We identified 144 unique alleles of Class I and II HLA genes in 82 veterans (66 with and 16 without GWI). We tested the hypothesis that a subset of HLA alleles may classify veterans in their respective group using a stepwise linear discriminant analysis. In addition, each participant rated symptom severity in 6 domains according to established GWI criteria, and an overall symptom severity was calculated. Findings We found 6 Class II alleles that classified participants 84.1% correctly (13/16 control and 56/66 GWI). The number of copies of the 6 alleles was significantly higher in the control group, suggesting a protective role. This was supported by a significant negative dependence of overall symptom severity on the number of allele copies, such that symptom severity was lower in participants with larger numbers of allele copies. Interpretation These results indicate a reduced HLA protection (i.e. genetic susceptibility) in veterans with GWI. Funding University of Minnesota and U.S. Department of Veterans Affairs. PMID:26870819

  3. HLA antigens and gold toxicity in American blacks with rheumatoid arthritis.

    PubMed

    Alarcón, G S; Barger, B O; Acton, R T; Koopman, W J

    1986-01-01

    An increase in the frequency of DR3 in rheumatoid arthritis (RA) patients exhibiting toxic reactions to gold salt (GS) therapy has been observed in several studies of Caucasoid patients. Likewise, the association of B35 with gold-induced mucocutaneous reactions has also been reported in Caucasoid RA patients. Similar studies in other ethnic groups have not been previously documented. The present study was performed in American black RA patients receiving GS to determine if there were similar HLA associations with toxic reactions as those reported in Caucasoids. Eight-two seropositive and 18 seronegative American black RA patients were studied. Forty-one of the seropositive (50.0%) and six of the seronegative (33.3%) developed a toxic manifestation. No significant differences in the frequency distribution of HLA-B8, HLA-B35, DR, or DQw antigens were observed between the patients who had a toxic reaction and those who did not in either the seropositive or the seronegative RA patients. In particular, DR3 was not increased in patients with renal toxicity and B35 was not increased in patients with mucocutaneous reaction. Our study demonstrates that American black RA patients exhibiting GS toxicity do not have the same HLA associations as Caucasoids. The possibility that other genetic factor(s) may account for the occurrence of gold salt toxicity in American blacks requires further investigation. PMID:3466334

  4. The graft-versus-leukemia effect using matched unrelated donors is not superior to HLA-identical siblings for hematopoietic stem cell transplantation

    PubMed Central

    Pavletic, Steven Z.; Anasetti, Claudio; Barrett, A. John; Wang, Tao; Wang, Dan; Antin, Joseph H.; Di Bartolomeo, Paolo; Bolwell, Brian J.; Bredeson, Christopher; Cairo, Mitchell S.; Gale, Robert P.; Gupta, Vikas; Hahn, Theresa; Hale, Gregory A.; Halter, Jorg; Jagasia, Madan; Litzow, Mark R.; Locatelli, Franco; Marks, David I.; McCarthy, Philip L.; Cowan, Morton J.; Petersdorf, Effie W.; Russell, James A.; Schiller, Gary J.; Schouten, Harry; Spellman, Stephen; Verdonck, Leo F.; Wingard, John R.; Horowitz, Mary M.; Arora, Mukta

    2009-01-01

    Do some patients benefit from an unrelated donor (URD) transplant because of a stronger graft-versus-leukemia (GVL) effect? We analyzed 4099 patients with acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), and chronic myeloid leukemia (CML) undergoing a myeloablative allogeneic hematopoietic cell transplantation (HCT) from an URD (8/8 human leukocyte antigen [HLA]–matched, n = 941) or HLA-identical sibling donor (n = 3158) between 1995 and 2004 reported to the CIBMTR. In the Cox regression model, acute and chronic GVHD were added as time-dependent variables. In multivariate analysis, URD transplant recipients had a higher risk for transplantation-related mortality (TRM; relative risk [RR], 2.76; P < .001) and relapse (RR, 1.50; P < .002) in patients with AML, but not ALL or CML. Chronic GVHD was associated with a lower relapse risk in all diagnoses. Leukemia-free survival (LFS) was decreased in patients with AML without acute GVHD receiving a URD transplant (RR, 2.02; P < .001) but was comparable to those receiving HLA-identical sibling transplants in patients with ALL and CML. In patients without GVHD, multivariate analysis showed similar risk of relapse but decreased LFS for URD transplants for all 3 diagnoses. In conclusion, risk of relapse was the same (ALL, CML) or worse (AML) in URD transplant recipients compared with HLA-identical sibling transplant recipients, suggesting a similar GVL effect. PMID:19059878

  5. Role of Metalloproteases in Vaccinia Virus Epitope Processing for Transporter Associated with Antigen Processing (TAP)-independent Human Leukocyte Antigen (HLA)-B7 Class I Antigen Presentation*

    PubMed Central

    Lorente, Elena; García, Ruth; Mir, Carmen; Barriga, Alejandro; Lemonnier, François A.; Ramos, Manuel; López, Daniel

    2012-01-01

    The transporter associated with antigen processing (TAP) translocates the viral proteolytic peptides generated by the proteasome and other proteases in the cytosol to the endoplasmic reticulum lumen. There, they complex with nascent human leukocyte antigen (HLA) class I molecules, which are subsequently recognized by the CD8+ lymphocyte cellular response. However, individuals with nonfunctional TAP complexes or tumor or infected cells with blocked TAP molecules are able to present HLA class I ligands generated by TAP-independent processing pathways. Herein, using a TAP-independent polyclonal vaccinia virus-polyspecific CD8+ T cell line, two conserved vaccinia-derived TAP-independent HLA-B*0702 epitopes were identified. The presentation of these epitopes in normal cells occurs via complex antigen-processing pathways involving the proteasome and/or different subsets of metalloproteinases (amino-, carboxy-, and endoproteases), which were blocked in infected cells with specific chemical inhibitors. These data support the hypothesis that the abundant cellular proteolytic systems contribute to the supply of peptides recognized by the antiviral cellular immune response, thereby facilitating immunosurveillance. These data may explain why TAP-deficient individuals live normal life spans without any increased susceptibility to viral infections. PMID:22298786

  6. Influence of non-inherited maternal HLA-DR antigens on susceptibility to rheumatoid arthritis

    PubMed Central

    van der Horst-Bru..., I E; Hazes, J; Schreuder, G; Radstake, T; Barrera, P; van de Putte, L B A; Mustamu, D; van Schaardenburg, D; Breedveld, F; de Vries, R R P

    1998-01-01

    OBJECTIVE—It has recently been observed that non-inherited maternal DR4 antigens (NIMAs) of DR4 negative rheumatoid arthritis (RA) patients were increased compared with non-inherited paternal DR4 antigens (NIPAs). The aim of this study was to determine the prevalence of non-inherited DR4 antigens and DRB1 alleles in parents of RA patients. 
METHODS—HLA-DR serology and DRB1 typing was performed in 97 RA patients and their parents. NIMA and NIPA frequencies were compared, stratified according to the presence of DR4 and/or the shared epitope (SE).
RESULTS—In DR4 negative patients, NIMA DR4 was increased compared with NIPA DR4 (OR 3.10, 95% CI 0.76, 12.70). When combined with results from a previous study this increase was significant (OR 3.65, 95% CI 1.29, 10.31). The NIMA effect of SE positive DR4 subtypes in this study (OR 4.73, 95% CI 0.94, 23.8) was stronger than the NIMA effect of combined SE positive DRB1 alleles (OR 2.19 95% CI 0.36, 13.22).
CONCLUSIONS—The association between non-inherited maternal HLA-DR4 alleles and the susceptibility to RA was observed in two independent populations.

 Keywords: rheumatoid arthritis; non-inherited maternal DR4 antigens; HLA; genetics PMID:9924209

  7. Association of Wegener's granulomatosis with HLA antigens and other genetic markers.

    PubMed Central

    Papiha, S S; Murty, G E; Ad'Hia, A; Mains, B T; Venning, M

    1992-01-01

    The frequencies of the HLA-A, B, C, DR, DQ antigens and of several other genetic markers in biopsy proved and well characterised patients with Wegener's granulomatosis were compared with control frequencies of the region. A highly significant increase in HLA-DR1 was found. The percentage combined frequency of DR1-DQw1 was significantly higher in patients than in the controls. Interestingly, association with the red cell enzyme GLOI and complement locus C4B was also seen. As both of these markers are either linked or within the major histocompatibility complex region (MHC) this is further evidence for the involvement of chromosome 6 in the pathogenesis of Wegener's granulomatosis. To understand the pathology of the disease fully molecular genetic studies of the MHC region are warranted. PMID:1550412

  8. Typing of HLA class II and class I antigens using PHA-activated, IL-2-propagated T lymphocytes.

    PubMed

    Leshem, B; Cohen, I; Sherman, L; Brautbar, C; Kedar, E

    1988-06-28

    We describe here a simple procedure, by which HLA class II antigens can be accurately and reliably identified in those patients where there is minimal or absent expression of HLA-DR,DQw antigens on B cells, or when the total number of leukocytes recovered from the patients do not permit reliable typing. Ficoll-Hypaque-separated peripheral blood mononuclear leukocytes, fresh or cryopreserved, were activated by PHA and then propagated in IL-2-containing medium until enough cells for typing were obtained (usually 7-14 days). At this stage, the cultured cells were shown to be primarily T cells (greater than 90% CD3+). Since the activated T cells propagate in the presence of IL-2, even a small number (10(4] of fresh or cryopreserved patients' cells suffice for this protocol. To date we have been able to successfully HLA-DR,DQw type 34/34 bone marrow transplantation candidates and 12/12 long-term dialysis patients, who were untypable using fresh cells. HLA-DR,DQw antigens on activated T cells from normal individuals were identical to those found on their uncultured B cells. In addition, class I antigens that were undetectable on the uncultured cells of one patient could be identified on activated T cells. The HLA antigens identified on the patients' activated T cells were confirmed by phenotypic analysis of cells from family members. PMID:3260612

  9. Dynamical System Modeling to Simulate Donor T Cell Response to Whole Exome Sequencing-Derived Recipient Peptides Demonstrates Different Alloreactivity Potential in HLA-Matched and -Mismatched Donor-Recipient Pairs.

    PubMed

    Abdul Razzaq, Badar; Scalora, Allison; Koparde, Vishal N; Meier, Jeremy; Mahmood, Musa; Salman, Salman; Jameson-Lee, Max; Serrano, Myrna G; Sheth, Nihar; Voelkner, Mark; Kobulnicky, David J; Roberts, Catherine H; Ferreira-Gonzalez, Andrea; Manjili, Masoud H; Buck, Gregory A; Neale, Michael C; Toor, Amir A

    2016-05-01

    Immune reconstitution kinetics and subsequent clinical outcomes in HLA-matched recipients of allogeneic stem cell transplantation (SCT) are variable and difficult to predict. Considering SCT as a dynamical system may allow sequence differences across the exomes of the transplant donors and recipients to be used to simulate an alloreactive T cell response, which may allow better clinical outcome prediction. To accomplish this, whole exome sequencing was performed on 34 HLA-matched SCT donor-recipient pairs (DRPs) and the nucleotide sequence differences translated to peptides. The binding affinity of the peptides to the relevant HLA in each DRP was determined. The resulting array of peptide-HLA binding affinity values in each patient was considered as an operator modifying a hypothetical T cell repertoire vector, in which each T cell clone proliferates in accordance with the logistic equation of growth. Using an iterating system of matrices, each simulated T cell clone's growth was calculated with the steady-state population being proportional to the magnitude of the binding affinity of the driving HLA-peptide complex. Incorporating competition between T cell clones responding to different HLA-peptide complexes reproduces a number of features of clinically observed T cell clonal repertoire in the simulated repertoire, including sigmoidal growth kinetics of individual T cell clones and overall repertoire, Power Law clonal frequency distribution, increase in repertoire complexity over time with increasing clonal diversity, and alteration of clonal dominance when a different antigen array is encountered, such as in SCT. The simulated, alloreactive T cell repertoire was markedly different in HLA-matched DRPs. The patterns were differentiated by rate of growth and steady-state magnitude of the simulated T cell repertoire and demonstrate a possible correlation with survival. In conclusion, exome wide sequence differences in DRPs may allow simulation of donor alloreactive T

  10. HLA-B27 antigen frequency among suspected Spondyloarthropathy patients attaining a tertiary level hospital of Bangladesh.

    PubMed

    Nessa, A; Tabassum, S; Sultana, S

    2014-12-01

    Human leukocyte antigen B27 (HLA-B27), a class I molecules of the major histocompatibility complex has a strong disease association with different types of spondarthropathies (SpA). The strength of this disease association varies markedly among racial and ethnic populations. The present study aimed to identify the HLA-B27 antigen frequencies among suspected SpA patients as well as healthy Bangladeshi individuals. The frequency of HLA-B27 was determined in 1500 patients and 1000 healthy subjects attending the Bangabandhu Sheikh Mujib Medical University (BSMMU). HLA-B 27 typing was done by microlymphocytotoxicity test using commercial kit. A total of 738 (49.2%) suspected SpA patients and 107 (10.7%) healthy subjects tested positive for HLA-B27 antigen with higher frequency among younger age groups (54.9%, 52.4% and 56.2% in 0-14 years, 15-24 years and 25-34 years of age respectively). The male female positivity was almost same (11.4% and 9.6%) among control group, but in patient group it was 53.0% and 41.2% respectively. The findings of this hospital based study showed a high frequency of HLA-B27 among suspected SpA patients with male preponderance which is comparable with neighboring countries. PMID:26402974

  11. Polymorphism in human cytomegalovirus UL40 impacts on recognition of human leukocyte antigen-E (HLA-E) by natural killer cells.

    PubMed

    Heatley, Susan L; Pietra, Gabriella; Lin, Jie; Widjaja, Jacqueline M L; Harpur, Christopher M; Lester, Sue; Rossjohn, Jamie; Szer, Jeff; Schwarer, Anthony; Bradstock, Kenneth; Bardy, Peter G; Mingari, Maria Cristina; Moretta, Lorenzo; Sullivan, Lucy C; Brooks, Andrew G

    2013-03-22

    Natural killer (NK) cell recognition of the nonclassical human leukocyte antigen (HLA) molecule HLA-E is dependent on the presentation of a nonamer peptide derived from the leader sequence of other HLA molecules to CD94-NKG2 receptors. However, human cytomegalovirus can manipulate this central innate interaction through the provision of a "mimic" of the HLA-encoded peptide derived from the immunomodulatory glycoprotein UL40. Here, we analyzed UL40 sequences isolated from 32 hematopoietic stem cell transplantation recipients experiencing cytomegalovirus reactivation. The UL40 protein showed a "polymorphic hot spot" within the region that encodes the HLA leader sequence mimic. Although all sequences that were identical to those encoded within HLA-I genes permitted the interaction between HLA-E and CD94-NKG2 receptors, other UL40 polymorphisms reduced the affinity of the interaction between HLA-E and CD94-NKG2 receptors. Furthermore, functional studies using NK cell clones expressing either the inhibitory receptor CD94-NKG2A or the activating receptor CD94-NKG2C identified UL40-encoded peptides that were capable of inhibiting target cell lysis via interaction with CD94-NKG2A, yet had little capacity to activate NK cells through CD94-NKG2C. The data suggest that UL40 polymorphisms may aid evasion of NK cell immunosurveillance by modulating the affinity of the interaction with CD94-NKG2 receptors. PMID:23335510

  12. HLA antigens in insulin dependent and non-insulin dependent Spanish diabetic patients.

    PubMed

    Serrano-Ríos, M; Regueiro, J R; Severino, R; López-Larrea, C; Arnaiz-Villena, A

    1983-01-01

    HLA-A, -B, -C, -DR and Bw4, Bw6 antigens and Bf and GLO alleles have been studied in a sample of Spanish insulin dependent (IDD) and non-insulin dependent (NIDD) diabetic patients. In IDD's there was no significant increase of B8 and B15; an increase of B18 secondary to that of DR3 has been found. DR4 was also increased in our sample. The GLO-S/DR2 haplotype was found to be decreased in IDD. It was observed that (Aw30)-B18-Cw5-Bw6-DR3-BfF1 is the commonest ID diabetic haplotype in our population. A relationship between DR4 and early IDD onset was also found. No association was found between HLA, or Bf, and age of onset, macroangiopathy, microangiopathy, retinopathy, nephropathy and peripheral or autonomic neuropathy. In NIDD's, DR3 was increased and DR3-non BfF1 and DR3-non B18 RRs were higher than DR3 RR.Aw30 and Cw5 tended to be decreased, although not significantly. These findings further support the hypothesis that several closely linked diabetic susceptibility factors may exist within an HLA haplotype (i.e.: (Aw30)-B18-Cw5-Bw6-DR3-BfF1 in our population) and that all of them may be necessary for developing an IDD form; lack of one or several factors might lead to the acquisition of the NIDD form. PMID:6352349

  13. The production and crystallization of the human leukocyte antigen class II molecules HLA-DQ2 and HLA-DQ8 complexed with deamidated gliadin peptides implicated in coeliac disease

    SciTech Connect

    Henderson, Kate N.; Reid, Hugh H.; Borg, Natalie A.; Broughton, Sophie E.; Huyton, Trevor; Anderson, Robert P.; McCluskey, James; Rossjohn, Jamie

    2007-12-01

    The production and crystallization of human leukocyte antigen class II molecules HLA-DQ2 and HLA-DQ8 in complex with deamidated gliadin peptides is reported. Crystals of HLA-DQ2{sup PQPELPYPQ} diffracted to 3.9 Å, while the HLA-DQ8{sup EGSFQPSQE} crystals diffracted to 2.1 Å, allowing structure determination by molecular replacement. The major histocompatibility complex (MHC) class II molecules HLA-DQ2 and HLA-DQ8 are key risk factors in coeliac disease, as they bind deamidated gluten peptides that are subsequently recognized by CD4{sup +} T cells. Here, the production and crystallization of both HLA-DQ2 and HLA-DQ8 in complex with the deamidated gliadin peptides DQ2 α-I (PQPELPYPQ) and DQ8 α-I (EGSFQPSQE), respectively, are reported.

  14. Association of Polymorphisms in HLA Antigen Presentation-Related Genes with the Outcomes of HCV Infection

    PubMed Central

    Lu, Xiaomei; Xu, Yin; Wang, Jie; Zhang, Yun; Yu, Rongbin; Su, Jing

    2015-01-01

    Antigen-presentation genes play a vital role in the pathogenesis of HCV infection. However, the relationship of variants of these genes with spontaneous outcomes of HCV infection has not been fully investigated. To explore novel loci in the Chinese population, 34 tagging-SNPs in 9 candidate genes were genotyped for their associations with the outcomes of HCV infection. The distributions of different genotypes and haplotypes were compared among 773 HCV-negative controls, 246 subjects with HCV natural clearance, and 218 HCV persistent carriers recruited from hemodialysis patients and intravenous drug users. Our study implicated that TAP2, HLA-DOA, HLA-DOB, and tapasin loci were novel candidate regions for susceptibility to HCV infection and viral clearance in the Chinese population. Logistic regression analyses showed that TAP2 rs1800454 A (OR = 1.48, P = 0.002) and HLA-DOB rs2071469 G (OR = 1.23, P = 0.048) were significantly associated with increased susceptibility to establishment of HCV infection. However, high-risk behavior exposure and age were stronger predictors of HCV infection. Mutation of tapasin rs9277972 T (OR = 1.57, P =0.043) increased the risk of HCV chronicity, and HLA-DOA rs3128935 C (OR = 0.62, P = 0.019) increased the chance of viral resolution. With regards to the effect of rs3128925, interactions were found with high-risk behavior (P = 0.013) and age (P = 0.035). The risk effect of rs3128925 T for persistent HCV infection was higher in injecting drug users (vs. dialysis patients) and in subjects ≥ 40 years old (vs. < 40 years old). PMID:25874709

  15. NK cells expressing inhibitory KIR for non-self-ligands remain tolerant in HLA-matched sibling stem cell transplantation.

    PubMed

    Björklund, Andreas T; Schaffer, Marie; Fauriat, Cyril; Ringdén, Olle; Remberger, Mats; Hammarstedt, Christina; Barrett, A John; Ljungman, Per; Ljunggren, Hans-Gustaf; Malmberg, Karl-Johan

    2010-04-01

    Natural killer (NK)-cell alloreactivity in recipients of hematopoietic stem cell grafts from HLA-identical siblings is intriguing and has suggested breaking of NK-cell tolerance during the posttransplantation period. To examine this possibility, we analyzed clinical outcomes in a cohort of 105 patients with myeloid malignancies who received T cell-replete grafts from HLA-matched sibling donors. Presence of inhibitory killer cell immunoglobulin-like receptors (KIRs) for nonself HLA class I ligands had no effect on disease-free survival, incidence of relapse, or graft-versus-host disease. A longitudinal analysis of the NK-cell repertoire and function revealed a global hyporesponsiveness of NK cells early after transplantation. Functional responses recovered at approximately 6 months after transplantation. Importantly, NKG2A(-) NK cells expressing KIRs for nonself HLA class I ligands remained tolerant at all time points. Furthermore, a direct comparison of NK-cell reconstitution in T cell-replete and T cell-depleted HLA-matched sibling stem cell transplantation (SCT) revealed that NKG2A(+) NK cells dominated the functional repertoire early after transplantation, with intact tolerance of NKG2A(-) NK cells expressing KIRs for nonself ligands in both settings. Our results provide evidence against the emergence of alloreactive NK cells in HLA-identical allogeneic SCT. PMID:20097883

  16. Detergent-soluble HLA antigens contain a hydrophilic region at the COOH-terminus and a penultimate hydrophobic region.

    PubMed Central

    Springer, T A; Strominger, J L

    1976-01-01

    Purified, detergent-soluble HLA antigens (p44,12) are composed of a glycoprotein of molecular weight 44,000 (p44) and a peptide of molecular weight 12,000 (p12), beta2-microglobulin. Upon digestion with papain, p44,12 is converted to p39,12, then to p34,12, which retains antigenic activity. The NH2-terminal amino acid sequences of p34 and p44 are identical. p44, p39, and p34 were purified, and comparison of their amino acid compositions showed that the COOH-terminal peptide removed by the first papain cleavage is hydrophilic and contains cysteine that can be alkylated after mild reduction. The penultimate COOH-terminal peptide removed by the second papain cleavage is hydrophobic, and presumably anchors HLA antigens to the membrane. This correlates with the observation that p44,12 and p39,12 bind detergent, while p34,12 does not. The orientation and integration of HLA antigens in the lymphocyte membrane were thus defined, and the structure suggests that HLA antigens span the plasma membrane. Images PMID:781677

  17. Ultrasonographic Assessment of Enthesitis in HLA-B27 Positive Patients with Rheumatoid Arthritis, a Matched Case-Only Study

    PubMed Central

    Mera-Varela, Antonio; Ferreiro-Iglesias, Aida; Perez-Pampin, Eva; Porto-Silva, Marisol; Gómez-Reino, Juan J.; Gonzalez, Antonio

    2013-01-01

    Introduction HLA-B27 has a modifier effect on the phenotype of multiple diseases, both associated and non-associated with it. Among these effects, an increased frequency of clinical enthesitis in patients with Rheumatoid Arthritis (RA) has been reported but never explored again. We aimed to replicate this study with a sensitive and quantitative assessment of enthesitis by using standardized ultrasonography (US). Methods The Madrid Sonography Enthesitis Index (MASEI) was applied to the US assessment of 41 HLA-B27 positive and 41 matched HLA-B27 negative patients with longstanding RA. Clinical characteristics including explorations aimed to evaluate spondyloarthrtitis and laboratory tests were also done. Results A significant degree of abnormalities in the entheses of the patients with RA were found, but the MASEI values, and each of its components including the Doppler signal, were similar in HLA-B27 positive and negative patients. An increase of the MASEI scores with age was identified. Differences in two clinical features were found: a lower prevalence of rheumatoid factor and a more common story of low back pain in the HLA-B27 positive patients than in the negative. The latter was accompanied by radiographic sacroiliitis in two HLA-B27 positive patients. No other differences were detected. Conclusion We have found that HLA-B27 positive patients with RA do not have more enthesitis as assessed with US than the patients lacking this HLA allele. However, HLA-B27 could be shaping the RA phenotype towards RF seronegativity and axial involvement. PMID:23505543

  18. Sampling From the Proteome to the Human Leukocyte Antigen-DR (HLA-DR) Ligandome Proceeds Via High Specificity*

    PubMed Central

    Mommen, Geert P. M.; Marino, Fabio; Meiring, Hugo D.; Poelen, Martien C. M.; van Gaans-van den Brink, Jacqueline A. M.; Mohammed, Shabaz; Heck, Albert J. R.; van Els, Cécile A. C. M.

    2016-01-01

    Comprehensive analysis of the complex nature of the Human Leukocyte Antigen (HLA) class II ligandome is of utmost importance to understand the basis for CD4+ T cell mediated immunity and tolerance. Here, we implemented important improvements in the analysis of the repertoire of HLA-DR-presented peptides, using hybrid mass spectrometry-based peptide fragmentation techniques on a ligandome sample isolated from matured human monocyte-derived dendritic cells (DC). The reported data set constitutes nearly 14 thousand unique high-confident peptides, i.e. the largest single inventory of human DC derived HLA-DR ligands to date. From a technical viewpoint the most prominent finding is that no single peptide fragmentation technique could elucidate the majority of HLA-DR ligands, because of the wide range of physical chemical properties displayed by the HLA-DR ligandome. Our in-depth profiling allowed us to reveal a strikingly poor correlation between the source proteins identified in the HLA class II ligandome and the DC cellular proteome. Important selective sieving from the sampled proteome to the ligandome was evidenced by specificity in the sequences of the core regions both at their N- and C- termini, hence not only reflecting binding motifs but also dominant protease activity associated to the endolysosomal compartments. Moreover, we demonstrate that the HLA-DR ligandome reflects a surface representation of cell-compartments specific for biological events linked to the maturation of monocytes into antigen presenting cells. Our results present new perspectives into the complex nature of the HLA class II system and will aid future immunological studies in characterizing the full breadth of potential CD4+ T cell epitopes relevant in health and disease. PMID:26764012

  19. Frequency of null allele of Human Leukocyte Antigen-G (HLA-G) locus in subjects to recurrent miscarriage

    PubMed Central

    Alizadeh, Nazila; Mosaferi, Elnaz; Farzadi, Laya; Majidi, Jafar; Monfaredan, Amir; Yousefi, Bahman; Baradaran, Behzad

    2016-01-01

    Background: Human leukocyte antigen-G (HLA-G) is a non-classical class I molecule highly expressed by extravillous cytotrophoblast cells. Due to a single base pair deletion, its function can be compensated by other isoforms. Investigating the frequency of null allele in Recurrent Miscarriage (RM) subjects could be useful in understanding the relationship between frequency of this allele and RM in a given population. Objective: This study aimed to determine the frequency of HLA-G*0105N null allele and its potential association with down-regulation of HLA-G in subjects with RM. Materials and Methods: Western blotting was used to assess the level of HLA-G protein expression. For investigating the frequency of HLA-G*0105N null allele in RM subjects, PCR-RFLP method was used. Exon 3 of HLA-G gene was amplified by polymerase chain reaction (PCR). Subsequently, PpuM-1 enzyme was employed to digest the PCR products and fragments were analyzed using gel electrophoresis. Results: Digestion using restriction enzyme showed the presence of heterozygous HLA-G*0105N null allele in 10% of the test population. Western blotting results confirmed the decrease in expression of HLA-G in the placental tissue of subjects with RM compared to subjects who could give normal birth. Conclusion: The frequency of heterozygous HLA-G*0105N null allele was high to some extent in subjects with RM. The mutation rate in subjects suggested that there is a significant association between RM and frequency of mutations in this allele. PMID:27525330

  20. HLA-DQA1 and HLA-DQB1 genes in Tsachilas Indians from Ecuador: new insights in population analysis by Human Leukocyte Antigens.

    PubMed

    Iorio, A; De Angelis, F; Garzoli, A; Battistini, A; De Stefano, G F

    2014-06-01

    Human Leucocyte Antigen (HLA) loci are widely known for their role in the generation of immune responses and are often considered to be effective in reconstructing human relationships. This is due to the high degree of polymorphism and the rarity of recombination observed at HLA loci. In this study, we have made an attempt to support the potential of HLA class II loci by analysing DQA1 and DQB1 in 52 Ecuadorians with ties to the Tsachilas community. Little is known about this populations either ethnologically or historically: they are considered retaining much of the ancient Chibchan culture in spite of the lack of significant genetic characterization. A total of 21 alleles were observed, with very low heterozygosity. The obtained data were then assessed for relationship reconstruction. The compiled database of 63 populations was segregated and resolved in clusters corresponding to the ethnogeographic distribution of the populations. This analysis of Central and Southern Amerindians allowed us to support a historical hypothesis related to the origin and migration of Ecuadorian people. Indeed, the relationships with neighbour human groups, especially Cayapas and Colombians, could shed light on the genetic similarity within ancient Chibchan culture that was dispersed by tribes coming up the Barbacoas. This indicates that if an appropriate analysis was to be carried out on a set of populations representative of different geographic locations, and that analysis was properly interpreted, then there would be a high possibility that HLA class II loci could infer accurate assessments, as revealed by uniparental markers. PMID:24775353

  1. Human Leukocyte Antigen-G (HLA-G) Expression in Cancers: Roles in Immune Evasion, Metastasis and Target for Therapy

    PubMed Central

    Lin, Aifen; Yan, Wei-Hua

    2015-01-01

    Aberrant induction of human leukocyte antigen-G (HLA-G) expression has been observed in various malignancies and is strongly associated with tumor immune escape, metastasis and poor prognosis. To date, great achievements have been made in understanding the underlying mechanisms of HLA-G involved in tumor progression. HLA-G could lead to tumor evasion by inhibition of immune cell cytolysis, differentiation and proliferation and inhibition of cytokine production, induction of immune cell apoptosis, generation of regulatory cells and expansion of myeloid-derived suppressive cells and by impairment of chemotaxis. Moreover, HLA-G could arm tumor cells with a higher invasive and metastatic potential with the upregulation of tumor-promoting factor expression such as matrix metalloproteinases (MMPs), indicating that ectopic HLA-G expression could render multiple effects during the progression of malignancies. In this review, we summarized the mechanisms of HLA-G involved in promoting tumor cell immune escaping, metastasis and disease progression. Special attention will be paid to its significance as an attractive therapeutic target in cancers. PMID:26322846

  2. High resolution human leukocyte antigen (HLA) class I and class II allele typing in Mexican mestizo women with sporadic breast cancer: case-control study

    PubMed Central

    2009-01-01

    Background The development of breast cancer is multifactorial. Hormonal, environmental factors and genetic predisposition, among others, could interact in the presentation of breast carcinoma. Human leukocyte antigen (HLA) alleles play an important role in immunity (cellular immunity) and may be important genetic traits. HLAAllele-specific interaction has not been well established. Recently, several studies had been conducted in order to do so, but the results are controversial and in some instances contradictory. Methods We designed a case-control study to quantify the association of HLA class I and II genes and breast cancer. HLA typing was performed by high resolution sequence-specific oligotyping after DNA amplification (PCR-SSOP) of 100 breast cancer Mexican mestizo patients and 99 matched healthy controls. Results HLA-A frequencies that we were able to observe that there was no difference between both groups from the statistical viewpoint. HLA-B*1501 was found three times more common in the case group (OR, 3.714; p = 0.031). HLA-Cw is not a marker neither for risk, nor protection for the disease, because we did not find significant statistical differences between the two groups. DRB1*1301, which is expressed in seven cases and in only one control, observing an risk increase of up to seven times and DRB1*1602, which behaves similarly in being present solely in the cases (OR, 16.701; 95% CI, 0.947 – 294.670). DQ*0301-allele expression, which is much more common in the control group and could be protective for the presentation of the disease (OR, 0.078; 95% CI, 0.027–0.223, p = 0.00001). Conclusion Our results reveal the role of the MHC genes in the pathophysiology of breast cancer, suggesting that in the development of breast cancer exists a disorder of immune regulation. The triggering factor seems to be restricted to certain ethnic groups and certain geographical regions since the relevant MHC alleles are highly diverse. This is the first study in Mexican

  3. HLA Antigens in Malay Patients with Systemic Lupus Erythematosus: Association with Clinical and Autoantibody Expression

    PubMed Central

    Azizah, MR; Ainol, SS; Kong, NCT; Normaznah, Y; Rahim, MN

    2001-01-01

    Background: Studies have shown that certain genes within the major histocompatibility complex predispose to systemic lupus erythematosus (SLE) and may influence clinical and autoantibody expression. Thus, we studied the frequency of HLA-DR, -DQA, -DQB and -DPB alleles in ethnic Malays with SLE to determine the role of these genes in determining disease susceptibility and their association with clinical and immunological manifestations. Methods: Fifty-six Malay SLE patients were enrolled into the study. Demographic, clinical and immunological findings were obtained from medical records. HLA-DR, DQ and DP typing were done using modified PCR-RELP. Controls were from ethnically-matched healthy individuals. Results: We found a strongly significant association of the DR2 and DQB1 *0501 and DQB1 *0601 (pcorr=0.03, rr=3.83, pcorr=0.0036, rr=4.56 and pcorr=0.0048 and rr=6.0, respectively). There was also a weak increase of DQB1 *0.201 and DPB1 *0.0901 with a weak decrease of DQA1 *0601 and DQB1 *0503 and *0301 which were not significant after corrections for multiple comparisons were made. There was a significant positive association of DR2 and DQB1 *0501 with renal involvement and DR8 with alopecia. A nonsignificant increase of DQB1 *0503 in patients with photosensitivity was noted. Significant autoantibody associations were also found: DQB1 *0601 with anti-Sm/RNP, DR2 with antiSSA (Ro)/SSB (La), and DR2, DQB1 *0501 and *0601 with antibodies to ds DNA. There was no specific DR, DQ or DP associations with age of disease onset (below 30 years or those at or above 30 years). Conclusion: Our data suggests the role of the HLA class II genes in conferring SLE susceptibility and in clinical and autoantibody expression PMID:11590899

  4. The impact of HLA class I and EBV latency-II antigen-specific CD8(+) T cells on the pathogenesis of EBV(+) Hodgkin lymphoma.

    PubMed

    Jones, K; Wockner, L; Brennan, R M; Keane, C; Chattopadhyay, P K; Roederer, M; Price, D A; Cole, D K; Hassan, B; Beck, K; Gottlieb, D; Ritchie, D S; Seymour, J F; Vari, F; Crooks, P; Burrows, S R; Gandhi, M K

    2016-02-01

    In 40% of cases of classical Hodgkin lymphoma (cHL), Epstein-Barr virus (EBV) latency-II antigens [EBV nuclear antigen 1 (EBNA1)/latent membrane protein (LMP)1/LMP2A] are present (EBV(+) cHL) in the malignant cells and antigen presentation is intact. Previous studies have shown consistently that HLA-A*02 is protective in EBV(+) cHL, yet its role in disease pathogenesis is unknown. To explore the basis for this observation, gene expression was assessed in 33 cHL nodes. Interestingly, CD8 and LMP2A expression were correlated strongly and, for a given LMP2A level, CD8 was elevated markedly in HLA-A*02(-) versus HLA-A*02(+) EBV(+) cHL patients, suggesting that LMP2A-specific CD8(+) T cell anti-tumoral immunity may be relatively ineffective in HLA-A*02(-) EBV(+) cHL. To ascertain the impact of HLA class I on EBV latency antigen-specific immunodominance, we used a stepwise functional T cell approach. In newly diagnosed EBV(+) cHL, the magnitude of ex-vivo LMP1/2A-specific CD8(+) T cell responses was elevated in HLA-A*02(+) patients. Furthermore, in a controlled in-vitro assay, LMP2A-specific CD8(+) T cells from healthy HLA-A*02 heterozygotes expanded to a greater extent with HLA-A*02-restricted compared to non-HLA-A*02-restricted cell lines. In an extensive analysis of HLA class I-restricted immunity, immunodominant EBNA3A/3B/3C-specific CD8(+) T cell responses were stimulated by numerous HLA class I molecules, whereas the subdominant LMP1/2A-specific responses were confined largely to HLA-A*02. Our results demonstrate that HLA-A*02 mediates a modest, but none the less stronger, EBV-specific CD8(+) T cell response than non-HLA-A*02 alleles, an effect confined to EBV latency-II antigens. Thus, the protective effect of HLA-A*02 against EBV(+) cHL is not a surrogate association, but reflects the impact of HLA class I on EBV latency-II antigen-specific CD8(+) T cell hierarchies. PMID:26422112

  5. Donor-Recipient Matching for KIR Genotypes Reduces Chronic GVHD and Missing Inhibitory KIR Ligands Protect against Relapse after Myeloablative, HLA Matched Hematopoietic Cell Transplantation

    PubMed Central

    Faridi, Rehan Mujeeb; Kemp, Taylor J.; Dharmani-Khan, Poonam; Lewis, Victor; Rajalingam, Raja; Berka, Noureddine; Storek, Jan; Masood Khan, Faisal

    2016-01-01

    Background Allogeneic hematopoietic cell transplantation (HCT) can be curative for many hematologic diseases. However, complications such as graft-versus-host disease (GVHD) and relapse of primary malignancy remain significant and are the leading causes of morbidity and mortality. Effects of killer Ig-like receptors (KIR)-influenced NK cells on HCT outcomes have been extensively pursued over the last decade. However, the relevance of the reported algorithms on HLA matched myeloablative HCT with rabbit antithymocyte globulin (ATG) is used for GVHD prophylaxis remains elusive. Here we examined the role of KIR and KIR-ligands of donor-recipient pairs in modifying the outcomes of ATG conditioned HLA matched sibling and unrelated donor HCT Methods and Findings The study cohort consisted of 281 HLA matched sibling and unrelated donor-recipient pairs of first allogeneic marrow or blood stem cell transplantation allocated into ‘discovery’ (135 pairs) and ‘validation’ (146 pairs) cohorts. High resolution HLA typing was obtained from the medical charts and KIR gene repertoires were obtained by a Luminex® based SSO method. All surviving patients were followed-up for a minimum of two years. KIR and HLA class I distributions of HCT pairs were stratified as per applicable definitions and were tested for their association with cause specific outcomes [acute GVHD grade II-IV (aGVHD), chronic GVHD needing systemic therapy (cGVHD) and relapse] using a multivariate competing risks regression model as well as with survival outcomes [relapse-free survival (RFS), cGVHD & relapse free survival (cGRFS) and overall survival (OS)] by multivariate Cox proportional hazards regression model. A significant association between KIR genotype mismatching (KIR-B/x donor into KIR-AA recipient or vice versa) and cGVHD was found in both discovery (p = 0.001; SHR = 2.78; 95%CI: 1.50–5.17) and validation cohorts (p = 0.005; SHR = 2.61; 95%CI: 1.33–5.11). High incidence of cGVHD associated

  6. Allele-Independent Turnover of Human Leukocyte Antigen (HLA) Class Ia Molecules.

    PubMed

    Prevosto, Claudia; Usmani, M Farooq; McDonald, Sarah; Gumienny, Aleksandra M; Key, Tim; Goodman, Reyna S; Gaston, J S Hill; Deery, Michael J; Busch, Robert

    2016-01-01

    Major histocompatibility complex class I (MHCI) glycoproteins present cytosolic peptides to CD8+ T cells and regulate NK cell activity. Their heavy chains (HC) are expressed from up to three MHC gene loci (human leukocyte antigen [HLA]-A, -B, and -C in humans), whose extensive polymorphism maps predominantly to the antigen-binding groove, diversifying the bound peptide repertoire. Codominant expression of MHCI alleles is thus functionally critical, but how it is regulated is not fully understood. Here, we have examined the effect of polymorphism on the turnover rates of MHCI molecules in cell lines with functional MHCI peptide loading pathways and in monocyte-derived dendritic cells (MoDCs). Proteins were labeled biosynthetically with heavy water (2H2O), folded MHCI molecules immunoprecipitated, and tryptic digests analysed by mass spectrometry. MHCI-derived peptides were assigned to specific alleles and isotypes, and turnover rates quantified by 2H incorporation, after correcting for cell growth. MHCI turnover half-lives ranged from undetectable to a few hours, depending on cell type, activation state, donor, and MHCI isotype. However, in all settings, the turnover half-lives of alleles of the same isotype were similar. Thus, MHCI protein turnover rates appear to be allele-independent in normal human cells. We propose that this is an important feature enabling the normal function and codominant expression of MHCI alleles. PMID:27529174

  7. Allele-Independent Turnover of Human Leukocyte Antigen (HLA) Class Ia Molecules

    PubMed Central

    Prevosto, Claudia; Usmani, M. Farooq; McDonald, Sarah; Gumienny, Aleksandra M.; Key, Tim; Goodman, Reyna S.; Gaston, J. S. Hill; Deery, Michael J.; Busch, Robert

    2016-01-01

    Major histocompatibility complex class I (MHCI) glycoproteins present cytosolic peptides to CD8+ T cells and regulate NK cell activity. Their heavy chains (HC) are expressed from up to three MHC gene loci (human leukocyte antigen [HLA]-A, -B, and -C in humans), whose extensive polymorphism maps predominantly to the antigen-binding groove, diversifying the bound peptide repertoire. Codominant expression of MHCI alleles is thus functionally critical, but how it is regulated is not fully understood. Here, we have examined the effect of polymorphism on the turnover rates of MHCI molecules in cell lines with functional MHCI peptide loading pathways and in monocyte-derived dendritic cells (MoDCs). Proteins were labeled biosynthetically with heavy water (2H2O), folded MHCI molecules immunoprecipitated, and tryptic digests analysed by mass spectrometry. MHCI-derived peptides were assigned to specific alleles and isotypes, and turnover rates quantified by 2H incorporation, after correcting for cell growth. MHCI turnover half-lives ranged from undetectable to a few hours, depending on cell type, activation state, donor, and MHCI isotype. However, in all settings, the turnover half-lives of alleles of the same isotype were similar. Thus, MHCI protein turnover rates appear to be allele-independent in normal human cells. We propose that this is an important feature enabling the normal function and codominant expression of MHCI alleles. PMID:27529174

  8. Clinical subgroups and HLA antigens in Italian patients with psoriatic arthritis.

    PubMed

    Salvarani, C; Macchioni, P L; Zizzi, F; Mantovani, W; Rossi, F; Baricchi, R; Ghirelli, L; Frizziero, L; Portioli, I

    1989-01-01

    The frequencies of HLA antigens were studied in 101 Italian patients with psoriatic arthritis. The total group showed a significant increase in frequency of A1 and B38, and a reduction of B5 when compared to healthy controls. No association between DR and/or DQw antigens and PA were demonstrated. The comparisons between the clinical subgroups and normal controls revealed a significant association of B38 with asymmetric peripheral arthritis, B27 and B39 with spondylitis (with or without peripheral involvement). When intergroup comparison were made, the patients with spondylitis had an increase in frequency of B27 and DQw3 as compared to those with symmetric and asymmetric peripheral disease. DR4 and DRw53 were associated with earlier age of onset of arthritis. There were also significant associations between DQw3 and severe disease, and between A9, B5 and presence of erosions and joint space narrowing. No association with DR4 was showed in a subgroup of patients with symmetric polyarthritis without DIP involvement. PMID:2591112

  9. Sibling versus Unrelated Donor Allogeneic Hematopoietic Cell Transplantation for CML: Refined HLA-matching shows more GVHD but not less relapse

    PubMed Central

    Weisdorf, Daniel J.; Nelson, Gene; Lee, Stephanie J; Haagenson, Michael; Spellman, Stephen; Antin, Joseph H; Bolwell, Brian; Cahn, Jean-Yves; Cervantes, Francisco; Copelan, Edward; Gale, Robert; Gratwohl, Alois; Khoury, H. Jean; McCarthy, Philip; Marks, David I; Szer, Jeff; Woolfrey, Ann; Cortes-Franco, Jorge; Horowitz, Mary M; Arora, Mukta

    2010-01-01

    Purpose Unrelated donor (URD) hematopoietic cell transplantation (HCT) can eradicate chronic myelogenous leukemia (CML). It has been postulated that greater donor:recipient-histoincompatibility can augment the graft vs. leukemia (GvL) effect. We previously reported similar, but not equivalent outcomes of URD vs. sibling donor HCT for CML using an older, less precise classification of HLA-matching. Methods Our recently refined HLA-matching classification, suitable for interpretation when complete allele-level typing is unavailable was used to reanalyze outcomes of previous HCT for CML. Results We observed that new matching criteria identifies substantially more frequent mismatch than older, less precise “6 of 6 antigen” matched URD-HCT. Only 37% of those previously called “HLA-matched” were HLA-well-matched in new classification and 44% were partially-matched. The refined matching classification confirmed that partially matched or mismatched URD:recipient pairs have significantly greater risks of graft failure compared to either sibling or well-matched URD-HCT. Acute and chronic GVHD are significantly more frequent with all levels of recategorized URD HLA-matching. Importantly, survival and leukemia-free survival remain significantly worse following URD-HCT at any matching level. No augmented GvL effect accompanied URD HLA-mismatch. Compared to sibling donor transplants, we observed marginally increased, but not significantly different risks of relapse in either well-matched, partially-matched or mismatched URD-HCT. Conclusions These data confirm the utility of our revised HLA-matching schema as applicable for analysis of retrospective data sets when fully informative, allele level-typing is unavailable. In this analysis, greater histoincompatibility can augment GVHD but does not improve protection against relapse thus the best donor is still the most closely matched. PMID:19822308

  10. Transgenic antigen-specific, HLA-A*02:01-allo-restricted cytotoxic T cells recognize tumor-associated target antigen STEAP1 with high specificity.

    PubMed

    Schirmer, David; Grünewald, Thomas G P; Klar, Richard; Schmidt, Oxana; Wohlleber, Dirk; Rubío, Rebeca Alba; Uckert, Wolfgang; Thiel, Uwe; Bohne, Felix; Busch, Dirk H; Krackhardt, Angela M; Burdach, Stefan; Richter, Günther H S

    2016-06-01

    Pediatric cancers, including Ewing sarcoma (ES), are only weakly immunogenic and the tumor-patients' immune system often is devoid of effector T cells for tumor elimination. Based on expression profiling technology, targetable tumor-associated antigens (TAA) are identified and exploited for engineered T-cell therapy. Here, the specific recognition and lytic potential of transgenic allo-restricted CD8(+) T cells, directed against the ES-associated antigen 6-transmembrane epithelial antigen of the prostate 1 (STEAP1), was examined. Following repetitive STEAP1(130) peptide-driven stimulations with HLA-A*02:01(+) dendritic cells (DC), allo-restricted HLA-A*02:01(-) CD8(+) T cells were sorted with HLA-A*02:01/peptide multimers and expanded by limiting dilution. After functional analysis of suitable T cell clones via ELISpot, flow cytometry and xCELLigence assay, T cell receptors' (TCR) α- and β-chains were identified, cloned into retroviral vectors, codon optimized, transfected into HLA-A*02:01(-) primary T cell populations and tested again for specificity and lytic capacity in vitro and in a Rag2(-/-)γc(-/-) mouse model. Initially generated transgenic T cells specifically recognized STEAP1(130)-pulsed or transfected cells in the context of HLA-A*02:01 with minimal cross-reactivity as determined by specific interferon-γ (IFNγ) release, lysed cells and inhibited growth of HLA-A*02:01(+) ES lines more effectively than HLA-A*02:01(-) ES lines. In vivo tumor growth was inhibited more effectively with transgenic STEAP1(130)-specific T cells than with unspecific T cells. Our results identify TCRs capable of recognizing and inhibiting growth of STEAP1-expressing HLA-A*02:01(+) ES cells in vitro and in vivo in a highly restricted manner. As STEAP1 is overexpressed in a wide variety of cancers, we anticipate these STEAP1-specific TCRs to be potentially useful for immunotherapy of other STEAP1-expressing tumors. PMID:27471654

  11. HLA-A is a Predictor of Hepatitis B e Antigen Status in HIV-Positive African Adults.

    PubMed

    Matthews, Philippa C; Carlson, Jonathan M; Beloukas, Apostolos; Malik, Amna; Jooste, Pieter; Ogwu, Anthony; Shapiro, Roger; Riddell, Lynn; Chen, Fabian; Luzzi, Graz; Jesuthasan, Gerald; Jeffery, Katie; Jojic, Nebojsa; Ndung'u, Thumbi; Carrington, Mary; Goulder, Philip J R; Geretti, Anna Maria; Klenerman, Paul

    2016-04-15

    Outcomes of chronic infection with hepatitis B virus (HBV) are varied, with increased morbidity reported in the context of human immunodeficiency virus (HIV) coinfection. The factors driving different outcomes are not well understood, but there is increasing interest in an HLA class I effect. We therefore studied the influence of HLA class I on HBV in an African HIV-positive cohort. We demonstrated that virologic markers of HBV disease activity (hepatitis B e antigen status or HBV DNA level) are associated with HLA-A genotype. This finding supports the role of the CD8(+) T-cell response in HBV control, and potentially informs future therapeutic T-cell vaccine strategies. PMID:26655301

  12. HLA-A is a Predictor of Hepatitis B e Antigen Status in HIV-Positive African Adults

    PubMed Central

    Matthews, Philippa C.; Carlson, Jonathan M.; Beloukas, Apostolos; Malik, Amna; Jooste, Pieter; Ogwu, Anthony; Shapiro, Roger; Riddell, Lynn; Chen, Fabian; Luzzi, Graz; Jesuthasan, Gerald; Jeffery, Katie; Jojic, Nebojsa; Ndung'u, Thumbi; Carrington, Mary; Goulder, Philip J. R.; Geretti, Anna Maria; Klenerman, Paul

    2016-01-01

    Outcomes of chronic infection with hepatitis B virus (HBV) are varied, with increased morbidity reported in the context of human immunodeficiency virus (HIV) coinfection. The factors driving different outcomes are not well understood, but there is increasing interest in an HLA class I effect. We therefore studied the influence of HLA class I on HBV in an African HIV-positive cohort. We demonstrated that virologic markers of HBV disease activity (hepatitis B e antigen status or HBV DNA level) are associated with HLA-A genotype. This finding supports the role of the CD8+ T-cell response in HBV control, and potentially informs future therapeutic T-cell vaccine strategies. PMID:26655301

  13. Defining the HLA class I‐associated viral antigen repertoire from HIV‐1‐infected human cells

    PubMed Central

    Yang, Hongbing; Partridge, Thomas; Llano, Anuska; Cedeño, Samandhy; Fischer, Roman; Charles, Philip D.; Dudek, Nadine L.; Mothe, Beatriz; Crespo, Manuel; Fischer, William M.; Korber, Bette T. M.; Nielsen, Morten; Borrow, Persephone; Purcell, Anthony W.; Brander, Christian; Dorrell, Lucy; Kessler, Benedikt M.; Hanke, Tomáš

    2015-01-01

    Recognition and eradication of infected cells by cytotoxic T lymphocytes is a key defense mechanism against intracellular pathogens. High‐throughput definition of HLA class I‐associated immunopeptidomes by mass spectrometry is an increasingly important analytical tool to advance our understanding of the induction of T‐cell responses against pathogens such as HIV‐1. We utilized a liquid chromatography tandem mass spectrometry workflow including de novo‐assisted database searching to define the HLA class I‐associated immunopeptidome of HIV‐1‐infected human cells. We here report for the first time the identification of 75 HIV‐1‐derived peptides bound to HLA class I complexes that were purified directly from HIV‐1‐infected human primary CD4+ T cells and the C8166 human T‐cell line. Importantly, one‐third of eluted HIV‐1 peptides had not been previously known to be presented by HLA class I. Over 82% of the identified sequences originated from viral protein regions for which T‐cell responses have previously been reported but for which the precise HLA class I‐binding sequences have not yet been defined. These results validate and expand the current knowledge of virus‐specific antigenic peptide presentation during HIV‐1 infection and provide novel targets for T‐cell vaccine development. PMID:26467324

  14. An evaluation of HLA cross-reactive group matching on graft survival in deceased donor kidney recipients.

    PubMed

    Lazda, V A; Mozes, M F

    2005-03-01

    Since September 20, 1999, our organ procurement organization (OPO) serving an ethnically diverse local distribution area has allocated kidneys using a cross-reactive group (CREG)-based variance. This variance awards 7 points for 0-CREG,0-DR mismatches and 6 points for 0-A,B mismatches in addition to points given for waiting time (3) and panel-reactive antibodies (PRA) > or = 80% (3). Previously, we have shown that awarding points for 0-CREG,0-DR mismatches in kidney allocation improves the access to HLA-matched transplants for racial groups, especially for the black race. In this study, we evaluated if there are outcome benefits as well. One- and 3-year uncensored graft survival data and analyses for the influence of HLA mismatching on graft outcome in black and nonblack recipients were provided by Scientific Registry of Transplant Recipients (SRTR). Overall, 1-year graft survival was 87.4% and not significantly different for blacks (86.1%, n = 467) vs nonblacks (88.8%, n = 730); 3-year graft survival was 74.6% and significantly lower P = .0001 for blacks (68.5%, n = 480) vs nonblacks (78.4%, n = 765). No significant advantage was observed for either the black or nonblack recipients in any of the HLA-mismatched categories, including the 0-CREG,0-DR mismatch group. An HLA matching effect also was not seen when data were stratified for patients nonsensitized (PRA < or = 10%) and sensitized (PRA > 10%) at the time of transplantation, except for the improved graft survival in sensitized nonblack recipients of 0- A,B,DR-mismatched grafts. Of the patients who lost their grafts and returned to the waiting list for retransplantation, the 0-A,B,DR mismatched were the least sensitized group (6%, n = 16), and there was a trend for less sensitization in the 0-CREG,0-DR-mismatched group (33%, n = 9), compared to those with other HLA mismatches (68%, n = 137). Thus, based on 1-year and 3-year follow-up data, there are no apparent graft outcome benefits for either CREG matching

  15. Expansion of NKG2A-LIR1- natural killer cells in HLA-matched, killer cell immunoglobulin-like receptors/HLA-ligand mismatched patients following hematopoietic cell transplantation.

    PubMed

    Rathmann, Silvia; Glatzel, Sabine; Schönberg, Kathrin; Uhrberg, Markus; Follo, Marie; Schulz-Huotari, Christian; Kaymer, Markus; Veelken, Hendrik; Finke, Jürgen; Fisch, Paul

    2010-04-01

    The prognosis after hematopoietic cell transplantation (HCT) for the treatment of leukemia or lymphoma in humans is influenced by donor-derived natural killer (NK) cells, which enhance the graft-versus-leukemia (GVL) effect. Such alloreactive killer cells can be generated in vivo after HCT if the donor expresses killer cell immunoglobulin-like receptors (KIRs), such as KIR2DL1, KIR2DL2/3, or KIR3DL1, for which the recipient lacks HLA class I ligands. We studied effector cells from 22 KIR/HLA-ligand mismatched and 14 KIR/HLA-ligand matched, primarily HLA-matched patient-donor pairs after allogeneic HCT. A novel 8-color flow cytometry panel allowed us to characterize effector-cell populations without "broadly reactive" inhibitory receptors such as CD94/NKG2A or LIR1. The numbers of such NKG2A(-) LIR1(-) NK cells increased following HCT in patients transplanted by KIR/HLA-ligand mismatched grafts, compared to KIR/HLA-ligand matched grafts, and in patients transplanted from donors of the A/B, compared to A/A, KIR haplotypes. NKG2A(-)LIR1(-) NK cells expressing only those inhibitory KIRs for which the patient had no HLA class I ligands could be stimulated by HLA class I-deficient cells to express CD107a. Thus, NKG2A(-)LIR1(-) NK cells may be important GVL effector cells following HCT, even in patients transplanted from HLA-matched donors. PMID:20044012

  16. Proceedings: Human Leukocyte Antigen Haplo-Homozygous Induced Pluripotent Stem Cell Haplobank Modeled After the California Population: Evaluating Matching in a Multiethnic and Admixed Population

    PubMed Central

    Pappas, Derek James; Gourraud, Pierre-Antoine; Le Gall, Caroline; Laurent, Julie; Trounson, Alan; DeWitt, Natalie; Talib, Sohel

    2015-01-01

    Summary The development of a California-based induced pluripotent stem cell (iPSC) bank based on human leukocyte antigen (HLA) haplotype matching represents a significant challenge and a valuable opportunity for the advancement of regenerative medicine. However, previously published models of iPSC banks have neither addressed the admixed nature of populations like that of California nor evaluated the benefit to the population as a whole. We developed a new model for evaluating an iPSC haplobank based on demographic and immunogenetic characteristics reflecting California. The model evaluates haplolines or cell lines from donors homozygous for a single HLA-A, HLA-B, HLA-DRB1 haplotype. We generated estimates of the percentage of the population matched under various combinations of haplolines derived from six ancestries (black/African American, American Indian, Asian/Pacific Islander, Hispanic, and white/not Hispanic) and data available from the U.S. Census Bureau, the California Institute for Regenerative Medicine, and the National Marrow Donor Program. The model included both cis (haplotype-level) and trans (genotype-level) matching between a modeled iPSC haplobank and the recipient population following resampling simulations. We showed that serving a majority (>50%) of a simulated California population through cis matching would require the creation, redundant storage, and maintenance of almost 207 different haplolines representing the top 60 most frequent haplotypes from each ancestry group. Allowances for trans matching reduced the haplobank to fewer than 141 haplolines found among the top 40 most frequent haplotypes. Finally, we showed that a model optimized, custom haplobank was able to serve a majority of the California population with fewer than 80 haplolines. PMID:25926330

  17. HLA Type Inference via Haplotypes Identical by Descent

    NASA Astrophysics Data System (ADS)

    Setty, Manu N.; Gusev, Alexander; Pe'Er, Itsik

    The Human Leukocyte Antigen (HLA) genes play a major role in adaptive immune response and are used to differentiate self antigens from non self ones. HLA genes are hyper variable with nearly every locus harboring over a dozen alleles. This variation plays an important role in susceptibility to multiple autoimmune diseases and needs to be matched on for organ transplantation. Unfortunately, HLA typing by serological methods is time consuming and expensive compared to high throughput Single Nucleotide Polymorphism (SNP) data. We present a new computational method to infer per-locus HLA types using shared segments Identical By Descent (IBD), inferred from SNP genotype data. IBD information is modeled as graph where shared haplotypes are explored among clusters of individuals with known and unknown HLA types to identify the latter. We analyze performance of the method in a previously typed subset of the HapMap population, achieving accuracy of 96% in HLA-A, 94% in HLA-B, 95% in HLA-C, 77% in HLA-DR1, 93% in HLA-DQA1 and 90% in HLA-DQB1 genes. We compare our method to a tag SNP based approach and demonstrate higher sensitivity and specificity. Our method demonstrates the power of using shared haplotype segments for large-scale imputation at the HLA locus.

  18. Ethnic differences in HLA antigens in Chilean donors and recipients: data from the National Renal Transplantation Program.

    PubMed

    Droguett, M A; Beltran, R; Ardiles, R; Raddatz, N; Labraña, C; Arenas, A; Flores, J; Alruiz, P; Mezzano, S; Ardiles, L

    2008-11-01

    To describe HLA antigen distribution, looking for possible markers of renal disease in Mapuche and non-Mapuche people in the renal transplantation program, we reviewed data from 1297 histocompatibility studies of the Chilean national renal transplantation program (421 donors and 876 recipients), performed between 2000 and 2005. Mapuche people were classified according to their family surnames. The most frequent antigens found among the total Chilean population were A2 (48%), A19 (33%), B16 (33%), B35 (26%), DR4 (38%), and DR6 (28%), without significant differences between donors and recipients. Among the 114 individuals (9%) classified as Mapuche, the most frequent antigens were A28 (49%), A2 (44%), B16 (63%), B35 (24%), DR4 (48%), and DR8 (30%), with A28/B16/DR4 as the most common haplotype. In contrast, A28, B16, DR4, and DR8 were significantly more frequent in Mapuche compared with non-Mapuche people. B8 was significantly more frequent in Mapuche recipients than in non-Mapuche recipients and Mapuche donors. The higher frequency of some HLA antigens in Mapuche people was confirmed, possibly corresponding to ethnic markers. The special concentration of B8 among Mapuche recipients might represent a genetic factor predisposing to chronic renal disease in this human group. PMID:19010245

  19. Error rate for HLA-B antigen assignment by serology: implications for proficiency testing and utilization of DNA-based typing methods.

    PubMed

    Bozón, M V; Delgado, J C; Selvakumar, A; Clavijo, O P; Salazar, M; Ohashi, M; Alosco, S M; Russell, J; Yu, N; Dupont, B; Yunis, E J

    1997-10-01

    Until recently, the majority of HLA class I typing has been performed by serology. Expensive commercial typing trays are frequently used for testing non-Caucasian subjects and new strategies using DNA-based methods have been adopted for improving clinical histocompatibility testing results and adapted as supplements in proficiency testing. A double-blind comparison of the typing of HLA-B specificities in 40 samples was carried out between serology and two polymerase chain reaction (PCR) methods, PCR amplification with sequence-specific primers (PCR-SSP) and PCR amplification and subsequent hybridization with sequence-specific oligonucleotide probes (PCR-SSOP). The results demonstrated 22.5% misassignments of HLA-B antigens by serology. There was complete concordance between the results obtained with the two PCR based typing methods. A second panel of 20 donor samples with incomplete or ambiguous serologic results was analyzed by PCR-SSP and SSOP Both PCR methods identified correctly the HLA-B antigens. Our results suggest that more accurate typing results can be achieved by complementing serologic testing with DNA-based typing techniques. The level of resolution for HLA-B antigen assignment can be obtained by this combination of serology and limited DNA-based typing is equivalent to the HLA-B specificities defined by the WHO-HLA Committee. This level of resolution cannot routinely be achieved in clinical histocompatibility testing or in proficiency testing using serologic reagents only. PMID:9349624

  20. Down-regulation of human leukocyte antigen class I (HLA-I) is associated with poor prognosis in patients with clear cell renal cell carcinoma.

    PubMed

    Yuan, Jinyang; Liu, Sulai; Yu, Qiuxia; Lin, Yang; Bi, Yunke; Wang, Yi; An, Ruihua

    2013-06-01

    Human leukocyte antigen class I (HLA-I) molecules are transmembrane glycoproteins that have been reported to be down-regulated in multiple types of human malignancies, including clear cell renal cell carcinoma (CCRCC). However, only one study has investigated its prognostic value in CCRCC. In the present study, HLA-I protein expression was analyzed in 120 archived, paraffin-embedded CCRCC samples and 10 adjacent normal tissues using immunohistochemistry. The correlation between HLA-I expression and clinicopathological factors was evaluated by the χ(2) test. Patients' overall survival was analyzed by the Kaplan-Meier method. HLA-I down-regulation was observed in 38.3% (46/120) of renal tumor samples, but only in 10% (1/10) of adjacent normal tissues. Statistical analysis showed a significant correlation of HLA-I expression with TNM stage, lymph node metastasis, and Fuhrman grade. Patients with tumors displaying down-regulation of HLA-I showed significantly shorter overall survival (P=0.021, log-rank test). More importantly, multivariate analysis indicated that down-regulation of HLA-I was an independent prognostic factor for CCRCC patients (P=0.033). Overall, our data suggest that HLA-I down-regulation is associated with tumor progression and a poor prognosis in CCRCC patients, and emphasize the importance of HLA-I in natural and therapeutic immune surveillance of patients with CCRCC. PMID:23245688

  1. HLA-Ig Based Artificial Antigen Presenting Cells for Efficient ex vivo Expansion of Human CTL

    PubMed Central

    Chiu, Yen-Ling; Schneck, Jonathan P.; Oelke, Mathias

    2011-01-01

    CTL with optimal effector function play critical roles in mediating protection against various intracellular infections and cancer. However, individuals may exhibit suppressive immune microenvironment and, in contrast to activating CTL, their autologous antigen presenting cells may tend to tolerize or anergize antigen specific CTL. As a result, although still in the experimental phase, CTL-based adoptive immunotherapy has evolved to become a promising treatment for various diseases such as cancer and virus infections. In initial experiments ex vivo expanded CMV (cytomegalovirus) specific CTL have been used for treatment of CMV infection in immunocompromised allogeneic bone marrow transplant patients. While it is common to have life-threatening CMV viremia in these patients, none of the patients receiving expanded CTL develop CMV related illness, implying the anti-CMV immunity is established by the adoptively transferred CTL1. Promising results have also been observed for melanoma and may be extended to other types of cancer2. While there are many ways to ex vivo stimulate and expand human CTL, current approaches are restricted by the cost and technical limitations. For example, the current gold standard is based on the use of autologous DC. This requires each patient to donate a significant number of leukocytes and is also very expensive and laborious. Moreover, detailed in vitro characterization of DC expanded CTL has revealed that these have only suboptimal effector function 3. Here we present a highly efficient aAPC based system for ex vivo expansion of human CMV specific CTL for adoptive immunotherapy (Figure 1). The aAPC were made by coupling cell sized magnetic beads with human HLA-A2-Ig dimer and anti-CD28mAb4. Once aAPC are made, they can be loaded with various peptides of interest, and remain functional for months. In this report, aAPC were loaded with a dominant peptide from CMV, pp65 (NLVPMVATV). After culturing purified human CD8+ CTL from a healthy

  2. Suppression of blastogenesis and proliferation of activated CD4+ T cells: intravenous immunoglobulin (IVIg) versus novel anti-human leucocyte antigen (HLA)-E monoclonal antibodies mimicking HLA-I reactivity of IVIg

    PubMed Central

    Ravindranath, M H; Terasaki, P I; Pham, T; Jucaud, V; Kawakita, S

    2014-01-01

    Activated CD4+ T cells undergo blastogenesis and proliferation and they express several surface receptors, including β2-microglobulin-free human leucocyte antigen (HLA) heavy chains (open conformers). Intravenous immunoglobulin (IVIg) suppresses activated T cells, but the mechanism is unclear. IVIg reacts with HLA-Ia/Ib antigens but its reactivity is lost when the anti-HLA-E Ab is adsorbed out. Anti-HLA-E antibodies may bind to the peptides shared by HLA-E and the HLA-I alleles. These shared peptides are cryptic in intact HLA, but exposed in open conformers. The hypothesis that anti-HLA-E monoclonal antibodies (mAbs) that mimic HLA-I reactivity of IVIg may suppress activated T cells by binding to the shared peptides of the open conformers on the T cell surface was tested by examining the relative binding affinity of those mAbs for open conformers coated on regular beads and for intact HLA coated on iBeads, and by comparing the effects on the suppression of phytohaemagglutinin (PHA)-activated T cells of three entities: IVIg, anti-HLA-E mAbs that mimic IVIg [Terasaki Foundation Laboratory (TFL)-006 and (TFL)-007]; and anti-HLA-E antibodies that do not mimic IVIg (TFL-033 and TFL-037). Suppression of blastogenesis and proliferation of those T cells by both IVIg and the anti-HLA-E mAbs was dose-dependent, the dose required with mAbs 50–150-fold lower than with IVIg. TFL-006 and TFL-007 significantly suppressed blastogenesis and proliferation of activated CD4+ T cells, but neither the non-IVIg-mimicking mAbs nor control antibodies did so. The suppression may be mediated by Fab-binding of TFL-006/TFL-007 to the exposed shared peptides. The mAb binding to the open conformer may signal T cell deactivation because the open conformers have an elongated cytoplasmic tail with phosphorylation sites (tryosine320/serine335). PMID:24889882

  3. Haplotype analysis of HLA-A, -B antigens and -DRB1 alleles in south Indian HIV-1-infected patients with and without pulmonary tuberculosis.

    PubMed

    Raghavan, S; Selvaraj, P; Swaminathan, S; Alagarasu, K; Narendran, G; Narayanan, P R

    2009-06-01

    We have shown earlier the association of human leucocyte antigen (HLA)-A11 with resistance and HLA-B40 and -DR2 with susceptibility to HIV and HIV-TB. In the present study, we have attempted to find out the HLA-DR2 subtypes and the possible HLA-A/-B/-DRB1 haplotype combinations that are associated with susceptibility or resistance to HIV and HIV with pulmonary tuberculosis (HIV+PTB+). HLA-DR2 subtyping was carried out by polymerase chain reaction-based sequence-specific oligonucleotide probe method. Overrepresentation of HLA-DRB1*1501 in HIV-positive PTB-negative (HIV+PTB-) patients (P = 0.004, P(c) = 0.06) and -DRB1*1502 in HIV-positive PTB-positive (HIV+PTB+) patients (P = 0.019) was observed as compared to healthy controls. Haplotype analysis revealed an increased frequency of HLA-A2-DRB1*1501 haplotype in HIV+PTB- patients (P = 0.008) and HLA-A2-DRB1*1502 among HIV+PTB+ patients (P = 0.01) compared to healthy controls. The haplotypes B40-DRB1*1501 and B40-DRB1*04 were found to be moderately increased in HIV+PTB(-) and HIV+PTB+ patients (P < 0.05). The study suggests that HLA-A2-DRB1*1501 haplotype may be associated with HIV infection while HLA-A2-DRB1*1502 haplotype might be associated with susceptibility to PTB in HIV patients. Moreover, HLA-B40-DRB1*1501 and HLA-B40-DRB1*04 haplotypes may be associated with susceptibility to HIV infection and to PTB in HIV patients. PMID:19392836

  4. Interferon-beta downregulates expression of VLA-4 antigen and antagonizes interferon-gamma-induced expression of HLA-DQ on human peripheral blood monocytes.

    PubMed

    Soilu-Hänninen, M; Salmi, A; Salonen, R

    1995-07-01

    We have studied the effect of recombinant human IFN-beta on the basal and IFN-gamma-induced expression of adhesion molecules and class II MHC antigens on human peripheral blood monocytes and on ICAM-1 (intercellular adhesion molecule-1) expression of a human umbilical vein endothelial cell line (EAhy 926). We show that IFN-beta downregulates both basal and IFN-gamma-induced expression of VLA-4 (very late activation antigen-4) antigen on monocytes, but has no effect on the expression of CD11a, CD11b, CD11c, L-selectin, CD18, ICAM-1, beta 1-integrin or CD44 on monocytes or ICAM-1 on EAhy 926 cells. We also show that IFN-beta antagonizes the IFN-gamma-induced expression of HLA-DQ-antigen, but not HLA-DR or HLA-DP antigens on monocyte surface. These findings may partially explain the beneficial effect of IFN-beta in multiple sclerosis, since VLA-4-antigen is critical for leukocyte recruitment into inflamed brain and downregulation of HLA-class II expression diminishes antigen presenting capacity of monocytes. PMID:7642754

  5. Tissue typing for hematopoietic cell transplantation: newer techniques and newer antigens for which cross-matching is helpful.

    PubMed

    Iannone, Robert; Davies, Stella M

    2005-12-01

    Refinements in human leukocyte antigen (HLA) typing techniques for hematopoietic cell transplantation (HCT) have permitted a more precise assessment of donor-recipient histocompatibility, which has impacted transplantation outcomes. More recently, differences in transplant outcomes associated with killer immunoglobulin-like receptor compatibility have emphasized the potential importance of natural killer (NK) cell typing in HCT. This article reviews the current state of the art for HCT donor selection based on both HLA and NK cell typing. PMID:16305621

  6. Repertoire of HLA-DR1-Restricted CD4 T-Cell Responses to Capsular Caf1 Antigen of Yersinia pestis in Human Leukocyte Antigen Transgenic Mice▿

    PubMed Central

    Musson, Julie A.; Ingram, Rebecca; Durand, Guillaume; Ascough, Stephanie; Waters, Emma L.; Hartley, M. Gillian; Robson, Timothy; Maillere, Bernard; Williamson, E. Diane; Sriskandan, Shiranee; Altmann, Daniel; Robinson, John H.

    2010-01-01

    Yersinia pestis is the causative agent of plague, a rapidly fatal infectious disease that has not been eradicated worldwide. The capsular Caf1 protein of Y. pestis is a protective antigen under development as a recombinant vaccine. However, little is known about the specificity of human T-cell responses for Caf1. We characterized CD4 T-cell epitopes of Caf1 in “humanized” HLA-DR1 transgenic mice lacking endogenous major histocompatibility complex class II molecules. Mice were immunized with Caf1 or each of a complete set of overlapping synthetic peptides, and CD4 T-cell immunity was measured with respect to proliferative and gamma interferon T-cell responses and recognition by a panel of T-cell hybridomas, as well as direct determination of binding affinities of Caf1 peptides to purified HLA-DR molecules. Although a number of DR1-restricted epitopes were identified following Caf1 immunization, the response was biased toward a single immunodominant epitope near the C terminus of Caf1. In addition, potential promiscuous epitopes, including the immunodominant epitope, were identified by their ability to bind multiple common HLA alleles, with implications for the generation of multivalent vaccines against plague for use in humans. PMID:20660611

  7. Cell Surface Expression Level Variation between Two Common Human Leukocyte Antigen Alleles, HLA-A2 and HLA-B8, Is Dependent on the Structure of the C Terminal Part of the Alpha 2 and the Alpha 3 Domains

    PubMed Central

    Dellgren, Christoffer; Nehlin, Jan O.; Barington, Torben

    2015-01-01

    Constitutive cell surface expression of Human Leukocyte Antigen (HLA) class I antigens vary extremely from tissue to tissue and individual antigens may differ widely in expression levels. Down-regulation of class I expression is a known immune evasive mechanism used by cancer cells and viruses. Moreover, recent observations suggest that even minor differences in expression levels may influence the course of viral infections and the frequency of complications to stem cell transplantation. We have shown that some human multipotent stem cells have high expression of HLA-A while HLA-B is only weakly expressed, and demonstrate here that this is also the case for the human embryonic kidney cell line HEK293T. Using quantitative flow cytometry and quantitative polymerase chain reaction we found expression levels of endogenous HLA-A3 (median 71,204 molecules per cell) 9.2-fold higher than the expression of-B7 (P = 0.002). Transfection experiments with full-length HLA-A2 and -B8 encoding plasmids confirmed this (54,031 molecules per cell vs. 2,466, respectively, P = 0.001) independently of transcript levels suggesting a post-transcriptional regulation. Using chimeric constructs we found that the cytoplasmic tail and the transmembrane region had no impact on the differential cell surface expression. In contrast, ~65% of the difference could be mapped to the six C-terminal amino acids of the alpha 2 domain and the alpha 3 domain (amino acids 176–284), i.e. amino acids not previously shown to be of importance for differential expression levels of HLA class I molecules. We suggest that the differential cell surface expression of two common HLA-A and–B alleles is regulated by a post-translational mechanism that may involve hitherto unrecognized molecules. PMID:26258424

  8. Association of genetic polymorphism of HLA-DRB1 antigens with the susceptibility to lepromatous leprosy

    PubMed Central

    ESCAMILLA-TILCH, MONICA; TORRES-CARRILLO, NORA MAGDALENA; PAYAN, ROSALIO RAMOS; AGUILAR-MEDINA, MARIBEL; SALAZAR, MA ISABEL; FAFUTIS-MORRIS, MARY; ARENAS-GUZMAN, ROBERTO; ESTRADA-PARRA, SERGIO; ESTRADA-GARCIA, IRIS; GRANADOS, JULIO

    2013-01-01

    Despite the introduction of multidrug therapy and the overall reduction of leprosy prevalence in Mexico, the disease remains endemic in certain regions of the country. A genetic basis for the immune susceptibility to Mycobacterium leprae has already been established in different populations worldwide. In this study, we investigated the possible association of the HLA-DRB1 alleles with leprosy in a Mexican Mestizo population. The results demonstrated that the HLA-DRB1*01 allele is associated with lepromatous and dimorphic leprosy [P<0.001, odds ratio (OR)=4.6, 95% confidence interval (95% CI): 1.8–11.4; and P=0.03, OR=6.2, 95% CI: 1.1–31.6, respectively] and the frequency of the HLA-DRB1*08 allele was found to be significantly lower among leprosy patients compared to controls (P=0.046, OR=2.4, 95% CI: 1–5.8). In conclusion, although the association of the HLA-DR locus with leprosy has been established in different populations and several studies have demonstrated significant differences in the DR alleles, this study demonstrated an association of the HLA-DRB1*01 allele with susceptibility to lepromatous and dimorphic leprosy, as well as an association of the HLA-DRB1*08 allele with protection against leprosy in a Mexican Mestizo population. PMID:24649058

  9. Evaluation of Soluble Human Leukocyte Antigen-G (sHLA-G) Isoforms and Regulatory T Cells in Relapsing-Remitting Multiple Sclerosis.

    PubMed

    Alsahebfosoul, Fereshteh; Zavaran Hosseini, Ahmad; Salehi, Rasoul; Etemadifar, Masood; Esmaeil, Nafiseh; Jamshidian, Azam

    2015-06-01

    Soluble forms of nonclassical human leukocyte antigen (HLA)-G have recently been suggested as immunomodulatory factors in multiple sclerosis (MS). HLA-G inhibits the effecter function of T cells and natural killer (NK) cells. Also regulatory T cells (Treg) are considered as pivotal players in MS pathogenesis. Thus, we aimed to evaluate the presence of HLA-G molecules and Treg cells in Relapsing-Remitting Multiple Sclerosis (RRMS) patients and compare it to healthy controls. Patients with RRMS (n=205, mean age=31.32±8.53) and healthy subjects (n=205, mean age=32.2±7.48) were studied. The patients subgrouped to untreated and treated with Interferon beta. Then sHLA-G levels (sHLA-G1 and sHLA-G5) were measured using ELISA method. Treg (CD4+ CD25+ Foxp3+) cells in patients who had sHLA-G>10 U/ml were characterized by using flow cytometry. Our data showed that there was no significant differences between RRMS patients and healthy controls in sHLA-G concentration (p>0.05). Treg cell frequencies were higher in the patients who had sHLA-G >10 U/ml compared to healthy subjects (p<0.05). Collectively, there was significant correlation between sHLA-G and frequency of Treg cells in treated RRMS patients and healthy individuals. It seems that high level sHLA-G has been instrumental in raising frequency of Treg cells in treated patients and could be associated with remission of MS disease. PMID:26546899

  10. Virus-epitope vaccine design: informatic matching the HLA-I polymorphism to the virus genome.

    PubMed

    Vider-Shalit, Tal; Raffaeli, Shai; Louzoun, Yoram

    2007-02-01

    Attempts to develop peptide vaccines, based on a limited number of peptides face two problems: HLA polymorphism and the high mutation rate of viral epitopes. We have developed a new genomic method that ensures maximal coverage and thus maximal applicability of the peptide vaccine. The same method also promises a large number of epitopes per HLA to prevent escape via mutations. Our design can be applied swiftly in order to face rapidly emerging viral diseases. We use a genomic scan of all candidate peptides and join them optimally. For a given virus, we use algorithms computing: peptide cleavage probability, transfer through TAP and MHC binding for a large number of HLA alleles. The resulting peptide libraries are pruned for peptides that are not conserved or are too similar to self peptides. We then use a genetic algorithm to produce an optimal protein composed of peptides from this list properly ordered for cleavage. The selected peptides represent an optimal combination to cover all HLA alleles and all viral proteins. We have applied this method to HCV and found that some HCV proteins (mainly envelope proteins) represent much less peptide than expected. A more detailed analysis of the peptide variability shows a balance between the attempts of the immune system to detect less mutating peptides, and the attempts of viruses to mutate peptides and avoid detection by the immune system. In order to show the applicability of our method, we have further used it on HIV-I, Influenza H3N2 and the Avian Flu Viruses. PMID:16930710

  11. Hepatitis B virus core antigen epitopes presented by HLA-A2 single-chain trimers induce functional epitope-specific CD8+ T-cell responses in HLA-A2.1/Kb transgenic mice.

    PubMed

    Zhang, Yuxia; Li, Shu; Shan, Ming; Pan, Xuwen; Zhuang, Ke; He, Lihua; Gould, Keith; Tien, Po

    2007-05-01

    The potency of CD8+ cytotoxic T lymphocyte (CTL) responses toward core antigen has been shown to affect the outcomes of hepatitis B virus (HBV) infection. Since single-chain trimers (SCT) composed of peptide epitope beta2-microglobulin (beta2m) and major histocompatibility complex (MHC) class I heavy chain covalently linked together in a single molecule have been shown to stimulate efficient CTL responses, we investigated the properties of human leucocyte antigen (HLA)-A2 SCTs encoding the HBV core antigen (HBcAg) epitopes C(18-27) and C(107-115). Transfection of NIH-3T3 cells with pcDNA3.0-SCT-C(18-27) and SCT-C(107-115) leads to stable presentation of HBcAg epitopes at the cell surface. HLA-A2.1/Kb transgenic mice vaccinated with the SCT constructs, either as a DNA vaccine alone or followed by a boost with recombinant vaccinia virus, were shown to generate HBcAg-specific CTL responses by enzyme-linked immunospot assay (ELISPOT) and in vitro interferon-gamma release experiments. HBcAg-specific CTLs from vaccinated HLA-A2.1/Kb transgenic mice were able to inhibit HBV surface and e antigen expression as indicated by HepG2.2.15 cells. Our data indicate that a DNA vaccine encoding a human HLA-A2 SCT with HBV epitopes can lead to stable, enhanced HBV core antigen presentation, and may be useful for the control of HBV infection in HLA-A2-positive HBV carriers. PMID:17244158

  12. Human leukocyte antigens (HLA) associated with selective IgA deficiency in Iran and Sweden.

    PubMed

    Mohammadi, Javad; Pourpak, Zahra; Jarefors, Sara; Saghafi, Shiva; Zendehdel, Kazem; Pourfathollah, Ali Akbar; Amirzargar, Ali Akbar; Aghamohammadi, Asghar; Moin, Mostafa; Hammarstrom, Lennart

    2008-12-01

    Selective IgA deficiency (IgAD) (serum IgA concentration of <0.07 g/l) is the most common primary immunodeficiency in Caucasians, with an estimated prevalence of 1/600. There are strong indications for involvement of genetic factors in development of the disease and the frequency of several extended major histocompatibility complex haplotypes (including HLA-A1, B8, DR3, DQ2) have previously been shown to be increased among Caucasian patients with IgAD.PCR was used to type HLA B, DR, and DQ alleles in 29 Iranian individuals with IgAD and 299 Swedish individuals with IgAD.The results indicate a strong association with the HLA B14, DR1 alleles in Iranian subjects and HLA B8, B12, B13, B14, B40, DR1, DR3, DR7, DQ2 and DQ5 alleles in Swedish subjects.Differences in HLA association of IgAD in Iran and Sweden confirm the notion of a genetic background of the disease and that multiple, potentially different genes within the MHC region might be involved in the pathogenesis of IgAD in different ethnic groups. PMID:19052350

  13. Influence of human leukocyte antigen matching on liver allograft survival and rejection: "the dualistic effect".

    PubMed

    Donaldson, P; Underhill, J; Doherty, D; Hayllar, K; Calne, R; Tan, K C; O'Grady, J; Wight, D; Portmann, B; Williams, R

    1993-06-01

    To date only one published large series of human leukocyte antigen matching and liver allograft survival exists, and considerable confusion has arisen about the advantage or disadvantage of human leukocyte antigen matching. In the present study we have reinvestigated the relationship between human leukocyte antigen mismatch and graft survival in 466 first liver allografts, seeking to clarify the relationship between human leukocyte antigen and both acute rejection and the vanishing bile duct syndrome. In view of current criticism regarding the accuracy of serological tissue typing for human leukocyte antigen-DR, we have used both classic serology and restriction fragment length polymorphism analysis to ensure the accurate assignment of recipient DR types. In addition, we have used polymerase chain reaction amplification and allele-specific and sequence-specific oligonucleotide probes to retest the hypothesis that human leukocyte antigen class II matching may increase susceptibility to the vanishing bile duct syndrome. One-year graft survival was significantly lower in patients with zero or two human leukocyte antigen-A mismatches (52% and 63%, respectively) than in those with one human leukocyte antigen--A mismatch (69%) (p = 0.016 and p = 0.018). A similar effect of B mismatching was observed, with a 1-yr graft survival of 73% for those with one compared with 60% for those with two human leukocyte antigen-B mismatches. In contrast no correlation was found between DR mismatch and graft survival. Human leukocyte antigen class I matching appears to influence graft survival largely through the occurrence of acute rejection and the development of the vanishing bile duct syndrome.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:8514248

  14. Nonpermissive HLA-DPB1 mismatch increases mortality after myeloablative unrelated allogeneic hematopoietic cell transplantation

    PubMed Central

    Lee, Stephanie J.; Ahn, Kwang Woo; Spellman, Stephen; Wang, Hai-Lin; Aljurf, Mahmoud; Askar, Medhat; Dehn, Jason; Fernandez Viña, Marcelo; Gratwohl, Alois; Gupta, Vikas; Hanna, Rabi; Horowitz, Mary M.; Hurley, Carolyn K.; Inamoto, Yoshihiro; Kassim, Adetola A.; Nishihori, Taiga; Mueller, Carlheinz; Oudshoorn, Machteld; Petersdorf, Effie W.; Prasad, Vinod; Robinson, James; Saber, Wael; Schultz, Kirk R.; Shaw, Bronwen; Storek, Jan; Wood, William A.; Woolfrey, Ann E.; Anasetti, Claudio

    2014-01-01

    We examined current outcomes of unrelated donor allogeneic hematopoietic cell transplantation (HCT) to determine the clinical implications of donor-recipient HLA matching. Adult and pediatric patients who had first undergone myeloablative-unrelated bone marrow or peripheral blood HCT for acute myelogenous leukemia, acute lymphoblastic leukemia, chronic myelogenous leukemia, and myelodysplastic syndrome between 1999 and 2011 were included. All had high-resolution typing for HLA-A, -B, -C, and -DRB1. Of the total (n = 8003), cases were 8/8 (n = 5449), 7/8 (n = 2071), or 6/8 (n = 483) matched. HLA mismatch (6-7/8) conferred significantly increased risk for grades II to IV and III to IV acute graft vs host disease (GVHD), chronic GVHD, transplant-related mortality (TRM), and overall mortality compared with HLA-matched cases (8/8). Type (allele/antigen) and locus (HLA-A, -B, -C, and -DRB1) of mismatch were not associated with overall mortality. Among 8/8 matched cases, HLA-DPB1 and -DQB1 mismatch resulted in increased acute GVHD, and HLA-DPB1 mismatch had decreased relapse. Nonpermissive HLA-DPB1 allele mismatch was associated with higher TRM compared with permissive HLA-DPB1 mismatch or HLA-DPB1 match and increased overall mortality compared with permissive HLA-DPB1 mismatch in 8/8 (and 10/10) matched cases. Full matching at HLA-A, -B, -C, and -DRB1 is required for optimal unrelated donor HCT survival, and avoidance of nonpermissive HLA-DPB1 mismatches in otherwise HLA-matched pairs is indicated. PMID:25161269

  15. Meta-analysis of the human leukocyte antigen-G (HLA-G) 14 bp insertion/deletion polymorphism as a risk factor for preeclampsia.

    PubMed

    Pabalan, N; Jarjanazi, H; Sun, C; Iversen, A C

    2015-09-01

    The non-classical major histocompatibility complex, human leukocyte antigen (HLA)-G, plays an important role in pregnancy. HLA-G mediates proper interaction between maternal immune cells and fetal trophoblasts invading the uterine wall, to ensure successful placental development and function. Several HLA-G gene variants have been shown to be associated with development of preeclampsia (PE), but the reported associations of the HLA-G 14 base pair (bp) insertion/deletion (I/D) polymorphism (rs66554220) with PE are inconsistent. In this meta-analysis of HLA-G 14 bp I/D in each member of the family triad, we estimated risk (odds ratio [OR], 95% confidence interval) of associations with PE based on nine published offspring, nine mother and three father case-control studies. No significant increased risk associations between PE and HLA-G 14 bp I/D were detected in any of the family triad members (offspring: OR = 1.08-1.21, P = 0.57-0.74; mothers: OR = 1.11-1.28, P = 0.07-0.44; fathers: OR = 1.09-1.65, P = 0.07-0.70). Of the 20 comparisons performed, 14 (70%) were non-heterogeneous and seven of these had zero heterogeneity (I(2) = 0%). Sensitivity treatment confirmed robustness for the overall lack of association for HLA-G 14 bp I/D. In subgroup analysis, significant association between HLA-G 14 bp I/D and PE was shown in offspring from primipara (OR = 1.66-1.95, P = 0.04) and European Caucasian pregnancies (OR = 1.37-2.03, P = 0.02-0.03). However, heterogeneity and sensitivity tests suggest that further investigation is needed to determine if HLA-G 14 bp I/D is involved in trophoblast HLA-G expression and PE development in these subgroups. PMID:26202804

  16. Extended HLA-D region haplotype associated with celiac disease

    SciTech Connect

    Howell, M.D.; Smith, J.R.; Austin, R.K.; Kelleher, D.; Nepom, G.T.; Volk, B.; Kagnoff, M.F.

    1988-01-01

    Celiac disease has one of the strongest associations with HLA (human leukocyte antigen) class II markers of the known HLA-linked diseases. This association is primarily with the class II serologic specificities HLA-DR3 and -DQw2. The authors previously described a restriction fragment length polymorphism (RFLP) characterized by the presence of a 4.0-kilobase Rsa I fragment derived from an HLA class II ..beta..-chain gene, which distinguishes the class II HLA haplotype of celiac disease patients from those of many serologically matched controls. They now report the isolation of this ..beta..-chain gene from a bacteriophage genomic library constructed from the DNA of a celiac disease patient. Based on restriction mapping and differential hybridization with class II cDNA and oligonucleotide probes, this gene was identified as one encoding an HLA-DP ..beta..-chain. This celiac disease-associated HLA-DP ..beta..-chain gene was flanked by HLA-DP ..cap alpha..-chain genes and, therefore, was probably in its normal chromosomal location. The HLA-DP..cap alpha..-chain genes of celiac disease patients also were studied by RFLP analysis. Celiac disease is associated with a subset of HLA-DR3, -DQw2 haplotypes characterized by HLA-DP ..cap alpha..- and ..beta..-chain gene RFLPs. Within the celiac-disease patient population, the joint segregation of these HLA-DP genes with those encoding the serologic specificities HLA-DR3 and -DQw2 indicates: (i) that the class II HLA haplotype associated with celiac disease is extended throughout the entire HLA-D region, and (ii) that celiac-disease susceptibility genes may reside as far centromeric on this haplotype as the HLA-DP subregion.

  17. Posttransplantation cyclophosphamide for prevention of graft-versus-host disease after HLA-matched mobilized blood cell transplantation.

    PubMed

    Mielcarek, Marco; Furlong, Terry; O'Donnell, Paul V; Storer, Barry E; McCune, Jeannine S; Storb, Rainer; Carpenter, Paul A; Flowers, Mary E D; Appelbaum, Frederick R; Martin, Paul J

    2016-03-17

    The cumulative incidence of National Institutes of Health (NIH)-defined chronic graft-versus-host disease (GVHD) requiring systemic treatment is ∼35% at 1 year after transplantation of granulocyte colony-stimulating factor (G-CSF)-mobilized blood cells from HLA-matched related or unrelated donors. We hypothesized that high-dose cyclophosphamide given after G-CSF-mobilized blood cell transplantation would reduce the cumulative 1-year incidence of chronic GVHD to 15% or less. Forty-three patients with high-risk hematologic malignancies (median age, 43 years) were enrolled between December 2011 and September 2013. Twelve (28%) received grafts from related donors, and 31 (72%) received grafts from unrelated donors. Pretransplant conditioning consisted of fludarabine and targeted busulfan (n = 25) or total body irradiation (≥12 Gy; n = 18). Cyclophosphamide was given at 50 mg/kg per day on days 3 and 4 after transplantation, followed by cyclosporine starting on day 5. The cumulative 1-year incidence of NIH-defined chronic GVHD was 16% (95% confidence interval, 5-28%). The cumulative incidence estimates of grades 2-4 and 3-4 acute GVHD were 77% and 0%, respectively. At 2 years, the cumulative incidence estimates of nonrelapse mortality and recurrent malignancy were 14% and 17%, respectively, and overall survival was projected at 70%. Of the 42 patients followed for ≥1 year, 21 (50%) were relapse-free and alive without systemic immunosuppression at 1 year after transplantation. Thus, myeloablative pretransplant conditioning can be safely combined with high-dose cyclophosphamide after transplantation, and the risk of chronic GVHD associated with HLA-matched mobilized blood cell grafts can be substantially reduced. This trial was registered at www.clinicaltrials.gov as #NCT01427881. PMID:26764356

  18. HLA typing in congenital toxoplasmosis.

    PubMed Central

    Meenken, C; Rothova, A; de Waal, L P; van der Horst, A R; Mesman, B J; Kijlstra, A

    1995-01-01

    HLA-A, HLA-B, HLA-C, and HLA-D typing was performed in 47 mothers of patients suffering from ocular toxoplasmosis to investigate whether an immunogenetic predisposition exists for developing congenital toxoplasmosis in their offspring. No significant association between any HLA antigen was observed in the mothers of patients with ocular toxoplasmosis, although a total absence of the HLA-B51 antigen was found in this group. HLA-A, HLA-B, and HLA-C typing was also performed in their children (52 patients with ocular toxoplasmosis), to investigate a possible relation between the severity of ocular toxoplasmosis and an eventual immunogenetic factor. In the patients with ocular toxoplasmosis an increased frequency of the HLA-Bw62 antigen was observed in correlation with severe ocular involvement. PMID:7612565

  19. Perivascular infiltration in normal skin of patients with rheumatoid arthritis: association with rheumatoid factors and HLA-DR antigens.

    PubMed Central

    Bernelot Moens, H J; Ament, H J; Vroom, T M; Feltkamp, T E; van der Korst, J K

    1988-01-01

    The relation between immunohistological findings in biopsy specimens of apparently normal skin, HLA antigens, and rheumatoid factors (RF) was studied in 120 patients with rheumatoid arthritis (RA), selected for treatment with D-penicillamine. Perivascular infiltration (PVI) of more than three mononuclear cells was present in 77 (68%) of 114 patients, accompanied usually by the presence of IgM or C3, or both, in immunofluorescence studies. The number of perivascular cells was associated significantly with the titre of circulating RF. A weak relation of both perivascular cellular infiltration and RF with HLA-DR3 and DR4 did not reach statistical significance. It is concluded that the histological presence of perivascular inflammation is associated mainly with deposition of RF. It is suggested that the first is merely an epiphenomenon of the latter. PVI was not prognostic for the occurrence of the clinical syndrome of rheumatoid vasculitis. For practical purposes skin biopsies do not appear to be useful in the evaluation of individual patients with RA. PMID:3058055

  20. HLA Haplotypes and Genotypes Frequencies in Brazilian Chronic Periodontitis Patients

    PubMed Central

    Sippert, Emília Ângela; Silva, Cléverson de Oliveira e; Ayo, Christiane Maria; Marques, Silvia Barbosa Dutra; Visentainer, Jeane Eliete Laguila; Sell, Ana Maria

    2015-01-01

    Human leukocyte antigens (HLA) have a pivotal role in immune response and may be involved in antigen recognition of periodontal pathogens. However, the associations of HLA with chronic periodontitis (CP) have not been previously studied in the Brazilian population. In an attempt to clarify the issue of genetic predisposition to CP, we examined the distribution of HLA alleles, genotypes, and haplotypes in patients from Southern Brazil. One hundred and eight CP patients and 151 healthy and unrelated controls with age-, gender-, and ethnicity-matched were HLA investigated by polymerase chain reaction with sequence specific oligonucleotides. To exclude smoking as a predisposing factor, statistical analyses were performed in the total sample and in nonsmoking individuals. The significant results showed a positive association of the A∗02/HLA-B∗40 haplotype with CP (total samples: 4.2% versus 0%, Pc = 0.03; nonsmokers: 4.3% versus 0%, Pc = 0.23) and a lower frequency of HLA-B∗15/HLA-DRB1∗11 haplotype in CP compared to controls (total samples: 0.0% versus 4.3%, Pc = 0.04; nonsmokers: 0 versus 5.1%, Pc = 1.0). In conclusion, the HLA-A∗02/B∗40 haplotype may contribute to the development of CP, while HLA-B∗15/DRB1∗11 haplotype might indicate resistance to disease among Brazilians. PMID:26339134

  1. Disruption of HLA class II antigen presentation in Burkitt lymphoma: implication of a 47 000 MW acid labile protein in CD4+ T-cell recognition

    PubMed Central

    God, Jason M; Zhao, Dan; Cameron, Christine A; Amria, Shereen; Bethard, Jennifer R; Haque, Azizul

    2014-01-01

    While Burkitt lymphoma (BL) has a well-known defect in HLA class I-mediated antigen presentation, the exact role of BL-associated HLA class II in generating a poor CD4+ T-cell response remains unresolved. Here, we found that BL cells are deficient in their ability to optimally stimulate CD4+ T cells via the HLA class II pathway. This defect in CD4+ T-cell recognition was not associated with low levels of co-stimulatory molecules on BL cells, as addition of external co-stimulation failed to elicit CD4+ T-cell activation by BL. Further, the defect was not caused by faulty antigen/class II interaction, because antigenic peptides bound with measurable affinity to BL-associated class II molecules. Interestingly, functional class II–peptide complexes were formed at acidic pH 5·5, which restored immune recognition. Acidic buffer (pH 5·5) eluate from BL cells contained molecules that impaired class II-mediated antigen presentation and CD4+ T-cell recognition. Biochemical analysis showed that these molecules were greater than 30 000 molecular weight in size, and proteinaceous in nature. In addition, BL was found to have decreased expression of a 47 000 molecular weight enolase-like molecule that enhances class II-mediated antigen presentation in B cells, macrophages and dendritic cells, but not in BL cells. These findings demonstrate that BL likely has multiple defects in HLA class II-mediated antigen presentation and immune recognition, which may be exploited for future immunotherapies. PMID:24628049

  2. X-ray diffraction analysis of crystals from the human major histocompatibility antigen HLA-B*2706 in complex with a viral peptide and with a self-peptide

    SciTech Connect

    Zawacka, Anna; Loll, Bernhard; Biesiadka, Jacek; Saenger, Wolfram

    2005-12-01

    The crystallization of HLA-B*2706 in complex with two peptides is reported. The human leukocyte antigen (HLA) alleles HLA-B*2704 and HLA-B*2706 show an ethnically restricted distribution and are differentially associated with ankylosing spondylitis, with HLA-B*2706 lacking association with this autoimmune disease. However, the products of the two alleles differ by only two amino acids, at heavy-chain residues 114 (His in HLA-B*2704; Asp in HLA-B*2706) and 116 (Asp in HLA-B*2704; Tyr in HLA-B*2706). Both residues could be involved in contacting amino acids of a bound peptide, suggesting that peptides presented by these subtypes play a role in disease pathogenesis. Two HLA-B*2706–peptide complexes were crystallized using the hanging-drop vapour-diffusion method with PEG as precipitant. Data sets were collected to resolutions of 2.70 Å (viral peptide pLMP2, RRRWRRLTV; space group P2{sub 1}2{sub 1}2{sub 1}) and 1.83 Å (self-peptide pVIPR, RRKWRRWHL; space group P2{sub 1}). Using HLA-B*2705 complexed with the pGR peptide (RRRWHRWRL) as a search model, unambiguous molecular-replacement solutions were found for both HLA-B*2706 complexes.

  3. Reversible HLA multimers (Streptamers) for the isolation of human cytotoxic T lymphocytes functionally active against tumor- and virus-derived antigens.

    PubMed

    Neudorfer, Julia; Schmidt, Burkhard; Huster, Katharina M; Anderl, Florian; Schiemann, Matthias; Holzapfel, Gerd; Schmidt, Thomas; Germeroth, Lothar; Wagner, Hermann; Peschel, Christian; Busch, Dirk H; Bernhard, Helga

    2007-03-30

    The development of MHC/peptide multimers has facilitated the visualization and purification of antigen-specific T cells. However, the persistence of multimers leads to prolonged T cell receptor signaling and subsequently to altered T-cell function. We have recently developed a new type of MHC/peptide multimers, which can be dissociated from the T cell. Herein, we have generated and tested for the first time reversible HLA/peptide multimers, termed Streptamers, for the isolation of human T cells. The Streptamer technique demonstrates the specificity and sensitivity of conventional HLA/peptide tetramers with regards to the sorting of human T lymphocytes. This is shown for T cells directed against immunogenic peptides derived from viral and tumor-associated antigens. We show that antigen-specific cytotoxic T cells remain functionally active following Streptamer dissociation, whereas lytic function and proliferation of the T cells is impaired in the presence of conventional tetramers. These novel HLA/peptide Streptamer reagents allow the isolation of antigen-specific T cells with preserved function and, therefore, facilitate the development of adoptive T cell transfer regimens for the treatment of patients with cancer or infectious diseases. PMID:17306825

  4. Molecular definition of a polymorphic antigen (LA45) of free HLA-A and -B heavy chains found on the surfaces of activated B and T cells.

    PubMed

    Madrigal, J A; Belich, M P; Benjamin, R J; Little, A M; Hildebrand, W H; Mann, D L; Parham, P

    1991-11-01

    A monomoprhic monoclonal antibody (LA45 antibody) reactive with "a new activation-induced surface structure on human T lymphocytes" (LA45 antigen) that resembled free class I heavy chains has recently been described (Schnabl, E., H. Stockinger, O. Majdic, H. Gaugitsch, I.J.D. Lindley, D. Maurer, A. Hajek-Rosenmayr, and W. Knapp. 1990. J. Exp. Med. 171:1431). This antibody was used to clone a class I-like heavy chain (LA45 gene) from the HUT 102 tumor cell, which paradoxically did not give rise to the LA45 antigen on transfection into monkey COS cells. We show here that the LA45 gene is HLA-Aw66.2, a previously uncharacterized allele of the HLA-A locus. The previously determined LA45 sequence differs from that of HLA-Aw66.2, from HUT 102, and the CR-B B cell line derived from the same individual as HUT 102 by substitution of tryptophan for serine at position 4 in the alpha 1 domain. Transfection of HLA-Aw66.2, and of a mutant of this gene with serine 4 substituted for tryptophan, into a human B cell line (C1R) both resulted in expression of the LA45 epitope. Furthermore, we find expression of the LA45 epitope on Epstein Barr virus-transformed B cell lines as well as lectin-activated T cells, but not on long-term T cell lines or unstimulated peripheral blood T cells. The specificity of the LA45 antibody is polymorphic and the presence of the LA45 epitope is precisely correlated with the sequence arginine, asparagine (RN) at residues 62 and 63 of the helix of the alpha 1 domain. The LA45 epitope is broadly distributed, being associated with half the alleles of both HLA-A and -B loci but none of the HLA-C locus. All the results are consistent with the presence of pools of free HLA-A and -B heavy chains at the surfaces of certain cell types but not others. Such molecules are probably responsible for the HLA-associated class I alloantigens of lectin-activated T cells. We hypothesize the free heavy chains result from dissociation of beta 2-microglobulin from

  5. Endoplasmic reticulum aminopeptidase-1 alleles associated with increased risk of Ankylosing Spondylitis reduce HLA-B27 mediated presentation of multiple antigens

    PubMed Central

    Seregin, Sergey S.; Rastall, David P.W.; Evnouchidou, Irini; Aylsworth, Charles F.; Quiroga, Dionisia; Kamal, Ram P.; Godbehere-Roosa, Sarah; Blum, Christopher F.; York, Ian A.; Stratikos, Efstratios; Amalfitano, Andrea

    2014-01-01

    Ankylosing spondylitis (AS) is a chronic systemic arthritic disease that leads to significant disability and loss of quality of life in the ~0.5% of the worldwide human population it affects. There is currently no cure for AS and mechanisms underlying its pathogenesis remain unclear. AS is highly genetic, with over 70% of the genetic risk being associated with the presence of HLA-B27 and endoplasmic reticulum aminopeptidase-1 (ERAP1) alleles. Furthermore, gene-gene interactions between HLA-B27 and ERAP1 AS risk alleles have recently been confirmed. Here, we demonstrate that various ERAP1 alleles can differentially mediate surface expression of antigens presented by HLA-B27 on human cells. Specifically, for all peptides tested, we found that an ERAP1 variant containing high AS risk SNPs reduced the amount of the peptide presented by HLA-B27, relative to low AS risk ERAP1 variants. These results were further validated using peptide catalysis assays in vitro, suggesting that high AS risk alleles have an enhanced catalytic activity that more rapidly destroys many HLA-B27-destined peptides, a result that correlated with decreased HLA-B27 presentation of the same peptides. These findings suggest that one mechanism underlying AS pathogenesis may involve an altered ability for AS patients harboring both HLA-B27 and high AS risk ERAP1 alleles to correctly display a variety of peptides to the adaptive arm of the immune system, potentially exposing such individuals to higher AS risk due to abnormal display of pathogen or self derived peptides by the adaptive immune system. PMID:24028501

  6. Endoplasmic reticulum aminopeptidase-1 alleles associated with increased risk of ankylosing spondylitis reduce HLA-B27 mediated presentation of multiple antigens.

    PubMed

    Seregin, Sergey S; Rastall, David P W; Evnouchidou, Irini; Aylsworth, Charles F; Quiroga, Dionisia; Kamal, Ram P; Godbehere-Roosa, Sarah; Blum, Christopher F; York, Ian A; Stratikos, Efstratios; Amalfitano, Andrea

    2013-12-01

    Ankylosing spondylitis (AS) is a chronic systemic arthritic disease that leads to significant disability and loss of quality of life in the ∼0.5% of the worldwide human population it affects. There is currently no cure for AS and mechanisms underlying its pathogenesis remain unclear. AS is highly genetic, with over 70% of the genetic risk being associated with the presence of HLA-B27 and endoplasmic reticulum aminopeptidase-1 (ERAP1) alleles. Furthermore, gene-gene interactions between HLA-B27 and ERAP1 AS risk alleles have recently been confirmed. Here, we demonstrate that various ERAP1 alleles can differentially mediate surface expression of antigens presented by HLA-B27 on human cells. Specifically, for all peptides tested, we found that an ERAP1 variant containing high AS risk SNPs reduced the amount of the peptide presented by HLA-B27, relative to low AS risk ERAP1 variants. These results were further validated using peptide catalysis assays in vitro, suggesting that high AS risk alleles have an enhanced catalytic activity that more rapidly destroys many HLA-B27-destined peptides, a result that correlated with decreased HLA-B27 presentation of the same peptides. These findings suggest that one mechanism underlying AS pathogenesis may involve an altered ability for AS patients harboring both HLA-B27 and high AS risk ERAP1 alleles to correctly display a variety of peptides to the adaptive arm of the immune system, potentially exposing such individuals to higher AS risk due to abnormal display of pathogen or self-derived peptides by the adaptive immune system. PMID:24028501

  7. Significance of the differences in the prevalence of anti-HLA antibodies in matched pairs of mother's and cord blood.

    PubMed

    Ravindranath, Mepur H; Jucaud, Vadim; Maehara, Curtis Y; Terasaki, Paul I

    2016-02-01

    The presence of IgG against pathogens in the cord blood (CB) of vaccinated mothers is attributed to transplacental transfer. However, previous studies using lymphocytotoxicity assay showed anti-HLA IgG in mother's blood (MB) but not in CB, perhaps due to non-transfer of anti-HLA IgG or assay limitations in detecting anti-HLA IgG. Anti-HLA IgG of native and purified sera of 16 MB and CB pairs were measured using an array of microbeads coated with HLA-I/-II molecules on a Luminex platform. Two cases showed no anti-HLA-I IgG in either MB or CB; four MB cases displayed polyallelic HLA-reactive IgG, with negligible or no reactivity by the corresponding CB sera. Notably, anti-HLA-I reactivity in cases 3-6/11/12 and anti-HLA-II reactivity in cases 1/3/4/6/8/11-13 were restricted to CB, with lower or no HLA-reactivity in MB. Mothers' HLA typing is done for HLA-A*, HLA-B* and DRB1* alleles. The mother in case 14 carried DRB1*11:01, the allele-reactive IgG is seen in both native and the purified fraction of sera of MB but not in CB. Also in cases 15 (DRB1*01:01) and 16 (B*49:01 and DBR1*07:01), the allele-reactive IgGs are seen in both native and purified fractions of MB but not in CB confirming the earlier reports on the absence of materno-fetal transfer of anti-HLA IgG. However, the mother of case 6 is homozygous for DRB1*03:01 and the allele-reactive IgG occurred in both MB and CB, confirming the presence of anti-HLA autoantibodies. In Case 13, the mother (HLA-A*24 and HLA-A*52) and CB carried allele-reactive IgG in both native and purified sera, indicating the possible occurrence of transplacental transfer of the IgG. Further confirmation is restricted by the paucity of detailed molecular HLA typing for both the parents and fetuses. While 37.5% of the native IgG in CB and 18.8% in MB showed DRB3*03:01 reactivity, 100% of purified IgG from both CB and MB showed anti-DRB3*03:01 and anti-DPA1*02:01\\ DPB1*23:01 antibodies. Several CB cases showed high-prevalence Ig

  8. X-ray diffraction analysis of crystals from the human major histocompatibility antigen HLA-B*2706 in complex with a viral peptide and with a self-peptide.

    PubMed

    Zawacka, Anna; Loll, Bernhard; Biesiadka, Jacek; Saenger, Wolfram; Uchanska-Ziegler, Barbara; Ziegler, Andreas

    2005-12-01

    The human leukocyte antigen (HLA) alleles HLA-B*2704 and HLA-B*2706 show an ethnically restricted distribution and are differentially associated with ankylosing spondylitis, with HLA-B*2706 lacking association with this autoimmune disease. However, the products of the two alleles differ by only two amino acids, at heavy-chain residues 114 (His in HLA-B*2704; Asp in HLA-B*2706) and 116 (Asp in HLA-B*2704; Tyr in HLA-B*2706). Both residues could be involved in contacting amino acids of a bound peptide, suggesting that peptides presented by these subtypes play a role in disease pathogenesis. Two HLA-B*2706-peptide complexes were crystallized using the hanging-drop vapour-diffusion method with PEG as precipitant. Data sets were collected to resolutions of 2.70 A (viral peptide pLMP2, RRRWRRLTV; space group P2(1)2(1)2(1)) and 1.83 A (self-peptide pVIPR, RRKWRRWHL; space group P2(1)). Using HLA-B*2705 complexed with the pGR peptide (RRRWHRWRL) as a search model, unambiguous molecular-replacement solutions were found for both HLA-B*2706 complexes. PMID:16511245

  9. RISK FACTORS AFFECTING OUTCOME OF SECOND HLA-MATCHED SIBLING DONOR TRANSPLANTS FOR GRAFT FAILURE IN SEVERE ACQUIRED APLASTIC ANEMIA

    PubMed Central

    Horan, John T.; Carreras, Jeanette; Tarima, Sergey; Camitta, Bruce M.; Gale, Robert Peter; Hale, Gregory A.; Hinterberger, Wolfgang; Marsh, Judith; Passweg, Jakob R.; Walters, Mark C.; Eapen, Mary

    2009-01-01

    We examined transplant outcomes after second HLA-matched sibling transplants for primary (16%) and secondary (84%) graft failure in 166 patients with severe acquired aplastic anemia. Performance scores were < 90 in 67% of patients. Most (88%) transplantations used the same donor for both transplants and 84% of second transplants used bone marrow graft. We identified two prognostic factors: inter-transplant interval (surrogate for primary graft failure and early secondary graft failure) and performance status. Shorter inter-transplant interval (≤3 months) and poor performance score (<90) at second transplantation were associated with high mortality. The 8-year probabilities of overall survival when second transplantation was ≤ 3 and > 3 months from first transplant in patients with performance scores of 90–100% were 56% and 76%, respectively. Corresponding probabilities in patients with lower performance scores were 33% and 61%. The predominant cause of failure after second transplantation was non-engraftment (72 of 166 patients) and frequent in patients with primary or early secondary graft failure (51 of 72; 71%). Therefore, novel approaches including conditioning regimens with greater immunosuppression should be explored for these patients. PMID:19361755

  10. Determination of an unrelated donor pool size for human leukocyte antigen-matched platelets in Brazil

    PubMed Central

    Bub, Carolina Bonet; Torres, Margareth Afonso; Moraes, Maria Elisa; Hamerschlak, Nelson; Kutner, José Mauro

    2015-01-01

    Background Successful transfusion of platelet refractory patients is a challenge. Many potential donors are needed to sustain human leukocyte antigen matched-platelet transfusion programs because of the different types of antigens and the constant needs of these patients. For a highly mixed population such as the Brazilian population, the pool size required to provide adequate platelet support is unknown. Methods A mathematical model was created to estimate the appropriate size of an unrelated donor pool to provide human leukocyte antigen-compatible platelet support for a Brazilian population. A group of 154 hematologic human leukocyte antigen-typed patients was used as the potential patient population and a database of 65,500 human leukocyte antigen-typed bone marrow registered donors was used as the donor population. Platelet compatibility was based on the grading system of Duquesnoy. Results Using the mathematical model, a pool containing 31,940, 1710 and 321 donors would be necessary to match more than 80% of the patients with at least five completely compatible (no cross-reactive group), partial compatible (one cross-reactive group) or less compatible (two cross-reactive group) donors, respectively. Conclusion The phenotypic diversity of the Brazilian population has probably made it more difficulty to find completely compatible donors. However, this heterogeneity seems to have facilitated finding donors when cross-reactive groups are accepted as proposed by the grading system of Duquesnoy. The results of this study may help to establish unrelated human leukocyte antigen-compatible platelet transfusions, a procedure not routinely performed in most Brazilian transfusion services. PMID:26969768

  11. HLA-Identical Sibling Compared With 8/8 Matched and Mismatched Unrelated Donor Bone Marrow Transplant for Chronic Phase Chronic Myeloid Leukemia

    PubMed Central

    Arora, Mukta; Weisdorf, Daniel J.; Spellman, Stephen R.; Haagenson, Michael D.; Klein, John P.; Hurley, Carolyn K.; Selby, George B.; Antin, Joseph H.; Kernan, Nancy A.; Kollman, Craig; Nademanee, Auayporn; McGlave, Philip; Horowitz, Mary M.; Petersdorf, Effie W.

    2009-01-01

    Purpose Transplantation of hematopoietic stem cells from an unrelated donor (URD) is an option for many patients who do not have an HLA-identical sibling donor (MSD). Current criteria for the selection of URDs include consideration for HLA alleles determined by high resolution typing methods, with preference for allele-matched donors. However, the utility and outcome associated with transplants from URDs compared with those from MSDs remains undefined. Patients and Methods We examined clinical outcome after patients received bone marrow transplants (BMTs) from MSDs; HLA-A, -B, -C, and DRB1 allele-matched URDs (8/8); and HLA-mismatched URDs in a homogeneous population of patients with chronic myeloid leukemia (CML) in first chronic phase (CP1) where a strong allogeneic effect and hence a lower risk of relapse is anticipated. Transplantation outcomes were compared between 1,052 URD and 3,514 MSD BMT recipients with CML in CP1. Results Five-year overall survival and leukemia-free survival (LFS) after receipt of BMTs from 8/8 matched URDs were worse than those after receipt of BMTs from MSDs (5-year survival, 55% v 63%; RR, 1.35; 95% CI, 1.17 to 1.56; P < .001; LFS, 50% v 55%; RR, 1.21; 95% CI, 1.06 to 1.40; P = .006). Survival was progressively worse with greater degrees of mismatch. Similar and low risk of relapse were observed after receipt of transplant from either MSD or URD. Conclusion In this homogeneous cohort of good risk patients with CML in CP1, 5-year overall survival and LFS after receipt of transplant from 8/8 allele-matched donors were modestly though significantly worse than those after receipt of transplant from MSDs. Additive adverse effects of multilocus mismatching are not well tolerated and should be avoided if possible. PMID:19224849

  12. A Gambian TNF haplotype matches the European HLA-A1,B8,DR3 and Chinese HLA-A33,B58,DR3 haplotypes.

    PubMed

    Price, P; Bolitho, P; Jaye, A; Glasson, M; Yindom, L-M; Sirugo, G; Chase, D; McDermid, J; Whittle, H

    2003-07-01

    Caucasians carry TNFA-308*2 in the 8.1 ancestral haplotype (AH) (HLA-A1,B8,DR3). In Gambians, TNFA-308*2 occurs without HLA-B8 or -DR3, suggesting an independent effect of TNFA-308 on disease. Hence we sought a segment of the 8.1 AH in Gambians. BAT1 (intron 10)*2 was selected as a specific marker of the haplotype and was found with TNFA-308*2 in Gambians. Samples homozygous at TNFA-308 and BAT1 (intron 10) demonstrated identity between the African TNFA-308*2 haplotype, the 8.1AH and the Asian diabetogenic 58.1AH (HLA-A33,B58,DR3) across a region spanning BAT1, ATP6G, IKBL, LTA, TNFA, LTB, LST-1 and AIF-1. Conservation of this block in geographically distinct populations suggests a common evolutionary origin and challenges current views of the role of TNFA-308*2 in disease. PMID:12859597

  13. Genetic editing of HLA expression in hematopoietic stem cells to broaden their human application

    PubMed Central

    Torikai, Hiroki; Mi, Tiejuan; Gragert, Loren; Maiers, Martin; Najjar, Amer; Ang, Sonny; Maiti, Sourindra; Dai, Jianliang; Switzer, Kirsten C.; Huls, Helen; Dulay, Gladys P.; Reik, Andreas; Rebar, Edward J.; Holmes, Michael C.; Gregory, Philip D.; Champlin, Richard E.; Shpall, Elizabeth J.; Cooper, Laurence J. N.

    2016-01-01

    Mismatch of human leukocyte antigens (HLA) adversely impacts the outcome of patients after allogeneic hematopoietic stem-cell transplantation (alloHSCT). This translates into the clinical requirement to timely identify suitable HLA-matched donors which in turn curtails the chances of recipients, especially those from a racial minority, to successfully undergo alloHSCT. We thus sought to broaden the existing pool of registered unrelated donors based on analysis that eliminating the expression of the HLA-A increases the chance for finding a donor matched at HLA-B, -C, and -DRB1 regardless of a patient’s race. Elimination of HLA-A expression in HSC was achieved using artificial zinc finger nucleases designed to target HLA-A alleles. Significantly, these engineered HSCs maintain their ability to engraft and reconstitute hematopoiesis in immunocompromised mice. This introduced loss of HLA-A expression decreases the need to recruit large number of donors to match with potential recipients and has particular importance for patients whose HLA repertoire is under-represented in the current donor pool. Furthermore, the genetic engineering of stem cells provides a translational approach to HLA-match a limited number of third-party donors with a wide number of recipients. PMID:26902653

  14. HLA-E: A Novel Player for Histocompatibility

    PubMed Central

    Kraemer, Thomas; Blasczyk, Rainer; Bade-Doeding, Christina

    2014-01-01

    The classical class I human leukocyte antigens (HLA-A, -B, and -C) present allele-specific self- or pathogenic peptides originated by intracellular processing to CD8+ immune effector cells. Even a single mismatch in the heavy chain (hc) of an HLA class I molecule can impact on the peptide binding profile. Since HLA class I molecules are highly polymorphic and most of their polymorphisms affect the peptide binding region (PBR), it becomes obvious that systematic HLA matching is crucial in determining the outcome of transplantation. The opposite holds true for the nonclassical HLA class I molecule HLA-E. HLA-E polymorphism is restricted to two functional versions and is thought to present a limited set of highly conserved peptides derived from class I leader sequences. However, HLA-E appears to be a ligand for the innate and adaptive immune system, where the immunological response to peptide-HLA-E complexes is dictated through the sequence of the bound peptide. Structural investigations clearly demonstrate how subtle amino acid differences impact the strength and response of the cognate CD94/NKG2 or T cell receptor. PMID:25401109

  15. IL-6 down-regulates HLA class II expression and IL-12 production of human dendritic cells to impair activation of antigen-specific CD4(+) T cells.

    PubMed

    Ohno, Yosuke; Kitamura, Hidemitsu; Takahashi, Norihiko; Ohtake, Junya; Kaneumi, Shun; Sumida, Kentaro; Homma, Shigenori; Kawamura, Hideki; Minagawa, Nozomi; Shibasaki, Susumu; Taketomi, Akinobu

    2016-02-01

    Immunosuppression in tumor microenvironments critically affects the success of cancer immunotherapy. Here, we focused on the role of interleukin (IL)-6/signal transducer and activator of transcription (STAT3) signaling cascade in immune regulation by human dendritic cells (DCs). IL-6-conditioned monocyte-derived DCs (MoDCs) impaired the presenting ability of cancer-related antigens. Interferon (IFN)-γ production attenuated by CD4(+) T cells co-cultured with IL-6-conditioned MoDCs corresponded with decreased DC IL-12p70 production. Human leukocyte antigen (HLA)-DR and CD86 expression was significantly reduced in CD11b(+)CD11c(+) cells obtained from peripheral blood mononuclear cells (PBMCs) of healthy donors by IL-6 treatment and was STAT3 dependent. Arginase-1 (ARG1), lysosomal protease, cathepsin L (CTSL), and cyclooxygenase-2 (COX2) were involved in the reduction of surface HLA-DR expression. Gene expressions of ARG1, CTSL, COX2, and IL6 were higher in tumor-infiltrating CD11b(+)CD11c(+) cells compared with PBMCs isolated from colorectal cancer patients. Expression of surface HLA-DR and CD86 on CD11b(+)CD11c(+) cells was down-regulated, and T cell-stimulating ability was attenuated compared with PBMCs, suggesting that an immunosuppressive phenotype might be induced by IL-6, ARG1, CTSL, and COX2 in tumor sites of colorectal cancer patients. There was a relationship between HLA-DR expression levels in tumor tissues and the size of CD4(+) T and CD8(+) T cell compartments. Our findings indicate that IL-6 causes a dysfunction in human DCs that activates cancer antigen-specific Th cells, suggesting that blocking the IL-6/STAT3 signaling pathway might be a promising strategy to improve cancer immunotherapy. PMID:26759006

  16. Artificial antigen-presenting cells expressing HLA class II molecules as an effective tool for amplifying human specific memory CD4(+) T cells.

    PubMed

    Garnier, Anthony; Hamieh, Mohamad; Drouet, Aurélie; Leprince, Jérôme; Vivien, Denis; Frébourg, Thierry; Le Mauff, Brigitte; Latouche, Jean-Baptiste; Toutirais, Olivier

    2016-08-01

    Owing to their multiple immune functions, CD4(+) T cells are of major interest for immunotherapy in chronic viral infections and cancer, as well as for severe autoimmune diseases and transplantation. Therefore, standardized methods allowing rapid generation of a large number of CD4(+) T cells for adoptive immunotherapy are still awaited. We constructed stable artificial antigen-presenting cells (AAPCs) derived from mouse fibroblasts. They were genetically modified to express human leukocyte antigen (HLA)-DR molecules and the human accessory molecules B7.1, Intercellular adhesion molecule-1 (ICAM-1) and lymphocyte function-associated antigen-3 (LFA-3). AAPCs expressing HLA-DR1, HLA-DR15 or HLA-DR51 molecules and loaded with peptides derived from influenza hemagglutinin (HA), myelin basic protein (MBP) or factor VIII, respectively, activated specific CD4(+) T-cell clones more effectively than Epstein-Barr virus (EBV)-transformed B cells. We also showed that AAPCs were able to take up and process whole Ag proteins, and present epitopes to specific T cells. In primary cultures, AAPCs loaded with HA peptide allowed generation of specific Th1 lymphocytes from healthy donors as demonstrated by tetramer and intracellular cytokine staining. Although AAPCs were less effective than autologous peripheral blood mononuclear cells (PBMCs) to stimulate CD4(+) T cells in primary culture, AAPCs were more potent to reactivate and expand memory Th1 cells in a strictly Ag-dependent manner. As the availability of autologous APCs is limited, the AAPC system represents a stable and reliable tool to achieve clinically relevant numbers of CD4(+) T cells for adoptive immunotherapy. For fundamental research in immunology, AAPCs are also useful to decipher mechanisms involved in the development of human CD4 T-cell responses. PMID:26924643

  17. Lack of HLA class I antigen expression by melanoma cells SK-MEL-33 caused by a reading frameshift in beta 2-microglobulin messenger RNA.

    PubMed Central

    Wang, Z; Cao, Y; Albino, A P; Zeff, R A; Houghton, A; Ferrone, S

    1993-01-01

    The lack of HLA class I antigen expression by the melanoma cell line SK-MEL-33 is caused by a unique lesion in beta 2-microglobulin (beta 2-mu). Sequencing of beta 2-mu mRNA detected a guanosine deletion at position 323 in codon 76 that causes a frameshift with a subsequent introduction of a stop codon at a position 54 base upstream of the normal position of the stop codon in the message. The loss of 18 amino acids and the change of 6 amino acids, including a cysteine at position 80 in the carboxy terminus of beta 2-mu, are likely to cause marked changes in the structure of the polypeptide. The latter may account for the inability of beta 2-mu to associate with HLA class I heavy chains and for its lack of reactivity with the anti-beta 2-mu mAb tested. HLA class I antigen expression on SK-MEL-33 cells was reconstituted after transfection with a wild-type B2m gene, therefore indicating that the abnormality of endogenous B2m gene is the only mechanism underlying lack of HLA class I antigen expression by SK-MEL-33 cells. The guanosine deletion in B2m gene was detected also in the melanoma tissue from which SK-MEL-33 cells had originated. Therefore, the molecular lesion identified in the SK-MEL-33 melanoma cell line is not caused by a mutation acquired during growth in vitro but is likely to reflect a somatic mutation during tumor progression. Images PMID:8432869

  18. Modern approaches to HLA-haploidentical blood or marrow transplantation

    PubMed Central

    Kanakry, Christopher G.; Fuchs, Ephraim J.; Luznik, Leo

    2015-01-01

    Allogeneic blood or bone-marrow transplantation (alloBMT) is a potentially curative treatment for a variety of haematological malignancies and nonmalignant diseases. Historically, human leukocyte antigen (HLA)-matched siblings have been the preferred source of donor cells owing to superior outcomes compared with alloBMT using other donors. Although only approximately one-third of patients have an HLA-matched sibling, nearly all patients have HLA-haploidentical related donors. Early studies using HLA-haploidentical alloBMT resulted in unacceptably high rates of graft rejection and graft-versus-host disease (GVHD), leading to high nonrelapse mortality and consequently poor survival. Several novel approaches to HLA-haploidentical alloBMT have yielded encouraging results with high rates of successful engraftment, effective GVHD control and favourable outcomes. In fact, outcomes of several retrospective comparative studies seem similar to those seen using other allograft sources, including those of HLA-matched-sibling alloBMT. In this Review, we provide an overview of the three most-developed approaches to HLA-haploidentical alloBMT: T-cell depletion with ‘megadose’ CD34+ cells; granulocyte colony-stimulating factor-primed allografts combined with intensive pharmacological immunosuppression, including antithymocyte globulin; and high-dose, post-transplantation cyclophosphamide. We review the preclinical and biological data supporting each approach, results from major clinical studies, and completed or ongoing clinical studies comparing these approaches with other alloBMT platforms. PMID:26305035

  19. Race/ethnicity affects the probability of finding an HLA-A, -B, -C and -DRB1 allele-matched unrelated donor and likelihood of subsequent transplant utilization

    PubMed Central

    Pidala, J; Kim, J; Schell, M; Lee, SJ; Hillgruber, R; Nye, V; Ayala, E; Alsina, M; Betts, B; Bookout, R; Fernandez, HF; Field, T; Locke, FL; Nishihori, T; Ochoa, JL; Perez, L; Perkins, J; Shapiro, J; Tate, C; Tomblyn, M; Anasetti, C

    2015-01-01

    Factors relevant to finding a suitable unrelated donor and barriers to effective transplant utilization are incompletely understood. Among a consecutive series of unrelated searches (n = 531), an 8/8 HLA-A, -B, -C and -DRB1-matched unrelated donor was available for 289 (54%) patients, 7/8 for 159 (30%) and no donor for 83 (16%). Patients of Caucasian race (P < 0.0001) were more likely to find a donor. Younger age (P = 0.01), Caucasian race (P = 0.03), lower CIBMTR (Center for International Blood and Marrow Transplantation Research) risk (P = 0.005), and 8/8 HLA matching (P = 0.005) were associated with higher odds of reaching hematopoietic cell transplantation (HCT). In a univariate analysis of OS, finding a donor was associated with hazard ratio (HR) of 0.85 (95% CI 0.63–1.2), P = 0.31. Karnofsky performance status (KPS) accounted for interaction between having a donor and survival. Patients with KPS 90–100 and a donor had significantly reduced hazard for death (HR 0.59, 95% CI 0.38–0.90, P = 0.02). These data provide estimates of the probability to find an unrelated donor in the era of high-resolution HLA typing, and identify potentially modifiable barriers to reaching HCT. Further efforts are needed to enhance effective donor identification and transplant utilization, particularly in non-Caucasian ethnic groups. PMID:22863723

  20. Functional polymorphism of each of the two HLA-DR beta chain loci demonstrated with antigen-specific DR3- and DRw52-restricted T cell clones

    PubMed Central

    1988-01-01

    HLA-DR3- and HLA-DRw52-associated functional polymorphism was investigated with selected tetanus toxoid (TT)-specific T cell clones. We have shown earlier that HLA-DR antigens are encoded by two distinct loci, DR beta I and DR beta III. The alloantigenic determinant(s) defined by the serological HLA-DR3 specificity map to the former, while the supratypic HLA-DRw52 determinants map to DR beta III. Furthermore, we have recently recognized by DNA sequencing three alleles of HLA- DRw52 at locus DR beta III, referred to as 52 a, b, and c. Our objective was to correlate the pattern of T cell restriction with the gene products of individual DR beta chain loci and with the three newly described alleles of locus DR beta III. Among the selected T cell clones, 5 reacted exclusively when TT was presented by HLA-DR3+ APCs (TT-DR3-APC). In contrast, two T cell clones were stimulated by TT- DRw52-APC. More specifically, these two T cell clones (Clones 10 and 16) were stimulated by different subsets of TT-DRw52-APC. Clone 16 responded to some DR3 and TT-DRw6-APC, while clone 10 was stimulated by other TT-DR3 and TT-DRw6, and all TT-DR5-APC. This same pattern of DRw52 restriction was found in panel, as well as in family studies. Because this suggested a correlation with the pattern of DRw52 polymorphism observed earlier by DNA sequencing and oligonucleotide hybridization, the APC used in these experiments were typed for the 52 a, b, and c alleles of locus DR beta III by allele-specific oligonucleotide probes. This distribution overlapped exactly with the stimulation pattern defined by the T cell clones. Clone 16 responded to TT-52a-APC, clone 10 to TT-52b-APC, and both clones to a TT-52c-APC. The response of the T cell clones was inhibited differentially by mAbs to DR. Raising TT concentration, or increasing HLA-class II expression with INF-gamma both affected the magnitude of response of the TT- specific clones but did not modify their specificities. These results demonstrate that

  1. Up-regulation of HLA class-I antigen expression and antigen-specific CTL response in cervical cancer cells by the demethylating agent hydralazine and the histone deacetylase inhibitor valproic acid

    PubMed Central

    Mora-García, María de Lourdes; Duenas-González, Alfonso; Hernández-Montes, Jorge; De la Cruz-Hernández, Erick; Pérez-Cárdenas, Enrique; Weiss-Steider, Benny; Santiago-Osorio, Edelmiro; Ortíz-Navarrete, Vianney Francisco; Rosales, Víctor Hugo; Cantú, David; Lizano-Soberón, Marcela; Rojo-Aguilar, Martha Patricia; Monroy-García, Alberto

    2006-01-01

    Background DNA hypermethylation and histone deacetylation are epigenetic events that contribute to the absence or downregulated expression of different components of the tumor recognition complex. These events affect the processing and presentation of antigenic peptides to CTLs by HLA class-I molecules. In this work evaluated the effect of the DNA hypomethylating agent hydralazine and the histone deacetylase inhibitor valproic acid, on the expression of HLA class-I molecules and on the antigen-specific immune recognition of cervical cancer cells. Methods Cell lines C33A (HPV-), CaSki (HPV-16+) and MS751 (HPV-18+) were treated with hydralazine and valproic acid to assess the expression of HLA class-I molecules by flow cytometry and RT-PCR. Promoter methylation of HLA class-I -A, -B and C, was also evaluated by Methylation-Specific PCR. Primary cervical tumors of four HLA-A*0201 allele patients were typed for HPV and their CTL's stimulated in vitro with the T2 cell line previously loaded with 50 μM of the HPV peptides. Cytotoxicity of stimulated CTL's was assayed against Caski and MS751 cells pre-treated with hydralazine and valproic acid. Results Valproic acid and hydralazine/valproic acid up-regulated the constitutive HLA class-I expression as evaluated by flow cytometry and RT-PCR despite constitutive promoter demethylation at these loci. Hydralazine and valproic acid in combination but no IFN-gamma hyperacetylated histone H4 as evaluated by ChiP assay. The antigenic immune recognition of CaSki and MS751 cells by CTLs specific to HPV-16/18 E6 and E7-derived epitopes, was increased by VA and H/VA and the combination of H/VA/IFN-gamma. Conclusion These results support the potential use of hydralazine and valproic acid as an adjuvant for immune intervention in cervical cancer patients whenever clinical protocols based on tumor antigen recognition is desirable, like in those cases where the application of E6 and E7 based therapeutic vaccines is used. PMID:17192185

  2. The T210M Substitution in the HLA-a*02:01 gp100 Epitope Strongly Affects Overall Proteasomal Cleavage Site Usage and Antigen Processing.

    PubMed

    Textoris-Taube, Kathrin; Keller, Christin; Liepe, Juliane; Henklein, Petra; Sidney, John; Sette, Alessandro; Kloetzel, Peter M; Mishto, Michele

    2015-12-18

    MHC class I-restricted epitopes, which carry a tumor-specific mutation resulting in improved MHC binding affinity, are preferred T cell receptor targets in innovative adoptive T cell therapies. However, T cell therapy requires efficient generation of the selected epitope. How such mutations may affect proteasome-mediated antigen processing has so far not been studied. Therefore, we analyzed by in vitro experiments the effect on antigen processing and recognition of a T210M exchange, which previously had been introduced into the melanoma gp100209-217 tumor epitope to improve the HLA-A*02:01 binding and its immunogenicity. A quantitative analysis of the main steps of antigen processing shows that the T210M exchange affects proteasomal cleavage site usage within the mutgp100201-230 polypeptide, leading to the generation of an unique set of cleavage products. The T210M substitution qualitatively affects the proteasome-catalyzed generation of spliced and non-spliced peptides predicted to bind HLA-A or -B complexes. The T210M substitution also induces an enhanced production of the mutgp100209-217 epitope and its N-terminally extended peptides. The T210M exchange revealed no effect on ERAP1-mediated N-terminal trimming of the precursor peptides. However, mutant N-terminally extended peptides exhibited significantly increased HLA-A*02:01 binding affinity and elicited CD8(+) T cell stimulation in vitro similar to the wtgp100209-217 epitope. Thus, our experiments demonstrate that amino acid exchanges within an epitope can result in the generation of an altered peptide pool with new antigenic peptides and in a wider CD8(+) T cell response also towards N-terminally extended versions of the minimal epitope. PMID:26507656

  3. Recurrent acute hemolytic transfusion reactions by antibodies against Doa antigens, not detected by cross-matching.

    PubMed

    Baumgarten, Ruben; van Gelder, Warry; van Wintershoven, Joyce; Maaskant-Van Wijk, Petra A; Beckers, Erik A M

    2006-02-01

    An 81-year-old male patient suffered from recurrent acute hemolytic transfusion reactions after transfusion with phenotyped cross-match-negative red blood cells (RBCs). Extensive posttransfusion workup eventually revealed Dombrock (a) (Do(a)) antibodies. Because commercially available cell panels do not allow for identification of anti-Do(a) and owing to the lack of Do(a) typing serum samples, selection of matched units of RBCs is dependent on negative cross-match results. In this case, selection of Do(a-) units by cross-matching failed, indicating that serologic methods were not reliable. A polymerase chain reaction with sequence-specific priming assay was used to detect DOA and DOB alleles, which encode Do(a) and Do(b) antigens, respectively. The patient was confirmed to be DOB/DOB by DNA sequencing. Furthermore, the involved mismatched units in each of the three hemolytic episodes were shown to be Do(a+). In the presenting case, DNA typing appeared to be superior to serologic methods in selecting matched RBC units in the presence of anti-Do(a). PMID:16441602

  4. High-resolution structure of HLA-A*0201 in complex with a tumour-specific antigenic peptide encoded by the MAGE-A4 gene.

    PubMed

    Hillig, R C; Coulie, P G; Stroobant, V; Saenger, W; Ziegler, A; Hülsmeyer, M

    2001-07-27

    The heterotrimeric complex of the human major histocompatibity complex (MHC) molecule HLA-A*0201, beta2-microglobulin and the decameric peptide GVYDGREHTV derived from the melanoma antigen (MAGE-A4 protein has been determined by X-ray crystallography at 1.4 A resolution. MAGE-A4 belongs to a family of genes that are specifically expressed in a variety of tumours. MAGE-A4-derived peptides are presented by MHC molecules at the cell surface to cytotoxic T-lymphocytes. As the HLA-A*0201:MAGE-A4 complex occurs only on tumour cells, it is considered to be an appropriate target for immunotherapy. The structure presented here reveals potential epitopes specific to the complex and indicates which peptide residues could be recognised by T-cell receptors. In addition, as the structure could be refined anisotropically, it was possible to describe the movements of the bound peptide in more detail. PMID:11502003

  5. The serodominant secreted effector protein of Salmonella, SseB, is a strong CD4 antigen containing an immunodominant epitope presented by diverse HLA class II alleles

    PubMed Central

    Reynolds, Catherine J; Jones, Claire; Blohmke, Christoph J; Darton, Thomas C; Goudet, Amelie; Sergeant, Ruhena; Maillere, Bernard; Pollard, Andrew J; Altmann, Daniel M; Boyton, Rosemary J

    2014-01-01

    Detailed characterization of the protective T-cell response in salmonellosis is a pressing unmet need in light of the global burden of human Salmonella infections and the likely contribution of CD4 T cells to immunity against this intracellular infection. In previous studies screening patient sera against antigen arrays, SseB was noteworthy as a serodominant target of adaptive immunity, inducing significantly raised antibody responses in HIV-seronegative compared with seropositive patients. SseB is a secreted protein, part of the Espa superfamily, localized to the bacterial surface and forming part of the translocon of the type III secretion system (T3SS) encoded by Salmonella pathogenicity island 2. We demonstrate here that SseB is also a target of CD4 T-cell immunity, generating a substantial response after experimental infection in human volunteers, with around 0·1% of the peripheral repertoire responding to it. HLA-DR/peptide binding studies indicate that this protein encompasses a number of peptides with ability to bind to several different HLA-DR alleles. Of these, peptide 11 (p11) was shown in priming of both HLA-DR1 and HLA-DR4 transgenic mice to contain an immunodominant CD4 epitope. Analysis of responses in human donors showed immunity focused on p11 and another epitope in peptide 2. The high frequency of SseB-reactive CD4 T cells and the broad applicability to diverse HLA genotypes coupled with previous observations of serodominance and protective vaccination in mouse challenge experiments, make SseB a plausible candidate for next-generation Salmonella vaccines. PMID:24891088

  6. Expression, purification and preliminary X-ray crystallographic analysis of the human major histocompatibility antigen HLA-B*1402 in complex with a viral peptide and with a self-peptide

    SciTech Connect

    Kumar, Pravin; Vahedi-Faridi, Ardeschir; Volz, Armin; Ziegler, Andreas; Saenger, Wolfram

    2007-07-01

    The crystallization of HLA-B*1402 in complex with two peptides is reported. The product of the human major histocompatibility (HLA) class I allele HLA-B*1402 only differs from that of allele HLA-B*1403 at amino-acid position 156 of the heavy chain (Leu in HLA-B*1402 and Arg in HLA-B*1403). However, both subtypes are known to be differentially associated with the inflammatory rheumatic disease ankylosing spondylitis (AS) in black populations in Cameroon and Togo. HLA-B*1402 is not associated with AS, in contrast to HLA-B*1403, which is associated with this disease in the Togolese population. The products of these alleles can present peptides with Arg at position 2, a feature shared by a small group of other HLA-B antigens, including HLA-B*2705, the prototypical AS-associated subtype. Complexes of HLA-B*1402 with a viral peptide (RRRWRRLTV, termed pLMP2) and a self-peptide (IRAAPPPLF, termed pCatA) were prepared and were crystallized using polyethylene glycol as precipitant. The complexes crystallized in space groups P2{sub 1} (pLMP2) and P2{sub 1}2{sub 1}2{sub 1} (pCatA) and diffracted synchrotron radiation to 2.55 and 1.86 Å resolution, respectively. Unambiguous solutions for both data sets were obtained by molecular replacement using a peptide-complexed HLA-B*2705 molecule (PDB code) as a search model.

  7. Outcomes of HLA Matched Sibling Donor Hematopoietic Cell Transplantation in Chronic Lymphocytic Leukemia: Myeloablative vs. Reduced-Intensity Conditioning Regimens

    PubMed Central

    Sobecks, Ronald M.; Leis, Jose F.; Gale, Robert Peter; Ahn, Kwang Woo; Zhu, Xiaochun; Sabloff, Mitchell; de Lima, Marcos; Brown, Jennifer R.; Inamoto, Yoshihiro; Hale, Gregory A.; Aljurf, Mahmoud D.; Kamble, Rammurti T.; Hsu, Jack W.; Pavletic, Steven Z.; Wirk, Baldeep; Seftel, Matthew D.; Lewis, Ian D.; Alyea, Edwin P.; Cortes, Jorge; Kalaycio, Matt E.; Maziarz, Richard T.; Saber, Wael

    2014-01-01

    Purpose Allogeneic hematopoietic cell transplantation (HCT) can cure some chronic lymphocytic leukemia (CLL) subjects. This study compared outcomes of myeloablative (MA) and reduced-intensity conditioning (RIC) transplants from HLA-matched sibling donors (MSD) for CLL. Patients and Methods From 1995–2007 there were 297 CLL subjects reported to the CIBMTR who received MA (N=163) and RIC (N=134) MSD HCT. The MA subjects were less often transplanted after 2000 and less commonly received anti-thymocyte globulin (4% vs. 13%, p=0.004) or prior antibody therapy (14% vs. 53%; p<0.001). Results RIC was associated with a greater likelihood of platelet recovery and less grade 2–4 acute GvHD compared to MA conditioning. 1 and 5-year treatment related mortality (TRM) were 24% (95% confidence intervals (CI), 16–33%) vs. 37% (95% CI, 30–45%; p=0.023), and 40% (95% CI, 29–51%) vs. 54% (95% CI, 46–62%; p=0.036), and the relapse/progression rates were 21% (95% CI, 14–29%) vs. 10% (95% CI, 6–15%; p=0.020), and 35% (95% CI, 26–46%) vs. 17% (95% CI, 12–24%; p=0.003). MA conditioning was associated with better progression-free (PFS) (relative risk (RR) 0.60; 95% CI, 0.37–0.97, p=0.038) and 3-year survival in transplants before 2001, but for subsequent years RIC was associated with better PFS and survival (RR 1.49 (95% CI, 0.92–2.42), p=0.10; and RR 1.86 (95% CI, 1.11–3.13), p=0.019). Pre-transplant disease status was the most important predictor of relapse (p=0.003) and PFS (p=0.0007) for both forms of transplant conditioning. Conclusion MA and RIC MSD transplants are effective for CLL. Future strategies to decrease TRM and reduce relapses are warranted. PMID:24880021

  8. Human Leukocyte Antigen (HLA) A*1101-restricted Epstein-Barr Virus-specific T-cell Receptor Gene Transfer to Target Nasopharyngeal Carcinoma

    PubMed Central

    Zheng, Yong; Parsonage, Greg; Zhuang, Xiaodong; Machado, Lee R; James, Christine H.; Salman, Asmaa; Searle, Peter F.; Hui, Edwin P.; Chan, Anthony T.C.; Lee, Steven P.

    2015-01-01

    Infusing virus-specific T cells is effective treatment for rare Epstein-Barr virus (EBV)-associated post-transplant lymphomas and more limited success has been reported using this approach to treat a far more common EBV-associated malignancy, nasopharyngeal carcinoma (NPC). However, current approaches using EBV-transformed lymphoblastoid cell lines to reactivate EBV-specific T cells for infusion take 2 to 3 months of in vitro culture and favour outgrowth of T cells targeting viral antigens expressed within EBV+ lymphomas but not in NPC. Here we explore T-cell receptor (TCR) gene transfer to rapidly and reliably generate T cells specific for the NPC-associated viral protein LMP2. We cloned a HLA A*1101-restricted TCR, which would be widely applicable since 40% of NPC patients carry this HLA allele. Studying both the wild-type and modified forms we have optimised expression of the TCR and demonstrated high avidity antigen-specific function (proliferation, cytotoxicity, cytokine release) in both CD8+ and CD4+ T cells. The engineered T cells also inhibited LMP2+ epithelial tumour growth in a mouse model. Furthermore, transduced T cells from patients with advanced NPC lysed LMP2-expressing NPC cell lines. Using this approach, within a few days large numbers of high avidity LMP2-specific T cells can be generated reliably to treat NPC, thus providing an ideal clinical setting to test TCR gene transfer without the risk of autoimmunity through targeting self-antigens. PMID:25711537

  9. Translation and assembly of HLA-DR antigens in Xenopus oocytes injected with mRNA from a human B-cell line.

    PubMed Central

    Long, E O; Gross, N; Wake, C T; Mach, J P; Carrel, S; Accolla, R; Mach, B

    1982-01-01

    HLA-DR antigens are polymorphic cell surface glycoproteins, expressed primarily in B lymphocytes and macrophages, which are thought to play an important role in the immune response. Two polypeptide chains, alpha and beta, are associated at the cell surface, and a third chain associates with alpha and beta intracellularly. RNA isolated from the human B-cell line Raji was injected in Xenopus laevis oocytes. Immunoprecipitates of translation products with several monoclonal antibodies revealed the presence of HLA-DR antigens similar to those synthesized in Raji cells. One monoclonal antibody was able to bind the beta chain after dissociation of the three polypeptide chains with detergent. The presence of all three chains was confirmed by two-dimensional gel electrophoresis. The glycosylation pattern of the three chains was identical to that observed in vivo, as evidenced in studies using tunicamycin, an inhibitor of N-linked glycosylation. The presence of alpha chains assembled with beta chains in equimolar ratio was further demonstrated by amino-terminal sequencing. An RNA fraction enriched for the three mRNAs, encoding alpha, beta, and intracellular chains, was isolated. This translation-assembly system and the availability of monoclonal antibodies make it possible to assay for mRNA encoding specific molecules among the multiple human Ia-like antigens. Images Fig. 1. Fig. 2. Fig. 3. Fig. 4. Fig. 5. PMID:6821356

  10. Promoter methylation and mRNA expression of HLA-G in relation to HLA-G protein expression in colorectal cancer.

    PubMed

    Swets, Marloes; Seneby, Lina; Boot, Arnoud; van Wezel, Tom; Gelderblom, Hans; van de Velde, Cornelis J H; van den Elsen, Peter J; Kuppen, Peter J K

    2016-09-01

    Expression of human leukocyte antigen-G (HLA-G) is a suggested mechanism used by tumor cells to escape from host immune recognition and destruction. Advances in the field have made it evident that HLA-G is expressed in different types of malignancies including colorectal cancer (CRC). We analyzed HLA-G expression in 21 low passage CRC cell lines. The level of DNA methylation of the HLA-G gene and the presence of mRNA encoding HLA-G was measured. Moreover, HLA-G protein expression was determined by flow cytometry and immunohistochemistry (IHC). IHC was performed with three different monoclonal antibodies (mAbs) (4H84, MEM-G/1 and MEM-G/2). In addition, HLA-G protein expression was measured in matching primary tumor tissues. RNA analysis using RT-PCR followed by sequencing in 6 samples indicated strong homology of the PCR product with HLA-G3 in 5 samples. In accordance, in none of the cell lines, HLA-G1 expression was detected by flow-cytometry. Furthermore, no association between HLA-G DNA methylation patterns and HLA-G mRNA expression was observed. In addition, different immunohistochemical staining profiles among various anti-HLA-G mAbs were observed. In conclusion, the results of this study show that the HLA-G3 isoform was expressed in some of the CRC cell lines irrespective of the level of DNA methylation of HLA-G. PMID:27245757

  11. Human peptide transporter deficiency: importance of HLA-B in the presentation of TAP-independent EBV antigens.

    PubMed

    de la Salle, H; Houssaint, E; Peyrat, M A; Arnold, D; Salamero, J; Pinczon, D; Stevanovic, S; Bausinger, H; Fricker, D; Gomard, E; Biddison, W; Lehner, P; UytdeHaag, F; Sasportes, M; Donato, L; Rammensee, H G; Cazenave, J P; Hanau, D; Tongio, M M; Bonneville, M

    1997-05-15

    Two siblings with a peptide TAP deficiency were recently described. Despite poor cell surface expression of HLA class I molecules, these patients were not unusually susceptible to viral infections. The majority of the cell surface-expressed class I molecules were HLA-B products as assessed by cytofluorometry and biochemical analysis. Analysis of two peptides eluted from the class I molecules expressed by TAP-deficient EBV B lymphoblastoid cell lines indicated that both were derived from cytosolic proteins and presented by HLA-B molecules. Peripheral alphabeta CD8+ T cells were present and their TCR repertoire was polyclonal. Most of the alphabeta CD8+ T cell clones studied (21 of 22) were nonreactive against cells expressing normal levels of the same HLA alleles as those of the TAP-deficient patients. However, it was possible to isolate one cytotoxic CD8+ alphabeta T cell clone recognizing the EBV protein LMP2 presented by HLA-B molecules on TAP-deficient cells. These observations suggest that in the TAP-deficient patients, CD8+ alphabeta T cells could mature and be recruited in immune responses to mediate HLA class I-restricted cytotoxic defense against viral infections. They also strengthen the physiologic importance of a TAP-independent processing pathway of the LMP2 protein, which was previously shown to contain several other TAP-independent epitopes. PMID:9144467

  12. Cyclosporin A and tissue antigen matching in bone transplantation. Fibular allografts studied in the dog.

    PubMed

    Welter, J F; Shaffer, J W; Stevenson, S; Davy, D T; Field, G A; Klein, L; Li, X Q; Zika, J M; Goldberg, V M

    1990-12-01

    We studied the mechanical, metabolic, and histologic properties of short-term nonvascularized cortical bone grafts in a canine fibular graft model. Sham operated nonvascularized autotransplanted and allotransplanted bones were compared. The allografts were performed between dog leukocyte antigen (DLA) class I and II matched; DLA class I and II mismatched; and cyclosporin A (CsA) treated, DLA class I and II mismatched animals. Cyclosporin was given for 1 month, and all the animals were followed for 3 months after surgery. Mechanical properties were investigated using standard torsional tests, metabolic kinetics were assessed using isotopic prelabeling techniques, and histomorphometric analysis of cross-sectional area properties and sequential fluorochrome labels were performed. Autografts were mechanically stronger and stiffer than all the types of allograft. CsA-treated, DLA-mismatched allografts performed better than matched allografts. These in turn were stronger than non-CsA-treated, mismatched allografts, which underwent nearly complete resorption. These relationships were preserved in the metabolic and histologic analyses. In this short-term animal study, although DLA matching resulted in a slight improvement in graft outcome, mismatched grafts in dogs receiving a short course of cyclosporin A fared even better. PMID:2281759

  13. Graft-versus-Host Disease after HLA-Matched Sibling Bone Marrow or Peripheral Blood Stem Cell Transplantation: Comparison of North American Caucasian and Japanese Populations.

    PubMed

    Kanda, Junya; Brazauskas, Ruta; Hu, Zhen-Huan; Kuwatsuka, Yachiyo; Nagafuji, Koji; Kanamori, Heiwa; Kanda, Yoshinobu; Miyamura, Koichi; Murata, Makoto; Fukuda, Takahiro; Sakamaki, Hisashi; Kimura, Fumihiko; Seo, Sachiko; Aljurf, Mahmoud; Yoshimi, Ayami; Milone, Giuseppe; Wood, William A; Ustun, Celalettin; Hashimi, Shahrukh; Pasquini, Marcelo; Bonfim, Carmem; Dalal, Jignesh; Hahn, Theresa; Atsuta, Yoshiko; Saber, Wael

    2016-04-01

    The risk of acute graft-versus-host disease (GVHD) after HLA-matched sibling bone marrow transplantation (BMT) is lower in Japanese than in Caucasian patients. However, race may have differential effect on GVHD dependent on the graft source. North American Caucasian and Japanese patients receiving their first allogeneic BMT or peripheral blood stem cell transplantation from an HLA-matched sibling for leukemia were eligible. BMT was performed in 13% of the Caucasian patients and in 53% of the Japanese patients. On multivariate analysis, the interaction term between race and graft source was not significant in any of the models, indicating that graft source does not affect the impact of race on outcomes. The risk of grade III or IV acute GVHD was significantly lower in the Japanese patients compared with the Caucasian patients (hazard ratio [HR], 0.74; 95% confidence interval [CI], 0.57 to 0.96), which resulted in lower risk of nonrelapse mortality in the Japanese patients (HR, 0.69; 95% CI, 0.54 to 0.89). The risk of relapse was also lower in this group. The lower risks of nonrelapse mortality and relapse resulted in lower overall mortality rates among the Japanese patients. In conclusion, our data indicate that irrespective of graft source, the risk of severe acute GVHD is lower in Japanese patients, resulting in a lower risk of nonrelapse mortality. PMID:26762681

  14. CD4+ and CD8+ clonal T cell expansions indicate a role of antigens in ankylosing spondylitis; a study in HLA-B27+ monozygotic twins

    PubMed Central

    Duchmann, R; Lambert, C; May, E; Höhler, T; Märker-Hermann, E

    2001-01-01

    Ankylosing spondylitis (AS) is a complex genetic disease in which both MHC and non-MHC genes determine disease susceptibility. To determine whether the T cell repertoires of individuals with AS show signs of increased stimulation by exogenous antigens, CD4+ and CD8+ T cell subsets of five monozygotic HLA-B27+ twins (two concordant and three discordant for AS) and CD8+ T cell repertoires of three healthy HLA-B27+ individuals were characterized by TCR β-chain (TCRB) CDR3 size spectratyping. Selected TCRB-CDR3 spectra were further analysed by BJ-segment analysis and TCRB-CDR3 from expanded T cell clones were sequenced. In an analysis of all data (519/598 possible TCRB-CDR3 spectra), AS was associated with increased T cell oligoclonality in both CD8+ (P = 0·0001) and CD4+ (P = 0·033) T cell subsets. This was also evident when data were compared between individual twins. Nucleotide sequence analysis of expanded CD8+ or CD4+ T cell clones did not show selection for particular TCRB-CDR3 amino acid sequence motifs but displayed sequence homologies with published sequences from intra-epithelial lymphocytes or synovial T cells from rheumatoid arthritis patients. Together, these results provide support for the hypothesis that responses to T cell-stimulating exogenous or endogenous antigens are involved in the induction and/or maintenance of AS. PMID:11207664

  15. Human Leucocyte Antigen-G (HLA-G) and Its Murine Functional Homolog Qa2 in the Trypanosoma cruzi Infection

    PubMed Central

    Dias, Fabrício C.; Mendes-Junior, Celso T.; Silva, Maria C.; Tristão, Fabrine S. M.; Dellalibera-Joviliano, Renata; Soares, Edson G.; Menezes, Jean G.; Schmidt, André; Dantas, Roberto O.; Marin-Neto, José A.; Silva, João S.; Donadi, Eduardo A.

    2015-01-01

    Genetic susceptibility factors, parasite strain, and an adequate modulation of the immune system seem to be crucial for disease progression after Trypanosoma cruzi infection. HLA-G and its murine functional homolog Qa2 have well-recognized immunomodulatory properties. We evaluated the HLA-G 3′ untranslated region (3′UTR) polymorphic sites (associated with mRNA stability and target for microRNA binding) and HLA-G tissue expression (heart, colon, and esophagus) in patients presenting Chagas disease, stratified according to the major clinical variants. Further, we investigated the transcriptional levels of Qa2 and other pro- and anti-inflammatory genes in affected mouse tissues during T. cruzi experimental acute and early chronic infection induced by the CL strain. Chagas disease patients exhibited differential HLA-G 3′UTR susceptibility allele/genotype/haplotype patterns, according to the major clinical variant (digestive/cardiac/mixed/indeterminate). HLA-G constitutive expression on cardiac muscle and colonic cells was decreased in Chagasic tissues; however, no difference was observed for Chagasic and non-Chagasic esophagus tissues. The transcriptional levels of Qa2 and other anti and proinflammatory (CTLA-4, PDCD1, IL-10, INF-γ, and NOS-2) genes were induced only during the acute T. cruzi infection in BALB/c and C57BL/6 mice. We present several lines of evidence indicating the role of immunomodulatory genes and molecules in human and experimental T. cruzi infection. PMID:25688175

  16. Variation in effects of non-Hodgkin lymphoma risk factors according to the human leukocyte antigen (HLA)-DRB1*01:01 allele and ancestral haplotype 8.1.

    PubMed

    Wang, Sophia S; Lu, Yani; Rothman, Nathaniel; Abdou, Amr M; Cerhan, James R; De Roos, Anneclaire; Davis, Scott; Severson, Richard K; Cozen, Wendy; Chanock, Stephen J; Bernstein, Leslie; Morton, Lindsay M; Hartge, Patricia

    2011-01-01

    Genetic variations in human leukocyte antigens (HLA) are critical in host responses to infections, transplantation, and immunological diseases. We previously identified associations with non-Hodgkin lymphoma (NHL) and the HLA-DRB1*01:01 allele and extended ancestral haplotype (AH) 8.1 (HLA-A*01-B*08-DR*03-TNF-308A). To illuminate how HLA alleles and haplotypes may influence NHL etiology, we examined potential interactions between HLA-DRB1*01:01 and AH 8.1, and a wide range of NHL risk factors among 685 NHL cases and 646 controls from a United States population-based case-control study. We calculated odds ratios and 95% confidence intervals by HLA allele or haplotype status, adjusted for sex, age, race and study center for NHL and two major subtypes using polychotomous unconditional logistic regression models. The previously reported elevation in NHL risk associated with exposures to termite treatment and polychlorinated biphenyls were restricted to individuals who did not possess HLA-DRB1*01:01. Previous associations for NHL and DLBCL with decreased sun exposure, higher BMI, and autoimmune conditions were statistically significant only among those with AH 8.1, and null among those without AH 8.1. Our results suggest that NHL risk factors vary in their association based on HLA-DRB1*01:01 and AH 8.1 status. Our results further suggest that certain NHL risk factors may act through a common mechanism to alter NHL risk. Finally, control participants with either HLA-DRB1*01:01 or AH 8.1 reported having a family history of NHL twice as likely as those who did not have either allele or haplotype, providing the first empirical evidence that HLA associations may explain some of the well-established relationship between family history and NHL risk. PMID:22096508

  17. Variation in Effects of Non-Hodgkin Lymphoma Risk Factors According to the Human Leukocyte Antigen (HLA)-DRB1*01:01 Allele and Ancestral Haplotype 8.1

    PubMed Central

    Wang, Sophia S.; Lu, Yani; Rothman, Nathaniel; Abdou, Amr M.; Cerhan, James R.; De Roos, Anneclaire; Davis, Scott; Severson, Richard K.; Cozen, Wendy; Chanock, Stephen J.; Bernstein, Leslie; Morton, Lindsay M.; Hartge, Patricia

    2011-01-01

    Genetic variations in human leukocyte antigens (HLA) are critical in host responses to infections, transplantation, and immunological diseases. We previously identified associations with non-Hodgkin lymphoma (NHL) and the HLA-DRB1*01:01 allele and extended ancestral haplotype (AH) 8.1 (HLA-A*01-B*08-DR*03-TNF-308A). To illuminate how HLA alleles and haplotypes may influence NHL etiology, we examined potential interactions between HLA-DRB1*01:01 and AH 8.1, and a wide range of NHL risk factors among 685 NHL cases and 646 controls from a United States population-based case-control study. We calculated odds ratios and 95% confidence intervals by HLA allele or haplotype status, adjusted for sex, age, race and study center for NHL and two major subtypes using polychotomous unconditional logistic regression models. The previously reported elevation in NHL risk associated with exposures to termite treatment and polychlorinated biphenyls were restricted to individuals who did not possess HLA-DRB1*01:01. Previous associations for NHL and DLBCL with decreased sun exposure, higher BMI, and autoimmune conditions were statistically significant only among those with AH 8.1, and null among those without AH 8.1. Our results suggest that NHL risk factors vary in their association based on HLA-DRB1*01:01 and AH 8.1 status. Our results further suggest that certain NHL risk factors may act through a common mechanism to alter NHL risk. Finally, control participants with either HLA-DRB1*01:01 or AH 8.1 reported having a family history of NHL twice as likely as those who did not have either allele or haplotype, providing the first empirical evidence that HLA associations may explain some of the well-established relationship between family history and NHL risk. PMID:22096508

  18. The Polyomavirus BK Large T-Antigen-Derived Peptide Elicits an HLA-DR Promiscuous and Polyfunctional CD4+ T-Cell Response▿

    PubMed Central

    Ramaswami, Bala; Popescu, Iulia; Macedo, Camila; Luo, Chunqing; Shapiro, Ron; Metes, Diana; Chalasani, Geetha; Randhawa, Parmjeet S.

    2011-01-01

    BK virus (BKV) nephropathy and hemorrhagic cystitis are increasingly recognized causes of disease in renal and hematopoietic stem cell transplant recipients, respectively. Functional characterization of the immune response to BKV is important for clinical diagnosis, prognosis, and vaccine design. A peptide mix (PepMix) and overlapping (OPP) or random (RPP) peptide pools derived from BKV large T antigen (LTA) were used to restimulate 14-day-expanded peripheral blood mononuclear cells (PBMC) from 27 healthy control subjects in gamma interferon (IFN-γ)-specific enzyme-linked immunospot (ELISPOT) assays. A T-cell response to LTA PepMix was detected in 15/27 subjects. A response was frequently observed with peptides derived from the helicase domain (9/15 subjects), while the DNA binding and host range domains were immunologically inert (0/15 subjects). For all nine subjects who responded to LTA peptide pools, the immune response could be explained largely by a 15-mer peptide designated P313. P313-specific CD4+ T-cell clones demonstrated (i) stringent LTA peptide specificity; (ii) promiscuous recognition in the context of HLA-DR alleles; (iii) cross recognition of homologous peptides from the polyomavirus simian virus 40 (SV40); (iv) an effector memory phenotype, CD107a expression, and intracellular production of IFN-γ and tumor necrosis factor alpha (TNF-α); (v) cytotoxic activity in a chromium release assay; and (vi) the ability to directly present cognate antigen to autologous T cells. In conclusion, T-cell-mediated immunity to BKV in healthy subjects is associated with a polyfunctional population of CD4+ T cells with dual T-helper and T-cytotoxic properties. HLA class II promiscuity in antigen presentation makes the targeted LTA peptide sequence a suitable candidate for inclusion in immunotherapy protocols. PMID:21367979

  19. Hepatitis B virus (HBV)-specific cytotoxic T-cell (CTL) response in humans: characterization of HLA class II-restricted CTLs that recognize endogenously synthesized HBV envelope antigens.

    PubMed Central

    Penna, A; Fowler, P; Bertoletti, A; Guilhot, S; Moss, B; Margolskee, R F; Cavalli, A; Valli, A; Fiaccadori, F; Chisari, F V

    1992-01-01

    In this study, we show that CD4+, hepatitis B virus (HBV) envelope-specific T-cell clones produced by stimulation with a particulate antigen preparation are able to recognize and kill not only autologous antigen-presenting cells incubated with exogenous HBV envelope antigens but also autologous HLA class II-positive cells expressing endogenously synthesized HBV envelope antigens following infection with recombinant vaccinia viruses or transfection with recombinant Epstein-Barr virus expression vectors. Experiments with lysosomotropic agents and brefeldin A suggest that the endosomal compartment is likely involved in the processing of endogenously synthesized viral proteins for recognition by CD4+ T cells. Our study indicates that HBV envelope-specific, HLA class II-restricted CD4+ cytotoxic T lymphocytes can potentially participate in the immune clearance of HBV-infected cells and the pathogenesis of hepatocellular injury in hepatitis B. PMID:1731098

  20. HLA-A, HLA-B and HLA-DRB1 allele and haplotype frequencies of 10 918 Koreans from bone marrow donor registry in Korea.

    PubMed

    Park, H; Lee, Y-J; Song, E Y; Park, M H

    2016-10-01

    The human leucocyte antigen (HLA) system is the most polymorphic genetic system in humans, and HLA matching is crucial in organ transplantation, especially in hematopoietic stem cell transplantation. We investigated HLA-A, HLA-B and HLA-DRB1 allele and haplotype frequencies at allelic level in 10 918 Koreans from bone marrow donor registry in Korea. Intermediate resolution HLA typing was performed using Luminex technology (Wakunaga, Japan), and additional allelic level typing was performed using PCR-single-strand conformation polymorphism method and/or sequence-based typing (Abbott Molecular, USA). Allele and haplotype frequencies were calculated by direct counting and maximum likelihood methods, respectively. A total of 39 HLA-A, 66 HLA-B and 47 HLA-DRB1 alleles were identified. High-frequency alleles found at a frequency of ≥5% were 6 HLA-A (A*02:01, *02:06, *11:01, *24:02, *31:01 and *33:03), 6 HLA-B (B*15:01, *35:01, *44:03, *51:01, 54:01 and *58:01) and 8 HLA-DRB1 (DRB1*01:01, *04:05, *04:06, *07:01, *08:03, *09:01, *13:02 and *15:01) alleles. At each locus, A*02, B*15 and DRB1*14 generic groups were most diverse at allelic level, consisting of 9, 12 and 11 different alleles, respectively. A total of 366, 197 and 21 different HLA-A-B-DRB1 haplotypes were estimated with frequencies of ≥0.05%, ≥0.1% and ≥0.5%, respectively. The five most common haplotypes with frequencies of ≥2.0% were A*33:03-B*44:03-DRB1*13:02 (4.97%), A*33:03-B*58:01-DRB1*13:02, A*33:03-B*44:03-DRB1*07:01, A*24:02-B*07:02-DRB1*01:01 and A*24:02-B*52:01-DRB1*15:02. Among 34 serologic HLA-A-B-DR haplotypes with frequencies of ≥0.5%, 17 haplotypes revealed allele-level diversity and majority of the allelic variation was arising from A2, A26, B61, B62, DR4 and DR14 specificities. Haplotype diversity obtained in this study is the most comprehensive data thus far reported in Koreans, and the information will be useful for unrelated stem cell transplantation as well as for disease

  1. HLA genes in Uros from Titikaka Lake, Peru: origin and relationship with other Amerindians and worldwide populations.

    PubMed

    Arnaiz-Villena, A; Gonzalez-Alcos, V; Serrano-Vela, J I; Reguera, R; Barbolla, L; Parga-Lozano, C; Gómez-Prieto, P; Abd-El-Fatah-Khalil, S; Moscoso, J

    2009-06-01

    Uros population from the Titikaka Lake live in about 42 floating reed ('totora') islands in front of Puno City (Peru) at a 4000 m high altiplano. They present both an mtDNA and a human leucocyte antigen (HLA) profile different from the surrounding populations: mtDNA A2 haplogroup is common to Uros and Amazon forest lowland Amerindians. HLA genetic distances between populations have been calculated and neighbour-joining dendrograms and correspondence analyses were carried out. Approximately 15 006 HLA chromosomes from worldwide populations have been used for comparisons. Only eight HLA-A alleles have been found, three of them accounting for most of the frequencies. The same phenomenon is seen for HLA-B, HLA-DRB1 and HLA-DQB1 alleles: a few alleles (3, 4 and 3, respectively) are present in most individuals. The presence of HLA-B*4801 and HLA-DRB1*0901 alleles in a relatively high frequency (although not the most frequent alleles found) is a characteristic shared with Asians and some populations from the Andean altiplano. Three specific Uros haplotypes have been found among the most frequent ones: HLA-A*680102-B*3505-DRB1*0403-DQB1*0302; HLA-A*2402-B*1504-DRB1*1402-DQB1*0301; and HLA-A*2402-B*4801-DRB1*0403-DQB1*0302. The present study suggests that Uros may have been one of the first populations from the shores of the Titikaka Lake coming from the Amazonian forest, which might have given rise to other later differentiated ethnic group (i.e. Aymaras). Uros HLA profile is also useful to study genetic epidemiology of diseases linked to HLA and to construct a future transplant waiting list by adding up regional lists in order to get a bigger pool for transplanting with better HLA matching. PMID:19490211

  2. Influence of genetic polymorphisms of cytokine genes in the outcome of HLA-matched allogeneic stem cell transplantation in a South East Asian population.

    PubMed

    Gan, G G; Leong, Y C; Bee, P C; Chin, E F M; Abdul Halim, H; Nadarajan, V S; Teh, A K H

    2016-02-01

    Non-HLA gene polymorphisms have been shown to be associated with the risk of graft-versus-host disease (GVHD) and outcome of allogeneic haematopoietic stem cell transplantation (AHSCT). This study aims to investigate the role of IL6, TNFα, IL10, IL2 and IL12 gene polymorphisms in the outcome of AHSCT in a South East Asian population. A total of 67 patients and 59 donors who underwent HLA-identical matched sibling AHSCT were available for analysis. There was no significant association between the different cytokine genotypes of patients with the incidence and severity of acute GVHD. Patients with IL2 166∗T allele and patients who received donor stem cells who had IL2 166∗G allele appeared to have reduced incidence of cGVHD. Patients who received donor stem cells with IL12 1188∗C allele are found to be associated with better disease free survival. These results suggest a possible role of IL2 and IL12 gene polymorphisms in the outcome of AHSCT in a South East Asian population. PMID:26638029

  3. Separation of uncompromised whole blood mixtures for single source STR profiling using fluorescently-labeled human leukocyte antigen (HLA) probes and fluorescence activated cell sorting (FACS).

    PubMed

    Dean, Lee; Kwon, Ye Jin; Philpott, M Katherine; Stanciu, Cristina E; Seashols-Williams, Sarah J; Dawson Cruz, Tracey; Sturgill, Jamie; Ehrhardt, Christopher J

    2015-07-01

    Analysis of biological mixtures is a significant problem for forensic laboratories, particularly when the mixture contains only one cell type. Contributions from multiple individuals to biologic evidence can complicate DNA profile interpretation and often lead to a reduction in the probative value of DNA evidence or worse, its total loss. To address this, we have utilized an analytical technique that exploits the intrinsic immunological variation among individuals to physically separate cells from different sources in a mixture prior to DNA profiling. Specifically, we applied a fluorescently labeled antibody probe to selectively bind to one contributor in a mixture through allele-specific interactions with human leukocyte antigen (HLA) proteins that are expressed on the surfaces of most nucleated cells. Once the contributor's cells were bound to the probe, they were isolated from the mixture using fluorescence activated cell sorting (FACS)-a high throughput technique for separating cell populations based on their optical properties-and then subjected to STR analysis. We tested this approach on two-person and four-person whole blood mixtures where one contributor possessed an HLA allele (A*02) that was not shared by other contributors to the mixture. Results showed that hybridization of the mixture with a fluorescently-labeled antibody probe complimentary to the A*02 allele's protein product created a cell population with a distinct optical profile that could be easily differentiated from other cells in the mixture. After sorting the cells with FACS, genetic analysis showed that the STR profile of this cell population was consistent with that of the contributor who possessed the A*02 allele. Minor peaks from the A*02 negative contributor(s) were observed but could be easily distinguished from the profile generated from A*02 positive cells. Overall, this indicates that HLA antibody probes coupled to FACS may be an effective approach for generating STR profiles of

  4. HLA mismatching as a strategy to reduce relapse after alternative donor transplantation.

    PubMed

    Fleischhauer, Katharina; Beelen, Dietrich W

    2016-04-01

    Human leukocyte antigen (HLA) mismatches are targets of alloreactive T cells, mediators of graft-versus-leukemia (GvL) and graft-versus-host disease (GvHD) after alternative donor transplantation. Exploitation of HLA mismatching in order to reduce relapse is hampered by necessary interventions aimed at controlling GvHD on the one hand, and by the possibility of immune escape through selective loss of mismatched HLA in relapsing leukemia on the other. Retrospective studies reporting the impact of HLA mismatches on post-transplant relapse need to be interpreted with caution, due to many confounding factors, including disease and use of T-cell depletion, and to be constantly updated to the rapidly changing clinical protocols. Current evidence suggests similar relapse rates for 8/8, 7/8 HLA-matched unrelated, T-cell-replete haploidentical and umbilical cord blood transplantation; however, investigations of locus-specific effects are still scarce in the latter two settings. In unrelated transplantation, a specific role for mismatches at HLA-C and HLA-DPB1, and therein of permissive mismatches defined on the basis of T-cell alloreactivity and/or expression levels, in reducing relapse has been demonstrated in independent studies. This observation suggests new approaches to utilize HLA matching in unrelated donor searches, and the need for further research in the field. PMID:27000727

  5. The production and crystallization of the human leukocyte antigen class II molecules HLA-DQ2 and HLA-DQ8 complexed with deamidated gliadin peptides implicated in coeliac disease

    PubMed Central

    Henderson, Kate N.; Reid, Hugh H.; Borg, Natalie A.; Broughton, Sophie E.; Huyton, Trevor; Anderson, Robert P.; McCluskey, James; Rossjohn, Jamie

    2007-01-01

    The major histocompatibility complex (MHC) class II molecules HLA-DQ2 and HLA-DQ8 are key risk factors in coeliac disease, as they bind deamidated gluten peptides that are subsequently recognized by CD4+ T cells. Here, the production and crystallization of both HLA-DQ2 and HLA-DQ8 in complex with the deamidated gliadin peptides DQ2 α-I (PQPELPYPQ) and DQ8 α-I (EGSFQPSQE), respectively, are reported. PMID:18084083

  6. Performance Characteristics and Validation of Next-Generation Sequencing for Human Leucocyte Antigen Typing.

    PubMed

    Weimer, Eric T; Montgomery, Maureen; Petraroia, Rosanne; Crawford, John; Schmitz, John L

    2016-09-01

    High-resolution human leukocyte antigen (HLA) matching reduces graft-versus-host disease and improves overall patient survival after hematopoietic stem cell transplant. Sanger sequencing has been the gold standard for HLA typing since 1996. However, given the increasing number of new HLA alleles identified and the complexity of the HLA genes, clinical HLA typing by Sanger sequencing requires several rounds of additional testing to provide allele-level resolution. Although next-generation sequencing (NGS) is routinely used in molecular genetics, few clinical HLA laboratories use the technology. The performance characteristics of NGS HLA typing using TruSight HLA were determined using Sanger sequencing as the reference method. In total, 211 samples were analyzed with an overall accuracy of 99.8% (2954/2961) and 46 samples were analyzed for precision with 100% (368/368) reproducibility. Most discordant alleles were because of technical error rather than assay performance. More important, the ambiguity rate was 3.5% (103/2961). Seventy-four percentage of the ambiguities were within the DRB1 and DRB4 loci. HLA typing by NGS saves approximately $6000 per run when compared to Sanger sequencing. Thus, TruSight HLA assay enables high-throughput HLA typing with an accuracy, precision, ambiguity rate, and cost savings that should facilitate adoption of NGS technology in clinical HLA laboratories. PMID:27376474

  7. The binding of monoclonal antibodies to cell-surface molecules. A quantitative analysis with immunoglobulin G against two alloantigenic determinants of the human transplantation antigen HLA-A2.

    PubMed Central

    Ways, J P; Parham, P

    1983-01-01

    Monoclonal IgG1 (immunoglobulin G1) PA2.1 and MA2.1 antibodies recognize polymorphic sites of the human transplantation antigen HLA-A2. They are distinguishable because MA2.1 binds HLA-A2 and HLA-B17, whereas PA2.1 binds HLA-A2 and HLA-A28. The affinities of PA2.1-Fab for HLA-A2, three HLA-A2 variants and HLA-A28 are similar and relatively low (1.9 X 10(7) M-1). The affinities of MA2.1-Fab for HLA-A2, three HLA-A2 variants and HLA-B17 are similar and high (1.2 X 10(9) M-1). The difference in affinity is due to the rates of dissociation, which give half-times of dissociation of 290 min for MA2.1-Fab and 4 min for PA2.1-Fab. For both Fab, equilibrium measurements and kinetic determinations gave consistent estimates for affinity. When PA2.1-F(ab)2 or IgG is incubated with cells it reaches equilibrium within 3 h, with most molecules bound bivalently to the cell. Under similar conditions, MA2.1-F(ab)2 does not reach equilibrium and a significant proportion of molecules bound with one and two sites are found. For the lower-affinity antibody (PA2.1), estimates of the binding constants for one- and two-site interactions could be made. By simple Scatchard analysis the avidity of F(ab)2 or IgG is 1.3 X 10(9) M-1, giving an enhancement factor of 68 between bivalent and univalent binding. This is a measure of the equilibrium constant for the interchange between bivalent and univalent binding. Analysis of the results with more realistic models indicates that the actual value is larger (10(3)-10(4) M-1) than 68 M-1. The avidities of F(ab)2 and IgG for HLA-A2 are identical, showing the Fc does not interfere with bivalent binding to cells. PMID:6197968

  8. Lights and shadows of anti-HLA antibodies detected by solid-phase assay.

    PubMed

    Picascia, Antonietta; Sabia, Chiara; Grimaldi, Vincenzo; Montesano, Maria Lourdes; Sommese, Linda; Schiano, Concetta; Napoli, Claudio

    2014-11-01

    Recently, management of patients awaiting solid organ transplantation has taken advantages after the development of more sensitive and accurate solid phase assays which have supported the historic complement dependent cytotoxicity. This approach has allowed the detection of antibodies in patients previously considered negative. The use of the single antigen beads resulted in a more accurate anti-human leukocyte antigen (HLA) antibody characterization. The detection of anti-HLA antibodies specific for C, DQ and DP loci that were not so well characterized has been possible through the implementation of the single antigen assay. The assessment of HLA compatibility has been expanded through the introduction of "epitope matching" concept and the definition of the unacceptable antigens for a more adequate evaluation of donor-recipient compatibility. However, the clinical impact of pre-formed and de novo anti-HLA antibodies detected by solid phase assays is still controversial due to the drawback related to result interpretation. Until today, the unresolved issues concern if all antibodies affect the medium and long term clinical outcome. An open debate on the clinical relevance of anti-HLA antibodies detected by single-antigen beads highlights needing to further investigations. Here, we describe the novel applications and the improvements of the solid-phase assay use. PMID:25171913

  9. The Royan Public Umbilical Cord Blood Bank: Does It Cover All Ethnic Groups in Iran Based on HLA Diversity?

    PubMed Central

    Ebrahimkhani, Saeideh; Farjadian, Shirin; Ebrahimi, Marzieh

    2014-01-01

    Summary Background Umbilical cord blood (UCB) stem cells allow the transplantation of partially human leukocyte antigen (HLA)-matched grafts and are a valuable resource for the treatment of hematologic malignancies and heritable hematologic, immunologic and metabolic diseases, especially when a compatible bone marrow donor is unavailable. The aim of this study was to determine how many ethnic groups in Iran are covered by the available UCB units based on HLA diversity. Methods From 2009 until mid-2013, 4,981 (30.3%) of the 16,437 UCB samples collected met the storage criteria and were cryopreserved at a public cord blood bank (CBB) in Tehran, Iran. HLA-A, -B and -DRB1 were typed in 1,793 samples. Results The mean volume of the cryopreserved samples was 81.25 ± 20.3 ml. The range of total nucleated cells per unit was 51 × 107-107 × 107. The most common HLA alleles were HLA-A*2 (17%) and HLA-A*24 (15.6%), HLA-B*35 (16.8%) and HLA-B*51 (13.9%), and HLA-DRB1*11 (20%) and HLA-DRB1*15 (14%). The predominant haplotypes were HLA-A*24-B*35-DRB1*11 (2%), HLA-A*02-B*50-DR*07 (1.8%), and HLA-A*02-B*51-DRB1*11 (1.5%). Conclusions Based on the HLA-DRB1 profiles, the UCB units available at the Royan public UCB bank are a potentially adequate resource for hematopoietic stem cell transplantation for Iranian recipients belonging to particular ethnic groups. Regular educational programs to improve the public knowledge of UCB for transplantation can enhance the public CBB stocks for all Iranian ethnic groups in the future. PMID:24847189

  10. An extended HLA-D region haplotype associated with celiac disease.

    PubMed Central

    Howell, M D; Smith, J R; Austin, R K; Kelleher, D; Nepom, G T; Volk, B; Kagnoff, M F

    1988-01-01

    Celiac disease has one of the strongest associations with HLA (human leukocyte antigen) class II markers of the known HLA-linked diseases. This association is primarily with the class II serologic specificities HLA-DR3 and -DQw2. We previously described a restriction fragment length polymorphism (RFLP) characterized by the presence of a 4.0-kilobase Rsa I fragment derived from an HLA class II beta-chain gene, which distinguishes the class II HLA haplotype of celiac disease patients from those of many serologically matched controls. We now report the isolation of this beta-chain gene from a bacteriophage genomic library constructed from the DNA of a celiac disease patient. Based on restriction mapping and differential hybridization with class II cDNA and oligonucleotide probes, this gene was identified as one encoding an HLA-DP beta chain. This celiac disease-associated HLA-DP beta-chain gene was flanked by HLA-DP alpha-chain genes and, therefore, was probably in its normal chromosomal location. The HLA-DP alpha-chain genes of celiac disease patients also were studied by RFLP analysis; 84% of HLA-DR3, -DQw2 patients had a 16-kb Xba I fragment that was present in only 36% of HLA-DR3, -DQw2 controls. Moreover, 79% of these patients had both alpha- and beta-chain polymorphisms in contrast to 27% of controls. Thus, celiac disease is associated with a subset of HLA-DR3, -DQw2 haplotypes characterized by HLA-DP alpha- and beta-chain gene RFLPs. Within the celiac-disease patient population, the joint segregation of these HLA-DP genes with those encoding the serologic specificities HLA-DR3 and -DQw2 indicates: (i) that the class II HLA haplotype associated with celiac disease is extended throughout the entire HLA-D region, and (ii) that celiac-disease susceptibility genes may reside as far centromeric on this haplotype as the HLA-DP subregion. Images PMID:2893373

  11. Predicted Indirectly Recognizable HLA Epitopes Presented by HLA-DRB1 Are Related to HLA Antibody Formation During Pregnancy.

    PubMed

    Geneugelijk, K; Hönger, G; van Deutekom, H W M; Thus, K A; Keşmir, C; Hösli, I; Schaub, S; Spierings, E

    2015-12-01

    Pregnancy can prime maternal immune responses against inherited paternal HLA of the fetus, leading to the production of child-specific HLA antibodies. We previously demonstrated that donor-specific HLA antibody formation after kidney transplantation is associated with donor-derived HLA epitopes presented by recipient HLA class II (predicted indirectly recognizable HLA epitopes presented by HLA class II [PIRCHE-II]). In the present study, we evaluated the role of PIRCHE-II in child-specific HLA antibody formation during pregnancy. A total of 229 mother-child pairs were HLA typed. For all mismatched HLA class I molecules of the child, we subsequently predicted the number of HLA epitopes that could be presented by maternal HLA class II molecules. Child-specific antigens were classified as either immunogenic or nonimmunogenic HLA based on the presence of specific antibodies and correlated to PIRCHE-II numbers. Immunogenic HLA contained higher PIRCHE-II numbers than nonimmunogenic HLA. Moreover, the probability of antibody production during pregnancy increased with the number of PIRCHE-II. In conclusion, our data suggest that the number of PIRCHE-II is related to the formation of child-specific HLA antibodies during pregnancy. Present confirmation of the role of PIRCHE-II in antibody formation outside the transplantation setting suggests the PIRCHE-II concept is universal. PMID:26512793

  12. Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines for human leukocyte antigen B (HLA-B) genotype and allopurinol dosing: 2015 update.

    PubMed

    Saito, Y; Stamp, L K; Caudle, K E; Hershfield, M S; McDonagh, E M; Callaghan, J T; Tassaneeyakul, W; Mushiroda, T; Kamatani, N; Goldspiel, B R; Phillips, E J; Klein, T E; Lee, M T M

    2016-01-01

    The Clinical Pharmacogenetics Implementation Consortium (CPIC) Guidelines for HLA-B*58:01 Genotype and Allopurinol Dosing was originally published in February 2013. We reviewed the recent literature and concluded that none of the evidence would change the therapeutic recommendations in the original guideline; therefore, the original publication remains clinically current. However, we have updated the Supplemental Material and included additional resources for applying CPIC guidelines into the electronic health record. Up-to-date information can be found at PharmGKB (http://www.pharmgkb.org). PMID:26094938

  13. Effects of donor/recipient human leukocyte antigen mismatch on human cytomegalovirus replication following liver transplantation

    PubMed Central

    Aldridge, RW; Mattes, FM; Rolando, N; Rolles, K; Smith, C; Shirling, G; Atkinson, C; Burroughs, AK; Milne, RSB; Emery, VC; Griffiths, PD

    2015-01-01

    Background Natural immunity against cytomegalovirus (CMV) can control virus replication after solid organ transplantation; however, it is not known which components of the adaptive immune system mediate this protection. We investigated whether this protection requires human leukocyte antigen (HLA) matching between donor and recipient by exploiting the fact that, unlike transplantation of other solid organs, liver transplantation does not require HLA matching, but some donor and recipient pairs may nevertheless be matched by chance. Methods To further investigate this immune control, we determined whether chance HLA matching between donor (D) and recipient (R) in liver transplants affected a range of viral replication parameters. Results In total, 274 liver transplant recipients were stratified according to matches at the HLA A, HLA B, and HLA DR loci. The incidence of CMV viremia, kinetics of replication, and peak viral load were similar between the HLA matched and mismatched patients in the D+/R+ and D−/R+ transplant groups. D+/R− transplants with 1 or 2 mismatches at the HLA DR locus had a higher incidence of CMV viremia >3000 genomes/mL blood compared to patients matched at this locus (78% vs. 17%; P = 0.01). Evidence was seen that matching at the HLA A locus had a small effect on peak viral loads in D+/R− patients, with median peak loads of 3540 and 14,706 genomes/mL in the 0 and combined (1 and 2) mismatch groups, respectively (P = 0.03). Conclusion Overall, our data indicate that, in the setting of liver transplantation, prevention of CMV infection and control of CMV replication by adaptive immunity is minimally influenced by HLA matching of the donor and recipient. Our data raise questions about immune control of CMV in the liver and also about the cells in which the virus is amplified to give rise to CMV viremia. PMID:25572799

  14. Single-agent GVHD prophylaxis with posttransplantation cyclophosphamide after myeloablative, HLA-matched BMT for AML, ALL, and MDS

    PubMed Central

    Kanakry, Christopher G.; Tsai, Hua-Ling; Bolaños-Meade, Javier; Smith, B. Douglas; Gojo, Ivana; Kanakry, Jennifer A.; Kasamon, Yvette L.; Gladstone, Douglas E.; Matsui, William; Borrello, Ivan; Huff, Carol Ann; Swinnen, Lode J.; Powell, Jonathan D.; Pratz, Keith W.; DeZern, Amy E.; Showel, Margaret M.; McDevitt, Michael A.; Brodsky, Robert A.; Levis, Mark J.; Ambinder, Richard F.; Fuchs, Ephraim J.; Rosner, Gary L.; Jones, Richard J.

    2014-01-01

    High-dose, posttransplantation cyclophosphamide (PTCy) reduces severe graft-versus-host disease (GVHD) after allogeneic blood or marrow transplantation (alloBMT), but the impact of PTCy on long-term, disease-specific outcomes is unclear. We conducted a retrospective study of 209 consecutive adult patients transplanted for acute myeloid leukemia (AML, n = 138), myelodysplastic syndrome (n = 28), or acute lymphoblastic leukemia (ALL, n = 43) using PTCy as sole GVHD prophylaxis after myeloablative conditioning and HLA-matched–related or –unrelated T-cell–replete allografting. At alloBMT, 30% of patients were not in morphologic complete remission. The cumulative incidences of grades II to IV and III to IV acute GVHD at 100 days and chronic GVHD at 2 years were 45%, 11%, and 13%, respectively. Forty-three percent of patients did not require immunosuppression for any reason beyond PTCy. At 3 years, relapse cumulative incidence was 36%, disease-free survival was 46%, survival free of disease and chronic GVHD was 39%, and overall survival was 58%. Lack of remission at alloBMT, adverse cytogenetics, and low allograft nucleated cell dose were associated with inferior survival for AML patients. Minimal residual disease but not t(9;22) was associated with inferior outcomes for ALL patients. The ability to limit posttransplantation immunosuppression makes PTCy a promising transplantation platform for the integration of postgrafting strategies to prevent relapse. PMID:25316679

  15. Directed sibling donor cord blood banking for children with beta-thalassemia major in Greece: usage rate and outcome of transplantation for HLA-matched units.

    PubMed

    Goussetis, Evgenios; Petrakou, Eftichia; Theodosaki, Maria; Kitra, Vasiliki; Peristeri, Ioulia; Vessalas, George; Dimopoulou, Maria N; Spiropoulos, Antonia; Papassavas, Andreas C; Stavropoulos-Giokas, Catherine; Graphakos, Stelios

    2010-01-01

    Several cord blood banks store cord blood units from healthy siblings of patients, who are candidates for stem cell transplantation. We analyzed the quality characteristics of 50 cord blood units collected from families with beta-thalassemia major and the outcome of subsequent stem cell transplantations during a 15-year period. All cord blood units were found suitable for banking based on a minimum net volume of 40 ml. The mean volume of the units was 98.9 ml; the mean total nucleated cell count (NC) was 7.8 x 10(8) and the mean CD34+ cell count was 2.8 x 10(6). Eight out of twelve HLA matched collections were released for transplantation. All but one recipient belonged to Pesaro II-III risk classes. Three patients received a cord blood graft with >5 x 10(7) NC/kg . One of them with Pesaro class I disease engrafted, whereas the other two who failed to engraft, were re-transplanted with bone marrow from the same donor later. Cord blood grafts containing NCs <4 x 10(7)/kg combined with reduced volume bone marrow from the same donor were used in all 5 remaining cases and stable engraftment was achieved. All patients survived, 7/8 thalassemia-free. Cord blood banking from healthy siblings of children with beta-thalassemia major can result in a successful transplantation in cases in which there is HLA compatibility. However, in high-risk patients, the use of combined cord blood and bone marrow grafts seems necessary in order to ensure stable engraftment, especially when cord blood unit cell counts are low. PMID:19931473

  16. Combined influences of Gm and HLA phenotypes upon multiple sclerosis susceptibility and severity.

    PubMed Central

    Salier, J P; Sesboüé, R; Martin-Mondière, C; Daveau, M; Cesaro, P; Cavelier, B; Coquerel, A; Legrand, L; Goust, J M; Degos, J D

    1986-01-01

    In some Caucasian populations, multiple sclerosis (MS) susceptibility has been independently related to given alleles of HLA or Gm systems that respectively code for major histocompatibility complex class I and II antigens or immunoglobulin G heavy chains. Whether given combinations of alleles at both series of loci simultaneously influence MS susceptibility and/or severity was investigated by comparing 147 French MS patients and 226 geographically-matched healthy controls. The G2m(-23)/HLA-B35 phenotype and G1m(-1)/HLA-B7(-)/HLA-DR2 phenotype were respectively associated with significant protection against (relative risk = 0.05) and susceptibility to (relative risk = 4.3) MS. When considering MS severity, the presence of HLA-B7 antigen correlated with a more severe disease in Gm1/Gm3 heterozygous patients, but not in Gm3/Gm3 homozygous patients. Conversely, an HLA-B12-associated milder disease was restricted to Gm3/Gm3 homozygotes. These results demonstrate the combined influence on MS of genetic loci that are unlinked but immune response-associated. Combined Gm and HLA typing is very likely able to serve as a prognostic indicator in this disease. PMID:3461005

  17. Combined influences of Gm and HLA phenotypes upon multiple sclerosis susceptibility and severity.

    PubMed

    Salier, J P; Sesboüé, R; Martin-Mondière, C; Daveau, M; Cesaro, P; Cavelier, B; Coquerel, A; Legrand, L; Goust, J M; Degos, J D

    1986-08-01

    In some Caucasian populations, multiple sclerosis (MS) susceptibility has been independently related to given alleles of HLA or Gm systems that respectively code for major histocompatibility complex class I and II antigens or immunoglobulin G heavy chains. Whether given combinations of alleles at both series of loci simultaneously influence MS susceptibility and/or severity was investigated by comparing 147 French MS patients and 226 geographically-matched healthy controls. The G2m(-23)/HLA-B35 phenotype and G1m(-1)/HLA-B7(-)/HLA-DR2 phenotype were respectively associated with significant protection against (relative risk = 0.05) and susceptibility to (relative risk = 4.3) MS. When considering MS severity, the presence of HLA-B7 antigen correlated with a more severe disease in Gm1/Gm3 heterozygous patients, but not in Gm3/Gm3 homozygous patients. Conversely, an HLA-B12-associated milder disease was restricted to Gm3/Gm3 homozygotes. These results demonstrate the combined influence on MS of genetic loci that are unlinked but immune response-associated. Combined Gm and HLA typing is very likely able to serve as a prognostic indicator in this disease. PMID:3461005

  18. Human leucocyte antigens in tympanosclerosis.

    PubMed

    Dursun, G; Acar, A; Turgay, M; Calgüner, M

    1997-02-01

    This study was designed to evaluate the association between certain HLA antigens and tympanosclerosis. The serum concentrations of HLA antigens were measured by a microlymphocytotoxicity technique in patients with tympanosclerosis and compared with a healthy control group. The serum levels of HLA-B35 and -DR3 were significantly higher in the patients with tympanosclerosis. This result suggests that certain types of HLA antigens may play an important role as an indicator or mediator in the pathogenesis of tympanosclerosis. PMID:9088683

  19. Induction of an antitumor response using dendritic cells transfected with DNA constructs encoding the HLA-A*02:01-restricted epitopes of tumor-associated antigens in culture of mononuclear cells of breast cancer patients.

    PubMed

    Sennikov, Sergey Vital'evich; Shevchenko, Julia Alexandrovna; Kurilin, Vasilii Vasil'evich; Khantakova, Julia Nikolaevna; Lopatnikova, Julia Anatol'evna; Gavrilova, Elena Vasil'evna; Maksyutov, Rinat Amirovich; Bakulina, Anastasiya Yur'evna; Sidorov, Sergey Vasil'evich; Khristin, Alexander Alexandrovich; Maksyutov, Amir Zakievich

    2016-02-01

    Advances in oncoimmunology related to the definition of the basic mechanisms of the formation of antitumor immune response, as well as the opening of tumor-associated antigens recognized by immune cells, allowed to start developing ways to influence the effector cells of the immune system to generate effective antitumor cytotoxic response. We investigated the possibility to stimulate an antitumor response in a culture of mononuclear cells of breast cancer patients by dendritic cells transfected with HLA-A*02:01-restricted DNA constructs. We isolated dendritic cells from peripheral blood monocytes and delivered our constructs to these cells by magnetic transfection. Additionally, a series of experiments with loading of dendritic cells with autologous tumor cell lysate antigens was conducted. We have shown that dendritic cells transfected with the HLA-A*02:01-restricted DNA constructs are effective in inducing an antitumor response in a culture of mononuclear cells of breast cancer patients. Dendritic cells transfected with DNA constructor dendritic cells loaded with lysate antigens revealed a comparable stimulated cytotoxic response of mononuclear cells to these two ways of antigen delivery. We conclude that using DNA constructs in conjunction with patient stratification by HLA type allows the application of transfected DCs as an effective method to stimulate antitumor immunity in vitro. PMID:26590947

  20. Human cytomegalovirus pp65- and immediate early 1 antigen-specific HLA class I-restricted cytotoxic T cell responses induced by cross-presentation of viral antigens.

    PubMed

    Tabi, Z; Moutaftsi, M; Borysiewicz, L K

    2001-05-01

    Dendritic cells (DCs) play a pivotal role in the development of anti-viral CD8(+) CTL responses. This is straightforward if they are directly infected with virus, but is less clear in response to viruses that cannot productively infect DCS: Human CMV (HCMV) shows strain-specific cell tropism: fibroblast (Fb)-adapted laboratory strains (AD169) and recent clinical isolates do not infect DCs, whereas endothelial cell-adapted strains (TB40/E) result in productive lytic DC infection. However, we show here that uninfected DCs induce CD8(+) T cell cytotoxicity and IFN-gamma production against HCMV pp65 and immediate early 1 Ags following in vitro coculture with HCMV-AD169-infected Fbs, regardless of the HLA type of these FBS: CD8(+) T cell stimulation was inhibited by pretreatment of DCs with cytochalasin B or brefeldin A, indicating a phagosome/endosome to cytosol pathway. HCMV-infected Fbs were not apoptotic as measured by annexin V binding, and induction of apoptosis of infected Fbs in vitro did not augment CTL induction by DCs, suggesting a mechanism other than apoptosis in the initiation of cross-presentation. Furthermore, HCMV-infected Fbs provided a maturation signal for immature DCs during coculture, as evidenced by increased CD83 and HLA class II expression. Cross-presentation of HCMV Ags by host DCs enables these professional APCs to bypass some of the evasion mechanisms HCMV has developed to avoid T cell recognition. It may also serve to explain the presence of immediate early 1 Ag-specific CTLs in the face of pp65-induced inhibition of Ag presentation at the level of the infected cell. PMID:11313411

  1. Effects of type II collagen epitope carbamylation and citrullination in human leucocyte antigen (HLA)-DR4(+) monozygotic twins discordant for rheumatoid arthritis.

    PubMed

    De Santis, M; Ceribelli, A; Cavaciocchi, F; Generali, E; Massarotti, M; Isailovic, N; Crotti, C; Scherer, H U; Montecucco, C; Selmi, C

    2016-09-01

    The aim of this study is to investigate the effect of the native, citrullinated or carbamylated type II human collagen T cell- and B cell-epitopes on the adaptive immune response in rheumatoid arthritis (RA). Peripheral blood T and B cells obtained from a human leucocyte D4-related (antigen DR4(-) HLA-DR4)(+) woman with early RA, her healthy monozygotic twin and an unrelated HLA-DR3(+) woman with early RA were analysed for activation (CD154/CD69), apoptosis (annexin/7-aminoactinomycin), cytokine production [interferon (IFN)γ/interleukin (IL)-17/IL-4/IL-10/IL-6] and functional phenotype (CD45Ra/CCR7) after stimulation with the collagen native T cell epitope (T261-273), the K264 carbamylated T cell epitope (carT261-273), the native B cell epitope (B359-369) or the R360 citrullinated B cell epitope (citB359-369), and the combinations of these. The T cell memory compartment was activated by T cell epitopes in both discordant DR4(+) twins, but not in the DR3(+) RA. The collagen-specific activation of CD4(+) T cells was induced with both the native and carbamylated T cell epitopes only in the RA twin. Both T cell epitopes also induced IL-17 production in the RA twin, but a greater IL-4 and IL-10 response in the healthy twin. The citrullinated B cell epitope, particularly when combined with the carbamylated T cell epitope, induced B cell activation and an increased IL-6/IL-10 ratio in the RA twin compared to a greater IL-10 production in the healthy twin. Our data suggest that circulating collagen-specific T and B cells are found in HLA-DR4(+) subjects, but only RA activated cells express co-stimulatory molecules and produce proinflammatory cytokines. Carbamylation and citrullination further modulate the activation and cytokine polarization of T and B cells. PMID:27314557

  2. Antigen

    MedlinePlus

    An antigen is any substance that causes your immune system to produce antibodies against it. This means your immune ... and is trying to fight it off. An antigen may be a substance from the environment, such ...

  3. The in vivo expressed Mycobacterium tuberculosis (IVE-TB) antigen Rv2034 induces CD4⁺ T-cells that protect against pulmonary infection in HLA-DR transgenic mice and guinea pigs.

    PubMed

    Commandeur, Susanna; van den Eeden, Susan J F; Dijkman, Karin; Clark, Simon O; van Meijgaarden, Krista E; Wilson, Louis; Franken, Kees L M C; Williams, Ann; Christensen, Dennis; Ottenhoff, Tom H M; Geluk, Annemieke

    2014-06-17

    Tuberculosis (TB) remains a life-threatening infectious disease of global proportions with serious negative health and economic consequences. The lack of sufficient protection induced by Mycobacterium bovis BCG, the current vaccine for TB, as well as the impact of HIV co-infection and the emergence of drug resistant Mycobacterium tuberculosis (Mtb) strains all urge for improved vaccines against TB. A minimal requirement for Mtb vaccine antigens is their in vivo expression during Mtb infection and ability to trigger significant immune responses. Recently we identified a new class of Mtb antigens, designated IVE-TB (in vivo expressed) antigens. These included Rv2034, a protein that was expressed during pulmonary infection and strongly recognized by human T-cells. Here, the in vivo immunogenicity and protective efficacy of Rv2034 was further analyzed using HLA-DR transgenic mice that lack endogenous murine MHC class II molecules. The Rv2034 protein indeed was highly immunogenic in HLA-DR3 transgenic mice and induced HLA-DR3 restricted IFN-γ(+)/TNF(+) and IFN-γ(+) CD4(+) T-cells, specific for an epitope encoded in peptide 31-50. CD4(+) T-cell responses were optimally induced when using TLR9- and TLR3-ligand-adjuvants or CAF09. Rv2034-specific antibodies were observed following immunization with either TLR2-, TLR3-, TLR4-, TLR5-, TLR7- or TLR9-ligands or CAF09. Importantly, immunization with Rv2034 or the hybrid-protein Ag85B-ESAT6-Rv2034 adjuvanted with CpG or CAF09, induced over one log reduction, relative to unvaccinated controls, in the number of bacilli in the lungs of Mtb challenged HLA-DR3 transgenic mice and guinea pigs. These data demonstrate the potential of Rv2034 as a novel, IVE-TB antigen for future TB vaccination. PMID:24837764

  4. HLA-matched family hematopoetic stem cell transplantation in children with beta thalassemia major: the experience of the Turkish Pediatric Bone Marrow Transplantation Group.

    PubMed

    Yesilipek, M Akif; Ertem, Mehmet; Cetin, Mualla; Öniz, Haldun; Kansoy, Savas; Tanyeli, Atila; Anak, Sema; Kurekci, Emin; Hazar, Volkan

    2012-12-01

    From January 1991 to June 2009, 245 children with beta thalassemia major who underwent their first allogeneic HSCT in Turkey and who were followed for a minimum of one yr post-transplantation were enrolled this study. The median age of the patients was 6.6 yr old (range, 1-22 yr). The distribution of Pesaro risk class I, II, and III categories was 41, 130, and 63 children, respectively. The median serum ferritin level was 2203 ng/mL. Eighty-eight patients received bone marrow (BM) stem cells; 137, peripheral blood (PB) stem cells; and 20, cord blood (CB) stem cells. The donors were HLA-matched siblings or parents. Median engraftment times were shorter in PBSCT patients compared with the BMT group (p < 0.001). Grade II-IV acute GvHD was observed in 33 children (13.5%), while cGvHD was observed in 28 patients (12.5%), eight of whom had the extensive form. Thalassemic reconstitution was observed in 43 (17%) of the transplant patients. Post-transplant aplasia occurred in three patients, and the TRM rate was 7.75%. Seventeen patients were lost after 100 days. The thalassemia-free survival and OS rates were 68% (95% CI, 61.8-74.2) and 85.0% (95% CI, 80.2-89.8), respectively. We believe that this study is important because it is the first multicenter national data for children with beta thalassemia major receiving HSCT. PMID:22931438

  5. HLA variants related to primary sclerosing cholangitis influence rejection after liver transplantation

    PubMed Central

    Fosby, Bjarte; Næss, Sigrid; Hov, Johannes R; Traherne, James; Boberg, Kirsten M; Trowsdale, John; Foss, Aksel; Line, Pål-Dag; Franke, Andre; Melum, Espen; Scott, Helge; Karlsen, Tom H

    2014-01-01

    AIM: To investigate influence of human leukocyte antigen (HLA) and killer immunoglobuline-like receptor (KIR) genotypes on risks of acute rejection (AR) after liver transplantation (LTX). METHODS: In this retrospective study we included 143 adult donor-recipient pairs with a minimum of 6 mo follow-up after LTX for whom DNA was available from both donor and recipients. Clinical data, all early complications including episodes and severity of AR and graft/patient survival were registered. The diagnosis of AR was based on clinical, biochemical and histological criteria. All suspected episodes of AR were biopsy confirmed. Key classical HLA loci (HLA-A, HLA-B, HLA-C and HLA-DRB1) were genotyped using Sanger sequencing. 16 KIR genes were genotyped using a novel real time PCR approach which allows for determination of the diploid copy number of each KIR gene. Immunohistochemical staining for T (CD3), B (CD20) and natural killer (NK) cells (CD56 and CD57) were performed on liver biopsies from 3 different patient groups [primary sclerosing cholangitis (PSC), primary biliary cirrhosis and non-autoimmune liver disease], 10 in each group, with similar grade of AR. RESULTS: Fourty-four (31%) patients were transplanted on the basis of PSC, 40% of them had AR vs 24% in the non-PSC group (P = 0.04). No significant impact of donor-recipient matching for HLA and KIR genotypes was detected. In the overall recipient population an increased risk of AR was detected for HLA-B*08 (P = 0.002, OR = 2.5; 95%CI: 1.4-4.6), HLA-C*07 (P = 0.001, OR = 2.4; 95%CI: 1.4-4.0) and HLA-DRB1*03 (P = 0.03, OR = 1.9; 95%CI: 1.0-3.3) and a decreased risk for HLA-DRB1*04 (P = 0.001, OR = 0.2; 95%CI: 0.1-0.5). For HLA-B*08, HLA-C*07 and DRB1*04 the associations remained evident in a subgroup analysis of non-PSC recipients (P = 0.04, P = 0.003 and P = 0.02, respectively). In PSC recipients corresponding P values were 0.002, 0.17 and 0.01 for HLA-B*08, HLA-C*07 and DRB1*04, respectively. A dosage effect of AR

  6. Structures of MART-126/27-35Peptide/HLA-A2 Complexes Reveal a Remarkable Disconnect between Antigen Structural Homology and T Cell Recognition

    SciTech Connect

    Borbulevych, Oleg Y; Insaidoo, Francis K; Baxter, Tiffany K; Powell, Jr., Daniel J.; Johnson, Laura A; Restifo, Nicholas P; Baker, Brian M

    2008-09-17

    Small structural changes in peptides presented by major histocompatibility complex (MHC) molecules often result in large changes in immunogenicity, supporting the notion that T cell receptors are exquisitely sensitive to antigen structure. Yet there are striking examples of TCR recognition of structurally dissimilar ligands. The resulting unpredictability of how T cells will respond to different or modified antigens impacts both our understanding of the physical bases for TCR specificity as well as efforts to engineer peptides for immunomodulation. In cancer immunotherapy, epitopes and variants derived from the MART-1/Melan-A protein are widely used as clinical vaccines. Two overlapping epitopes spanning amino acid residues 26 through 35 are of particular interest: numerous clinical studies have been performed using variants of the MART-1 26-35 decamer, although only the 27-35 nonamer has been found on the surface of targeted melanoma cells. Here, we show that the 26-35 and 27-35 peptides adopt strikingly different conformations when bound to HLA-A2. Nevertheless, clonally distinct MART-1{sub 26/27-35}-reactive T cells show broad cross-reactivity towards these ligands. Simultaneously, however, many of the cross-reactive T cells remain unable to recognize anchor-modified variants with very subtle structural differences. These dichotomous observations challenge our thinking about how structural information on unligated peptide/MHC complexes should be best used when addressing questions of TCR specificity. Our findings also indicate that caution is warranted in the design of immunotherapeutics based on the MART-1 26/27-35 epitopes, as neither cross-reactivity nor selectivity is predictable based on the analysis of the structures alone.

  7. Presence of a non-HLA B cell antigen in rheumatic fever patients and their families as defined by a monoclonal antibody.

    PubMed Central

    Khanna, A K; Buskirk, D R; Williams, R C; Gibofsky, A; Crow, M K; Menon, A; Fotino, M; Reid, H M; Poon-King, T; Rubinstein, P

    1989-01-01

    Numerous investigators have suspected that there is a genetic predisposition to rheumatic fever (RF). In this context we have recently produced a series of monoclonal antibodies directed against B cells obtained from RF patients one of which, labeled D8/17, identifies a B cell antigen present in 100% of all RF patients studied. While the highest percentage of positive cells were exhibited by RF probands (33.5% +/- SE), the percentage of cells in unaffected siblings and parents was 14.6 and 13%, respectively. The percentage of positive cells in APSGN probands, unaffected siblings, and parents was 2.96, 3.86, and 2.8%, respectively. A low level of B cells (5-7%) bearing the D8/17 marker was seen in control patients. The segregation pattern of the phenotypes defined by the percentage of D8/17 positive cells within HLA-typed RF families are consistent with an autosomal recessive mode of inheritance not associated with the human MHC system. We postulate that these phenotypes indicate the presence of at least one necessary genetic factor for susceptibility to RF. PMID:2785121

  8. Chimeric peptide containing both B and T cells epitope of tumor-associated antigen L6 enhances anti-tumor effects in HLA-A2 transgenic mice.

    PubMed

    Lin, Su-I; Huang, Ming-Hsi; Chang, Yu-Wen; Chen, I-Hua; Roffler, Steve; Chen, Bing-Mae; Sher, Yuh-Pyng; Liu, Shih-Jen

    2016-07-28

    Synthetic peptides are attractive for cancer immunotherapy because of their safety and flexibility. In this report, we identified a new B cell epitope of tumor-associated antigen L6 (TAL6) that could induce antibody-dependent cellular cytotoxicity (ADCC) in vivo. We incorporated the B cell epitope with a cytotoxic T lymphocyte (CTL) and a helper T (Th) epitope to form a chimeric long peptide. We formulated the chimeric peptide with different adjuvants to immunize HLA-A2 transgenic mice and evaluate their immunogenicity. The chimeric peptide formulated with an emulsion type nanoparticle (PELC) adjuvant and a toll-like receptor 9 agonist (CpG ODN) (PELC/CpG) induced the greatest ADCC and CTL responses. The induced anti-tumor immunity inhibited the growth of TAL6-positive cancer cells. Moreover, we observed that immunization with the chimeric peptide inhibited cancer cell migration in vitro and metastasis in vivo. These data suggest that a chimeric peptide containing both B and T cell epitopes of TAL6 formulated with PELC/CpG adjuvant is feasible for cancer immunotherapy. PMID:27130449

  9. Class II HLA interactions modulate genetic risk for multiple sclerosis

    PubMed Central

    Dilthey, Alexander T; Xifara, Dionysia K; Ban, Maria; Shah, Tejas S; Patsopoulos, Nikolaos A; Alfredsson, Lars; Anderson, Carl A; Attfield, Katherine E; Baranzini, Sergio E; Barrett, Jeffrey; Binder, Thomas M C; Booth, David; Buck, Dorothea; Celius, Elisabeth G; Cotsapas, Chris; D’Alfonso, Sandra; Dendrou, Calliope A; Donnelly, Peter; Dubois, Bénédicte; Fontaine, Bertrand; Fugger, Lars; Goris, An; Gourraud, Pierre-Antoine; Graetz, Christiane; Hemmer, Bernhard; Hillert, Jan; Kockum, Ingrid; Leslie, Stephen; Lill, Christina M; Martinelli-Boneschi, Filippo; Oksenberg, Jorge R; Olsson, Tomas; Oturai, Annette; Saarela, Janna; Søndergaard, Helle Bach; Spurkland, Anne; Taylor, Bruce; Winkelmann, Juliane; Zipp, Frauke; Haines, Jonathan L; Pericak-Vance, Margaret A; Spencer, Chris C A; Stewart, Graeme; Hafler, David A; Ivinson, Adrian J; Harbo, Hanne F; Hauser, Stephen L; De Jager, Philip L; Compston, Alastair; McCauley, Jacob L; Sawcer, Stephen; McVean, Gil

    2016-01-01

    Association studies have greatly refined the understanding of how variation within the human leukocyte antigen (HLA) genes influences risk of multiple sclerosis. However, the extent to which major effects are modulated by interactions is poorly characterized. We analyzed high-density SNP data on 17,465 cases and 30,385 controls from 11 cohorts of European ancestry, in combination with imputation of classical HLA alleles, to build a high-resolution map of HLA genetic risk and assess the evidence for interactions involving classical HLA alleles. Among new and previously identified class II risk alleles (HLA-DRB1*15:01, HLA-DRB1*13:03, HLA-DRB1*03:01, HLA-DRB1*08:01 and HLA-DQB1*03:02) and class I protective alleles (HLA-A*02:01, HLA-B*44:02, HLA-B*38:01 and HLA-B*55:01), we find evidence for two interactions involving pairs of class II alleles: HLA-DQA1*01:01–HLA-DRB1*15:01 and HLA-DQB1*03:01–HLA-DQB1*03:02. We find no evidence for interactions between classical HLA alleles and non-HLA risk-associated variants and estimate a minimal effect of polygenic epistasis in modulating major risk alleles. PMID:26343388

  10. Enriched HLA-DQ3 phenotype and decreased class I major histocompatibility complex antigen expression in recurrent respiratory papillomatosis.

    PubMed Central

    Bonagura, V R; Siegal, F P; Abramson, A L; Santiago-Schwarz, F; O'Reilly, M E; Shah, K; Drake, D; Steinberg, B M

    1994-01-01

    Respiratory papillomas, caused by human papillomaviruses, are benign tumors that recur following removal. We evaluated immune function and major histocompatibility complex (MHC) phenotype and expression in these patients. MHC-independent immune function appeared normal. The frequency of peripheral blood MHC class II phenotypes was highly enriched for DQ3 and DR11, one split of DR5. Class I MHC antigen expression on papilloma tissue was markedly reduced. Together, these phenomena may facilitate papillomavirus evasion of the cellular immune response. Images PMID:7496977

  11. HLA-B alleles and complotypes in Mexican patients with seronegative spondyloarthropathies.

    PubMed Central

    Vargas-Alarcón, G; Garcia, A; Bahena, S; Melin-Aldana, H; Andrade, F; Ibañez-de-Kasep, G; Alcocer-Varela, J; Alarcón-Segovia, D; Granados, J

    1994-01-01

    OBJECTIVES--To analyse major histocompatibility complex (MHC) haplotypes in Mexican mestizo patients with seronegative spondyloarthropathies (SSpA) and normal controls, to discover if there are other antigens, besides B27, in the HLA region that might show association with the disease. METHODS--The study included 100 Mexican mestizo patients with SSpA and 200 of their first degree relatives. These groups were compared with 85 ethnically matched controls. The class I and class III MHC antigens were obtained by standard methods. The significance of differences between patients and controls was tested by chi 2 analysis; linkage disequilibrium among the different alleles in each haplotype was estimated by computing delta values. RESULTS--We found a significantly increased frequency of the HLA-B27 antigen (pcorr. = 1 x 10(-5), odds ratio (OR) = 33.4, 95% confidence interval (CI) = 9.3-142.0). In the group of 45 SSpA patients negative for the B27 antigen, independent increased frequencies of HLA-B49 antigen (pcorr. = 0.03, OR = 6.5, 95% CI = 1.5-32.8)) and the FC31 complotype (pcorr. = 0.04, OR = 3.7, 95% CI = 1.2-11.1) were found. Significant delta values were obtained for the [B27;SC30] haplotype (p = 0.0005) but not for haplotypes marked by the FC31 complotype. HLA-B antigens on the homologous chromosome in B27 positive patients were mainly HLA-B51 (18%) and HLA-B60 (16%); however, the observed genotypes B27/B51 and B27/B60 were not significantly different than expected from the allele frequencies alone. CONCLUSIONS--These data suggest that in Mexicans additional genes within the MHC region besides the HLA-B27 antigen, might be related to the genetic susceptibility for developing SSpA. Relevant antigens included the HLA-B49 and the FC31 complotype. PMID:7826137

  12. The two neutrophil plasma membrane markers alkaline phosphatase and HLA class I antigen localize differently in granule-deficient cytoplasts. An ideal plasma membrane marker in human neutrophils is still lacking.

    PubMed

    Pellmé, Sara; Dahlgren, Claes; Karlsson, Anna

    2007-08-31

    Neutrophil function relies largely on the ability of the cell to mobilize its different granules and vesicles to the cell surface and thereby expose and/or release effector molecules to the surrounding tissue. To properly identify these subcellular compartments is thus a prerequisite for studies of neutrophil physiology. A range of specific markers for the classical granules is available, but finding optimal markers for the secretory vesicles and plasma membrane has historically been more challenging. Latent and non-latent alkaline phosphatase activities are often used to distinguish these two light membrane structures, but the outcome using this technique depends on the level of cellular activation. Therefore, HLA-I was introduced some years ago as a specific, stimulation-independent marker for the plasma membrane. In this study we however report that detailed fractionation studies of neutrophil cytoplasts, lacking secretory vesicles, granules and other dense organelles, reveal that the HLA-I antigen is not only co-localizing with the plasma membrane marker ALP, but is also present in other, more dense organelles. Further, we found the mixed enzyme-linked immunosorbent assay (MELISA), detecting the beta(2)-microglobulin/HLA-I complex, to be negatively influenced by uncomplexed beta(2)-microglobulin present in the specific granules and secretory vesicles, making it difficult to use HLA-I as a plasma membrane marker during maturation of for example phagolysosomes. PMID:17673253

  13. Fludarabine/2 Gy TBI is Superior to 2 Gy TBI as Conditioning for HLA-Matched Related HCT: A Phase III Randomized Trial

    PubMed Central

    Kornblit, Brian; Maloney, David G.; Storb, Rainer; Storek, Jan; Hari, Parameswaran; Vucinic, Vladan; Maziarz, Richard T.; Chauncey, Thomas R.; Pulsipher, Michael A.; Bruno, Benedetto; Petersen, Finn B.; Bethge, Wolfgang A.; Hübel, Kai; Bouvier, Michelle E.; Fukuda, Takahiro; Storer, Barry E.; Sandmaier, Brenda M.

    2013-01-01

    The risk/benefit of adding fludarabine to a 2 Gy total body irradiation nonmyeloablative regimen is unknown. For this reason we conducted a prospective randomized trial comparing 2 Gy TBI alone or in combination with 90mg/m2 fludarabine (FLU/TBI) before transplantation of peripheral blood stem cells from HLA-matched related donors. Eighty-five patients with hematological malignancies were randomized to be conditioned with TBI alone (n=44) or FLU/TBI (n=41). All patients had initial engraftment. Two graft rejections were observed, both in the TBI group. Infection rates, nonrelapse mortality, and GVHD were similar between groups. Three-year overall survival was lower in the TBI group (54% vs. 65%; hazard ratio (HR) 0.57; p=0.09), with higher incidences of relapse/progression (55% vs. 40%; HR 0.55; p=0.06) and relapse-related mortality (37% vs. 28%; HR 0.53; p=0.09), and a lower progression-free survival (36% vs. 53%; HR 0.56; p=0.05). Median donor T-cell chimerism levels were significantly lower in the TBI group at days 28 (61% vs. 90%; p<0.0001) and 84 (68% vs. 92%; p<0.0001), as was NK-cell chimerism on day 28 (75% vs. 96%, p=0.0005). In conclusion, this randomized trial demonstrates the importance of fludarabine in augmenting the graft-versus-tumor effect by ensuring prompt and durable high level donor engraftment early post-transplant. PMID:23769990

  14. Pre and post-natal antigen exposure can program the stress axis of adult zebra finches: evidence for environment matching.

    PubMed

    Merrill, Loren; Grindstaff, Jennifer L

    2015-03-01

    Both maternal exposure to stressors and exposure of offspring to stressors during early life can have lifelong effects on the physiology and behavior of offspring. Stress exposure can permanently shape an individual's phenotype by influencing the development of the hypothalamic-pituitary-adrenal (HPA) axis, which is responsible for the production and regulation of glucocorticoids such as corticosterone (CORT). In this study we used captive zebra finches (Taeniopygia guttata) to examine the effects of matching and mismatching maternal and early post-natal exposure to one of two types of antigens or a control on HPA axis reactivity in adult offspring. Prior to breeding, adult females were injected with lipopolysaccharide (LPS), keyhole limpet hemocyanin (KLH) or a control. Offspring of females in each of the three treatments were themselves exposed to LPS, KLH or a control injection at 5 and 28days post-hatch. When offspring were at least 18months of age, standardized capture and restraint stress tests were conducted to determine the impact of the treatments on adult stress responsiveness. We found significant interaction effects between maternal and offspring treatments on stress-induced CORT levels, and evidence in support of the environment matching hypothesis for KLH-treated birds, not LPS-treated birds. KLH-treated offspring of KLH-treated mothers exhibited reduced stress-induced CORT levels, whereas LPS-treated or control offspring of KLH-treated mothers exhibited elevated stress-induced CORT levels. Although the treatment effects on baseline CORT were non-significant, the overall pattern was similar to the effects observed on stress-induced CORT levels. Our results highlight the complex nature of HPA axis programming, and to our knowledge, provide the first evidence that a match or mismatch between pre and post-natal antigen exposure can have life-long consequences for HPA axis function. PMID:25535860

  15. Pre and post-natal antigen exposure can program the stress axis of adult zebra finches: evidence for environment matching

    PubMed Central

    Merrill, Loren; Grindstaff, Jennifer L.

    2014-01-01

    Both maternal exposure to stressors and exposure of offspring to stressors during early life can have lifelong effects on the physiology and behavior of offspring. Stress exposure can permanently shape an individual’s phenotype by influencing the development of the hypothalamic-pituitary-adrenal (HPA) axis, which is responsible for the production and regulation of glucocorticoids such as corticosterone (CORT). In this study we used captive zebra finches (Taeniopygia guttata) to examine the effects of matching and mismatching maternal and early post-natal exposure to one of two types of antigens or a control on HPA axis reactivity in adult offspring. Prior to breeding, adult females were injected with lipopolysaccharide (LPS), keyhole limpet hemocyanin (KLH) or a control. Offspring of females in each of the three treatments were themselves exposed to LPS, KLH or a control injection at 5 and 28 days post-hatch. When offspring were at least 18 months of age, standardized capture and restraint stress tests were conducted to determine the impact of the treatments on adult stress responsiveness. We found significant interaction effects between maternal and offspring treatments on stress-induced CORT levels, and evidence in support of the environment matching hypothesis for KLH-treated birds not LPS-treated birds. KLH-treated offspring of KLH-treated mothers exhibited reduced stress-induced CORT levels, whereas LPS-treated or control offspring of KLH-treated mothers exhibited elevated stress-induced CORT levels. Although the treatment effects on baseline CORT were non-significant, the overall pattern was similar to the effects observed on stress-induced CORT levels. Our results highlight the complex nature of HPA axis programming, and to our knowledge, provide the first evidence that a match or mismatch between pre and post-natal antigen exposure can have life-long consequences for HPA axis function. PMID:25535860

  16. Direct recognition of SLA- and HLA-like class II antigens on porcine endothelium by human T cells results in T cell activation and release of interleukin-2.

    PubMed

    Bravery, C A; Batten, P; Yacoub, M H; Rose, M L

    1995-11-15

    To investigate whether human T cells can directly recognize pig xenoantigens, highly purified human CD4+ and CD8+ T cells were incubated with pig aortic endothelial cells (PAEC). The response was measured by [3H]thymidine uptake and release of bioactive interleukin-2. A detailed examination of MHC expression by cultured PAEC and tissue sections of porcine aorta and heart showed porcine endothelial cells (EC) to be constitutively positive for SLA class II and antigens that crossreact with HLA class II molecules. Low level expression of B7 receptors was detected by binding of both human and mouse CTLA-4-Ig to untreated PAEC, which was enhanced significantly by treatment with recombinant porcine interferon-gamma. Human T cells, purified by positive selection and residual DR+ cells removed by lymphocytolysis, were shown to be functionally free of monocytes. Untreated PAEC elicited strong proliferation by human CD4+ T cells: CD8+ T cells also proliferated, but more weakly. This response was inhibited by CTLA-4-Ig. Blocking studies were performed with mAbs that bind to PAEC and not human EC (MSA3, TH16B), an mAb that binds to human and porcine EC (DA6.231), and L243, which binds to human and not porcine EC. The proliferative response of CD4+ T cells to PAEC was inhibited significantly by mAbs against swine and human determinants. In contrast, the response of CD4+ T cells to human EC was inhibited only by mAbs against human determinants. Experiments that directly compared the CD4+ and CD8+ T cell responses to PAEC and the human EC line EAhy.926, both with and without prior treatment with species-specific interferon gamma, demonstrated greater proliferation and 5-10 times more interleukin-2 in response to pig EC than to human EC. PMID:7491676

  17. Lab-on-a-chip enabled HLA diagnostic: combined sample preparation and real time PCR for HLA-B57 diagnosis

    NASA Astrophysics Data System (ADS)

    Gärtner, Claudia; Becker, Holger; Hlawatsch, Nadine; Klemm, Richard; Moche, Christian; Schattschneider, Sebastian; Frank, Rainer; Willems, Andreas

    2015-05-01

    The diverse human HLA (human leukocyte antigen) system is responsible for antigen presentation and recognition. It is essential for the immune system to maintain a stable defense line, but also is also involved in autoimmunity as well as metabolic disease. HLA-haplotype (HLA-B27), for instance, is associated with inflammatory diseases such as Bechterew's disease. The administration of the HIV drug Abacavir in combination with another HLA-haplotype (HLAB57) is associated with severe hypersensitivity reactions. Accordingly, the HLA status has to be monitored for diagnosis or prior to start of therapy. Along this line, a miniaturized microfluidic platform has been developed allowing performing the complete analytical process from "sample-in" to "answer-out" in a point-of-care environment. The main steps of the analytical cascade inside the integrated system are blood cell lysis and DNA isolation, DNA purification, real-time PCR and quantitative monitoring of the rise of a fluorescent signal appearing during the PCR based sequence amplification. All bio-analytical steps were intended to be performed inside one chip and will be actuated, controlled and monitored by a matching device. This report will show that all required processes are established and tested and all device components work well and interact with the functional modules on the chips in a harmonized fashion.

  18. Reduction in HLA-DR, HLA-DQ and HLA-DP expression by Leu-M3+ cells from the peripheral blood of patients with thermal injury.

    PubMed Central

    Gibbons, R A; Martinez, O M; Lim, R C; Horn, J K; Garovoy, M R

    1989-01-01

    Monocytes that bear HLA Class II antigens, such as HLA-DR, HLA-DQ, or HLA-DP, are obligatory for many cell-mediated immunological processes. Patients with thermal injury suffer from hypoimmunity and are at risk for developing life-threatening septic episodes. To determine whether an alteration in expression of HLA Class II antigens is involved in the defect, monocytes from the peripheral blood of burn patients and controls were double-stained with anti-Leu-M3 and either anti-HLA-DR, HLA-DQ, or HLA-DP monoclonal antibodies. As analysed by flow cytometry the percentage of Leu-M3+ monocytes from the peripheral blood from patients and controls was the same. The percentage of Leu-M3+ monocytes bearing the HLA Class II antigens and the density of antigen on the monocytes, however, was significantly reduced post-burn compared with controls. In nearly all cases these changes were detected as early as 24 h post-burn before any drug therapy was implemented. In-vivo re-expression of normal levels of HLA Class II coincided with patient recovery. In-vitro exposure of post-burn Leu-M3+ cells to IFN-gamma for 72 h restored HLA Class II expression to control levels. It is possible that the reductions in HLA Class II expression may be involved in the general immunosuppression that follows thermal injury. PMID:2495202

  19. HLA mismatches and hematopoietic cell transplantation: structural simulations assess the impact of changes in peptide binding specificity on transplant outcome

    PubMed Central

    Yanover, Chen; Petersdorf, Effie W.; Malkki, Mari; Gooley, Ted; Spellman, Stephen; Velardi, Andrea; Bardy, Peter; Madrigal, Alejandro; Bignon, Jean-Denis; Bradley, Philip

    2013-01-01

    The success of hematopoietic cell transplantation from an unrelated donor depends in part on the degree of Human Histocompatibility Leukocyte Antigen (HLA) matching between donor and patient. We present a structure-based analysis of HLA mismatching, focusing on individual amino acid mismatches and their effect on peptide binding specificity. Using molecular modeling simulations of HLA-peptide interactions, we find evidence that amino acid mismatches predicted to perturb peptide binding specificity are associated with higher risk of mortality in a large and diverse dataset of patient-donor pairs assembled by the International Histocompatibility Working Group in Hematopoietic Cell Transplantation consortium. This analysis may represent a first step toward sequence-based prediction of relative risk for HLA allele mismatches. PMID:24482668

  20. The TAG family of cancer/testis antigens is widely expressed in a variety of malignancies and gives rise to HLA-A2-restricted epitopes.

    PubMed

    Adair, Sara J; Carr, Tiffany M; Fink, Mitsú J; Slingluff, Craig L; Hogan, Kevin T

    2008-01-01

    The TAG-1, TAG-2a, TAG-2b, and TAG-2c cancer/testis genes, known to be expressed in an unusually high percentage of melanoma cell lines, are shown here to be expressed in a variety of tumor lines of diverse histologic type, including cancers of the brain, breast, colon, lung, ovary, pharynx, and tongue. The genes are also expressed in fresh, uncultured melanoma, and ovarian cancer cells. Epitope prediction algorithms were used to identify potential HLA-A1, HLA-A2, HLA-A3, HLA-B7, and HLA-B8 epitopes, and these potential epitopes were tested for their ability to stimulate a peptide-specific cytotoxic T lymphocyte response using lymphocytes from healthy donors. Two HLA-A2-restricted epitopes (SLGWLFLLL and LLLRLECNV) were identified using this approach. Cytotoxic T lymphocytes specific for each of these peptides were capable of recognizing tumor cells expressing both the corresponding class I major histocompatibility complex encoded molecule and the TAG genes. These results indicate that TAG-derived peptides may be good components of a therapeutic vaccine designed to target melanoma and a variety of epithelial cell-derived malignancies. PMID:18157007

  1. HLA-DP, HLA-DQ, and HLA-DR-restricted epitopes in GRA5 of toxoplasma gondii strains

    NASA Astrophysics Data System (ADS)

    Haryati, S.; Sari, Y.; APrasetyo, A.; Sariyatun, R.

    2016-02-01

    The dense granular (GRA) proteins of Toxoplasma gondii(T. gondii) have been demonstrated as potential sources of T. gondii vaccine antigens. However, data of the GRA5 protein are limited. This study analyzed twenty-one complete GRA5 sequences of T. gondii GT1, RH, ME49, VEG, MAS, RUB, FOU, p89, VAND, and GAB2-2007-GAL-DOM2 strains to identify potential epitopes restricted by Major Histocompatibility Complex class II (MHC- II) molecules (human leukocyte antigen (HLA)-DP, HLA-DQ, and HLA-DR) in the protein. In all T. gondii strains, peptides positioned at amino acid (aa) 15-29, 16-30, 17-31, 18-32, 19-33, 83-97, 84-98, 86-100, 87-101, 89-103, and 90-104 were predicted to pose high affinity and binding with HLA-DRB1*0101, HLA-DRB1*0301 (DR17), HLA-DRB1*0401 (DR4Dw4), HLA-DRB1*0701, HLA-DRB1*1101, HLA-DRB1*1501 (DR2b), and/or HLA-DRB5*0101. Considering the epitope's affinity, ligation strength, and hydrophilicity, LRLLRRRRRRAIQEE sequence (aa 90-104) restricted by HLA-DRB1*0101, HlA- DRB1*0301 (DR17), and HLA-DRB1*0401 (DR4Dw4) was considered as the most potential MHC-II epitope in GRA5 of T. gondii. These results would be useful for studies concerning in developing T. gondii vaccine and diagnostic method.

  2. Human HLA-G+ extravillous trophoblasts: Immune-activating cells that interact with decidual leukocytes.

    PubMed

    Tilburgs, Tamara; Crespo, Ângela C; van der Zwan, Anita; Rybalov, Basya; Raj, Towfique; Stranger, Barbara; Gardner, Lucy; Moffett, Ashley; Strominger, Jack L

    2015-06-01

    Invading human leukocyte antigen-G+ (HLA-G+) extravillous trophoblasts (EVT) are rare cells that are believed to play a key role in the prevention of a maternal immune attack on foreign fetal tissues. Here highly purified HLA-G+ EVT and HLA-G- villous trophoblasts (VT) were isolated. Culture on fibronectin that EVT encounter on invading the uterus increased HLA-G, EGF-Receptor-2, and LIF-Receptor expression on EVT, presumably representing a further differentiation state. Microarray and functional gene set enrichment analysis revealed a striking immune-activating potential for EVT that was absent in VT. Cocultures of HLA-G+ EVT with sample matched decidual natural killer cells (dNK), macrophages, and CD4+ and CD8+ T cells were established. Interaction of EVT with CD4+ T cells resulted in increased numbers of CD4+CD25(HI)FOXP3+CD45RA+ resting regulatory T cells (Treg) and increased the expression level of the Treg-specific transcription factor FOXP3 in these cells. However, EVT did not enhance cytokine secretion in dNK, whereas stimulation of dNK with mitogens or classical natural killer targets confirmed the distinct cytokine secretion profiles of dNK and peripheral blood NK cells (pNK). EVT are specialized cells involved in maternal-fetal tolerance, the properties of which are not imitated by HLA-G-expressing surrogate cell lines. PMID:26015573

  3. Some Basic Aspects of HLA-G Biology

    PubMed Central

    Fernandez-Landázuri, Sara; González, Alvaro

    2014-01-01

    Human leukocyte antigen-G (HLA-G) is a low polymorphic nonclassical HLA-I molecule restrictively expressed and with suppressive functions. HLA-G gene products are quite complex, with seven HLA-G isoforms, four membrane bound, and other three soluble isoforms that can suffer different posttranslational modifications or even complex formations. In addition, HLA-G has been described included in exosomes. In this review we will focus on HLA-G biochemistry with special emphasis to the mechanisms that regulate its expression and how the protein modifications affect the quantification in biological fluids. PMID:24818168

  4. Gene–environment interaction between HLA-DRB1 shared epitope and heavy cigarette smoking in predicting incident rheumatoid arthritis

    PubMed Central

    Karlson, E W; Chang, S-C; Cui, J; Chibnik, L B; Fraser, P A; De Vivo, I; Costenbader, K H

    2010-01-01

    Background: Previous studies have reported an interaction between ever cigarette smoking and the presence of the human leukocyte antigen (HLA)-DRB1 shared epitope (SE) genotype and rheumatoid arthritis (RA) risk. To address the effect of dosage, a case-control study nested within two prospective cohorts to determine the interaction between heavy smoking and the HLA-SE was conducted. Methods: Blood was obtained from 32 826 women in the Nurses’ Health Study and 29 611 women in the Nurses’ Health Study II. Incident RA diagnoses were validated by chart review. Controls were matched for age, menopausal status and postmenopausal hormone use. High-resolution HLA-DRB1 genotyping was performed for SE alleles. HLA-SE, smoking, HLA-SE* smoking interactions and RA risk, were assessed using conditional logistic regression models, adjusted for age and reproductive factors. Additive and multiplicative interactions were tested. Results: In all, 439 Caucasian matched pairs were included. Mean age at RA diagnosis was 55.2 years; 62% of cases were seropositive. A modest additive interaction was observed between ever smoking and HLA-SE in seropositive RA risk. A strong additive interaction (attributable proportion due to interaction (AP) = 0.50; p<0.001) and significant multiplicative interaction (p = 0.05) were found between heavy smoking (>10 pack-years) and any HLA-SE in seropositive RA risk. The highest risk was in heavy smokers with double copy HLA-SE (odds ratio (OR) 7.47, 95% CI 2.77 to 20.11). Conclusions: A strong gene–environment interaction was observed between HLA-SE and smoking when stratifying by pack-years of smoking rather than by ever smoking. Future studies should assess cumulative exposure to cigarette smoke when testing for gene–smoking interactions. PMID:19151010

  5. In silico Derivation of HLA-Specific Alloreactivity Potential from Whole Exome Sequencing of Stem-Cell Transplant Donors and Recipients: Understanding the Quantitative Immunobiology of Allogeneic Transplantation

    PubMed Central

    Jameson-Lee, Max; Koparde, Vishal; Griffith, Phil; Scalora, Allison F.; Sampson, Juliana K.; Khalid, Haniya; Sheth, Nihar U.; Batalo, Michael; Serrano, Myrna G.; Roberts, Catherine H.; Hess, Michael L.; Buck, Gregory A.; Neale, Michael C.; Manjili, Masoud H.; Toor, Amir Ahmed

    2014-01-01

    Donor T-cell mediated graft versus host (GVH) effects may result from the aggregate alloreactivity to minor histocompatibility antigens (mHA) presented by the human leukocyte antigen (HLA) molecules in each donor–recipient pair undergoing stem-cell transplantation (SCT). Whole exome sequencing has previously demonstrated a large number of non-synonymous single nucleotide polymorphisms (SNP) present in HLA-matched recipients of SCT donors (GVH direction). The nucleotide sequence flanking each of these SNPs was obtained and the amino acid sequence determined. All the possible nonameric peptides incorporating the variant amino acid resulting from these SNPs were interrogated in silico for their likelihood to be presented by the HLA class I molecules using the Immune Epitope Database stabilized matrix method (SMM) and NetMHCpan algorithms. The SMM algorithm predicted that a median of 18,396 peptides weakly bound HLA class I molecules in individual SCT recipients, and 2,254 peptides displayed strong binding. A similar library of presented peptides was identified when the data were interrogated using the NetMHCpan algorithm. The bioinformatic algorithm presented here demonstrates that there may be a high level of mHA variation in HLA-matched individuals, constituting a HLA-specific alloreactivity potential. PMID:25414699

  6. Luminex-Based Methods in High-Resolution HLA Typing.

    PubMed

    Testi, Manuela; Andreani, Marco

    2015-01-01

    Luminex-based technology has been applied to discriminate between the different Human Leukocyte Antigens (HLA) alleles. The typing method consists in a reverse-SSO assay: Target DNA is PCR-amplified using biotinylated group-specific primers. A single PCR reaction is used for each HLA locus. The biotinylated PCR product is chemically denatured using a pH change and allowed to rehybridize to complementary DNA probes conjugated to microspheres. These beads are characterized by two internal fluorescent dyes that create a unique combination of color, make them identifiable. Washes are performed to eliminate any additional PCR product that does not exactly match the sequence detected by the probe. The biotinylated PCR product bound to the microsphere is labelled with streptavidin conjugated with R-phycoerythrin (SAPE). A flow analyzer identifies the fluorescent intensity SAPE on each microsphere. Software is used to assign positive or negative reactions based on the strength of the fluorescent signal. The assignment of the HLA typing is based on positive and negative probe reactions compared with published HLA gene sequences. Recently kits characterized by an extensive number of probes/beads designed to potentially reduce the number of ambiguities or to directly lead to an allele level typing, have been made available. PMID:26024639

  7. Association of HLA-DRw2 with autoimmune thrombocytopenic purpura.

    PubMed Central

    Karpatkin, S; Fotino, M; Gibofsky, A; Winchester, R J

    1979-01-01

    Peripheral blood lymphocytes from 38 patients with autoimmune thrombocytopenic purpura (AITP) were tested for HLA-A, -B, and -C alloantigens. Isolated B lymphocytes from 20 of these patients were tested for HLA-DRw (Ia) alloantigens. The profile of HLA alloantigens in the patients with AITP was significantly different from that of a matched control population. The most significant finding was the presence of the HLA-DRw2 alloantigen in 75% of patients as compared with 23% in the control population, P less than 0.001, relative risk 10.0 (A relative risk of 1 would indicate no association between the presence of the antigen and the disease.) The co-occurrence of either A3 and B7 (known to be in linkage disequilibrium with DRw2) or A26 and Bw38 was significantly increased as compared with the control population (P less than 0.001). Of the patients positive for DRw2, 47% had the association A26 and Bw38 as compared with the control population association incidence of 21% (P less than 0.1). Thus, in the patient population, A26-Bw38 appears to be a haplotype that is in linkage disequilibrium with DRw2 (as presumably is the case with A3-B7). These data indicate that a predisposition to AITP is inherited with a DRw2 gene of the major histocompatibility system. PMID:571874

  8. HLA-A*0201 T-cell epitopes in severe acute respiratory syndrome (SARS) coronavirus nucleocapsid and spike proteins

    SciTech Connect

    Tsao, Y.-P.; Lin, J.-Y.; Jan, J.-T.; Leng, C.-H.; Chu, C.-C.; Yang, Y.-C.; Chen, S.-L. . E-mail: showlic@ha.mc.ntu.edu.tw

    2006-05-26

    The immunogenicity of HLA-A*0201-restricted cytotoxic T lymphocyte (CTL) peptide in severe acute respiratory syndrome coronavirus (SARS-CoV) nuclear capsid (N) and spike (S) proteins was determined by testing the proteins' ability to elicit a specific cellular immune response after immunization of HLA-A2.1 transgenic mice and in vitro vaccination of HLA-A2.1 positive human peripheral blood mononuclearcytes (PBMCs). First, we screened SARS N and S amino acid sequences for allele-specific motif matching those in human HLA-A2.1 MHC-I molecules. From HLA peptide binding predictions (http://thr.cit.nih.gov/molbio/hla{sub b}ind/), ten each potential N- and S-specific HLA-A2.1-binding peptides were synthesized. The high affinity HLA-A2.1 peptides were validated by T2-cell stabilization assays, with immunogenicity assays revealing peptides N223-231, N227-235, and N317-325 to be First identified HLA-A*0201-restricted CTL epitopes of SARS-CoV N protein. In addition, previous reports identified three HLA-A*0201-restricted CTL epitopes of S protein (S978-986, S1203-1211, and S1167-1175), here we found two novel peptides S787-795 and S1042-1050 as S-specific CTL epitopes. Moreover, our identified N317-325 and S1042-1050 CTL epitopes could induce recall responses when IFN-{gamma} stimulation of blood CD8{sup +} T-cells revealed significant difference between normal healthy donors and SARS-recovered patients after those PBMCs were in vitro vaccinated with their cognate antigen. Our results would provide a new insight into the development of therapeutic vaccine in SARS.

  9. HLA-A2, HLA-B44 and HLA-DR15 are associated with lower risk of BK viremia

    PubMed Central

    Masutani, Kosuke; Ninomiya, Toshiharu; Randhawa, Parmjeet

    2013-01-01

    Background Human leucocyte antigens (HLAs) modulate immunity to polyomavirus BK (BKV). Identification of HLAs that alter the course of infection will facilitate risk stratification, and customization of pre-emptive intervention strategies. Methods We performed a retrospective cohort study with 998 kidney transplant patients with BKV infection status confirmed by polymerase chain reaction (PCR). Clinical parameters and donor–recipient matching for specific HLAs were examined in relation to occurrence of viremia. An emphasis was placed on donor–recipient matching rather than the actual frequency of specific HLA-alleles, since a successful immune response requires sharing of HLAs between a virus-infected target cell and the anti-viral effector cell. Results Using multivariate statistics, low risk of BK viremia was associated with matching of HLA-A2 [hazard ratio (HR) 0.51, 95% confidence interval (CI) 0.28–0.85], HLA-B44 (HR 0.31, 95% CI 0.076–0.85) and HLA-DR15 (HR 0.35, 95% CI 0.084–0.93) (P < 0.05), whereas high risk of viremia was associated with male gender (HR 2.38, 95% CI 1.46–4.09, P < 0.001). Conclusions HLAs that associated with a lower predisposition to the development of BK viremia have been identified. Evaluation of donor–recipient mismatching for these HLAs could potentially be used to (i) fine tune virus screening strategies for BKV in individual patients and (ii) facilitate discovery of major histocompatibility complex (MHC) class I and II binding peptides that can elicit clinically meaningful BKV-specific immunity. PMID:24084328

  10. The HLA system and diabetes mellitus.

    PubMed

    Cudworth, A G; Woodrow, J C

    1977-06-01

    There is a significant positive association between insulin dependent diabetes, irrespective of age of onset, and the HLA system, whereas there is no association of HLA antigens with non-insulin dependent diabetes. There is a significant concordance value for HLA antigen frequencies in insulin dependent diabetics from three different centres, indicating that the genes (s) conferring susceptibility to this type of diabetes is possibly present in all "juvenile-onset" diabetics and is in linkage disequilibrium with all the B locus alleles. PMID:892129

  11. Risk factors and outcome of graft failure after HLA matched and mismatched unrelated donor hematopoietic stem cell transplantation: a study on behalf of SFGM-TC and SFHI.

    PubMed

    Cluzeau, T; Lambert, J; Raus, N; Dessaux, K; Absi, L; Delbos, F; Devys, A; De Matteis, M; Dubois, V; Filloux, M; Fort, M; Hau, F; Jollet, I; Labalette, M; Masson, D; Mercier, B; Pedron, B; Perrier, P; Picard, C; Quainon, F; Ramounau-Pigot, A; Renac, V; Van Endert, P; Charron, D; Peffault de la Tour, R; Taupin, J L; Loiseau, P

    2016-05-01

    Graft failure remains a severe complication of hematopoietic stem cell transplantation (HSCT). Several risk factors have already been published. In this study, we re-evaluated them in a large cohort who had the benefit of the recent experience in HSCT (2006-2012). Data from 4684 unrelated donor HSCT from 2006 to 2012 were retrospectively collected from centers belonging to the French Society for Stem Cell Transplantation. Among the 2716 patients for whom HLA typing was available, 103 did not engraft leading to a low rate of no engraftment at 3.8%. In univariate analysis, only type of disease and status of disease at transplant for malignant diseases remained significant risk factors (P=0.04 and P<0.0001, respectively). In multivariate analysis, only status of disease was a significant risk factor (P<0.0001). Among the 61 patients who did not engraft and who were mismatched for 1 HLA class I and/or HLA-DP, 5 donor-specific antibodies (DSAs) were detected but only 1 was clearly involved in graft failure, for the others their role was more questionable. Second HSCT exhibited a protective although not statistically significant effect on OS (hazard ratio=0.57 [0.32-1.02]). In conclusion, only one parameter (disease status before graft) remains risk factor for graft failure in this recent cohort. PMID:26855158

  12. Competition-based cellular peptide binding assays for 13 prevalent HLA class I alleles using fluorescein-labeled synthetic peptides.

    PubMed

    Kessler, Jan H; Mommaas, Bregje; Mutis, Tuna; Huijbers, Ivo; Vissers, Debby; Benckhuijsen, Willemien E; Schreuder, Geziena M Th; Offringa, Rienk; Goulmy, Els; Melief, Cornelis J M; van der Burg, Sjoerd H; Drijfhout, Jan W

    2003-02-01

    We report the development, validation, and application of competition-based peptide binding assays for 13 prevalent human leukocyte antigen (HLA) class I alleles. The assays are based on peptide binding to HLA molecules on living cells carrying the particular allele. Competition for binding between the test peptide of interest and a fluorescein-labeled HLA class I binding peptide is used as read out. The use of cell membrane-bound HLA class I molecules circumvents the need for laborious biochemical purification of these molecules in soluble form. Previously, we have applied this principle for HLA-A2 and HLA-A3. We now describe the assays for HLA-A1, HLA-A11, HLA-A24, HLA-A68, HLA-B7, HLA-B8, HLA-B14, HLA-B35, HLA-B60, HLA-B61, and HLA-B62. Together with HLA-A2 and HLA-A3, these alleles cover more than 95% of the Caucasian population. Several allele-specific parameters were determined for each assay. Using these assays, we identified novel HLA class I high-affinity binding peptides from HIVpol, p53, PRAME, and minor histocompatibility antigen HA-1. Thus these convenient and accurate peptide-binding assays will be useful for the identification of putative cytotoxic T lymphocyte epitopes presented on a diverse array of HLA class I molecules. PMID:12559627

  13. Crystal structure of HLA-DP2 and implications for chronic beryllium disease

    SciTech Connect

    Dai, Shaodong; Murphy, Guinevere A.; Crawford, Frances; Mack, Douglas G.; Falta, Michael T.; Marrack, Philippa; Kappler, John W.; Fontenot, Andrew P.

    2010-06-15

    Chronic beryllium disease (CBD) is a fibrotic lung disorder caused by beryllium (Be) exposure and is characterized by granulomatous inflammation and the accumulation of Be-responsive CD4{sup +} T cells in the lung. Genetic susceptibility to CBD has been associated with certain alleles of the MHCII molecule HLA-DP, especially HLA-DPB1*0201 and other alleles that contain a glutamic acid residue at position 69 of the {beta}-chain ({beta}Glu69). The HLA-DP alleles that can present Be to T cells match those implicated in the genetic susceptibility, suggesting that the HLA contribution to disease is based on the ability of those molecules to bind and present Be to T cells. The structure of HLA-DP2 and its interaction with Be are unknown. Here, we present the HLA-DP2 structure with its antigen-binding groove occupied by a self-peptide derived from the HLA-DR {alpha}-chain. The most striking feature of the structure is an unusual solvent exposed acidic pocket formed between the peptide backbone and the HLA-DP2 {beta}-chain {alpha}-helix and containing three glutamic acids from the {beta}-chain, including {beta}Glu69. In the crystal packing, this pocket has been filled with the guanidinium group of an arginine from a neighboring molecule. This positively charged moiety forms an extensive H-bond/salt bridge network with the three glutamic acids, offering a plausible model for how Be-containing complexes might occupy this site. This idea is strengthened by the demonstration that mutation of any of the three glutamic acids in this pocket results in loss of the ability of DP2 to present Be to T cells.

  14. HLA-DRB1 and HLA-DQB1 methylation changes promote the occurrence and progression of Kazakh ESCC

    PubMed Central

    Hu, Jian Ming; Li, Ling; Chen, Yun Zhao; Liu, Chunxia; Cui, Xiaobin; Yin, Liang; Yang, Lan; Zou, Hong; Pang, Lijuan; Zhao, Jin; Qi, Yan; Cao, Yuwen; Jiang, Jinfang; Liang, Weihua; Li, Feng

    2014-01-01

    Human leukocyte antigen II (HLA-II) plays an important role in host immune responses to cancer cells. Changes in gene methylation may result in aberrant expression of HLA-II, serving a key role in the pathogenesis of Kazakh esophageal squamous cell carcinoma (ESCC). We analyzed the expression level of HLA-II (HLA-DP, -DQ, and -DR) by immunohistochemistry, as well as the methylation status of HLA-DRB1 and HLA-DQB1 by MassARRAY spectrometry in Xinjiang Kazakh ESCC. Expression of HLA-II in ESCC was significantly higher than that in cancer adjacent normal (ACN) samples (P < 0.05). Decreased HLA-II expression was closely associated with later clinical stages of ESCC (P < 0.05). Hypomethylation of HLA-DRB1 and hypermethylation of HLA-DQB1 was significantly correlated with occurrence of Kazakh ESCC (P < 0.01), and mainly manifested as hypomethylation of CpG9, CpG10-11, and CpG16 in HLA-DRB1 and hypermethylation of CpG6-7 and CpG16-17 in HLA-DQB1 (P < 0.01). Moreover, hypomethylation of HLA-DQB1 CpG6-7 correlated with poor differentiation in ESCCs, whereas hypermethylation of HLA-DRB1 CpG16 and hypomethylation of HLA-DQB1 CpG16-17 were significantly associated with later stages of ESCC (P < 0.05). A significant inverse association between HLA-DRB1 CpG9 methylation and HLA-II expression was found in ESCC (P < 0.05). These findings suggest aberrant HLA-DRB1 and HLA-DQB1 methylation contributes to the aberrant expression of HLA-II. These molecular changes may influence the immune response to specific tumor epitopes, promoting the occurrence and progression of Kazakh ESCC. PMID:25437052

  15. Do human leukocyte antigen E polymorphisms influence graft-versus-leukemia after allogeneic hematopoietic stem cell transplantation?

    PubMed

    Hosseini, Ehteramolsadat; Schwarer, Anthony P; Ghasemzadeh, Mehran

    2015-03-01

    Hematopoietic-stem-cell transplantation (HSCT) is complicated by histocompatibility-dependent immune responses such as graft-versus-host disease, relapse, and graft rejection. The severity of these common adverse effects is directly related to the degree of human leukocyte antigen (HLA) incompatibility. In addition to the key role of classic HLA matching in influencing HSCT outcome, several lines of evidence suggest an important role for nonclassic major histocompatibility complex class I molecule, HLA-E. The interaction of HLA-E with NKG2A, its main receptor on natural killer cells, modulates cell-mediated cytotoxicity and cytokine production, an important role in innate immune responses. In addition, the HLA-E molecule can present peptides to different subtypes of T cells that may either support graft-versus-leukemia effects or be involved in bridging innate and acquired immunity. To date, the role of HLA-E and its polymorphisms in HSCT outcomes such as graft-versus-host disease, transplant-related mortality, and improved survival has been published by a number of groups. In addition, these data suggest an association between HLA-E polymorphisms and relapse. Whether the engagement of the HLA-E molecule in the modulation of donor T cells is involved in the graft-versus-leukemia effect, or whether a different mechanism of HLA-E dependent reduction of relapse is involved, requires further investigation. PMID:25434712

  16. Neuroantibodies (NAB) in African-American Children with Heavy Metal Exposures are Associated with Cytokine and Human Leukocyte Antigen (HLA) Polymorphisms (SNP)

    EPA Science Inventory

    Polymorphisms in cytokine and HLA genes are associated with allergies, autoimmunity and neurodegeneration (ND). Samples from 131 African-American children (71 males; 60 females) in the Mechanistic Indicators of Childhood Asthma (MICA) study were used to determine SNPs of IL-4, IL...

  17. Conservation of minor histocompatibility antigens between human and non-human primates.

    PubMed

    den Haan, J M; Bontrop, R E; Pool, J; Sherman, N; Blokland, E; Engelhard, V H; Hunt, D F; Goulmy, E

    1996-11-01

    It is well accepted that minor histocompatibility antigens (mHag) can function as transplantation barriers between HLA-matched individuals. Little is known about the molecular nature and evolutionary conservation of mHag. It is only very recently that the first human mHag were identified. The HLA-A2.1-restricted mHag HA-2 and the HLA-B7-restricted mHag H-Y appeared to be peptides derived from polymorphic self proteins. Here we show that the HLA-A2.1-restricted mHag HA-1, HA-2, and the H-Y peptides are conserved between man, chimpanzees and rhesus macaques. Human cytotoxic T cell clones specific for the HLA-A2.1-restricted mHag HA-1, HA-2, and H-Y recognized HLA-A2.1 gene-transfected chimpanzee and rhesus macaque cells. High-pressure liquid chromatography fractionation of HLA-A2.1-bound peptides isolated from the HLA-A2.1-transfected chimpanzee cells revealed that the chimpanzee HA-1 and HA-2 co-eluted with the human HA-1 and HA-2. Subsequent amino acid sequencing showed that the chimpanzee HA-2 peptide is identical to the human HA-2 peptide. Our functional and biochemical results demonstrate that mHag peptides are conserved for over 35 million years. PMID:8921955

  18. Complementarity of Binding Motifs is a General Property of HLA-A and HLA-B Molecules and Does Not Seem to Effect HLA Haplotype Composition.

    PubMed

    Rao, Xiangyu; De Boer, Rob J; van Baarle, Debbie; Maiers, Martin; Kesmir, Can

    2013-01-01

    Different human leukocyte antigen (HLA) haplotypes (i.e., the specific combinations of HLA-A, -B, -DR alleles inherited together from one parent) are observed in different frequencies in human populations. Some haplotypes, like HLA-A1-B8, are very frequent, reaching up to 10% in the Caucasian population, while others are very rare. Numerous studies have identified associations between HLA haplotypes and diseases, and differences in haplotype frequencies can in part be explained by these associations: the stronger the association with a severe (autoimmune) disease, the lower the expected HLA haplotype frequency. The peptide repertoires of the HLA molecules composing a haplotype can also influence the frequency of a haplotype. For example, it would seem advantageous to have HLA molecules with non-overlapping binding specificities within a haplotype, as individuals expressing such an haplotype would present a diverse set of peptides from viruses and pathogenic bacteria on the cell surface. To test this hypothesis, we collect the proteome data from a set of common viruses, and estimate the total ligand repertoire of HLA class I haplotypes (HLA-A-B) using in silico predictions. We compare the size of these repertoires to the HLA haplotype frequencies reported in the National Marrow Donor Program (NMDP). We find that in most HLA-A and HLA-B pairs have fairly distinct binding motifs, and that the observed haplotypes do not contain HLA-A and -B molecules with more distinct binding motifs than random HLA-A and HLA-B pairs. In addition, the population frequency of a haplotype is not correlated to the distinctness of its HLA-A and HLA-B peptide binding motifs. These results suggest that there is a not a strong selection pressure on the haplotype level favoring haplotypes having HLA molecules with distinct binding motifs, which would result the largest possible presented peptide repertoires in the context of infectious diseases. PMID:24294213

  19. On Modeling Human Leukocyte Antigen-Identical Sibling Match Probability for Allogeneic Hematopoietic Cell Transplantation: Estimating the Need for an Unrelated Donor Source.

    PubMed

    Besse, Kelsey; Maiers, Martin; Confer, Dennis; Albrecht, Mark

    2016-03-01

    Prior studies of allogeneic hematopoietic cell transplantation (HCT) therapy for the treatment of malignant or nonmalignant blood disorders assume a 30% likelihood that a patient will find a match among siblings and, therefore, a 70% likelihood of needing an unrelated donor source. This study utilizes birth data and statistical modeling to assess the adequacy of these estimates to describe the probability among US population cohorts segmented by race/ethnicity and age, including ages of greatest HCT utilization. Considerable variation in the likelihood of an HLA-identical sibling was found, ranging from 13% to 51%, depending upon patient age and race/ethnicity. Low sibling match probability, compounded with increased genetic diversity and lower availability among unrelated donors, put the youngest minority patients at the greatest risk for not finding a suitable related or unrelated HCT donor. Furthermore, the present 40-year decline in birth rates is expected to lead to 1.5-fold decrease in access to a matched sibling for today's young adults (18 to 44 years of age) when they reach peak HCT utilization years (near age 61 years) versus their contemporary adult counterparts (44 to 64 years). Understanding the sibling match probability by race/ethnicity and age cohort leads to forecasting the demand for unrelated HCT sources. PMID:26403513

  20. HLA-B polymorphisms and intracellular assembly modes.

    PubMed

    Raghavan, Malini; Geng, Jie

    2015-12-01

    Human leukocyte antigen (HLA) class I molecules are ligands for antigen receptors of cytotoxic T cells (CTL) and inhibitory receptors of natural killer (NK) cells. The high degree of HLA class I polymorphism allows for the selection of distinct and diverse sets of antigenic peptide ligands for presentation to CTL. The extensive polymorphisms of the HLA class I genes also result in large variations in their intracellular folding and assembly characteristics. Recent findings indicate that North American HLA-B variants differ significantly in the stabilities of their peptide-deficient forms and in the requirements for the endoplasmic reticulum (ER)-resident factor tapasin for proper assembly. In HIV-infected individuals, the presence of tapasin-independent HLA-B allotypes links to more rapid progression to death. Further studies are important to better understand how the intrinsic structural characteristics of HLA class I folding intermediates affect immune responses mediated by CTL and NK cells. PMID:26239417

  1. Down-regulation of HLA-A and HLA-Bw6, but not HLA-Bw4, allospecificities in leukemic cells: an escape mechanism from CTL and NK attack?

    PubMed

    Demanet, Christian; Mulder, Arend; Deneys, Veronique; Worsham, Maria J; Maes, Piet; Claas, Frans H; Ferrone, Soldano

    2004-04-15

    Human leukocyte antigen (HLA) class I antigen defects may have a negative impact on the growing application of T-cell-based immunotherapeutic strategies for treatment of leukemia. Therefore in the present study, taking advantage of a large panel of HLA class I allele-specific human monoclonal antibodies, we have compared HLA class I antigen expression on leukemic cells with that on autologous and allogeneic normal cells. Down-regulation of HLA-A and/or -B allospecificities was present in the majority of the patients studied. However, down-regulation did not affect all HLA class I alleles uniformly, but was almost exclusively restricted to HLA-A allospecificities and to HLA-B allospecificities which belong to the HLA-Bw6 group. The latter allospecificities, at variance from those that belong to the HLA-Bw4 group, do not modulate the interactions of leukemic cells with natural killer (NK) cells. Therefore, our results suggest that the selective down-regulation of HLA-A and HLA-Bw6 allospecificities associated with HLA-Bw4 preservation provides leukemic cells with an escape mechanism not only from cytotoxic T lymphocytes (CTLs), but also from NK cells. As a result T-cell-based immunotherapeutic strategies for leukemia should utilize HLA-Bw4 alloantigens as restricting elements since a selective HLA-Bw4 allele loss would provide leukemic cells with an escape mechanism from CTLs, but would increase their susceptibility to NK cell-mediated lysis. PMID:15070694

  2. A population response analysis approach to assign class II HLA-epitope restrictions

    PubMed Central

    Arlehamn, Cecilia S. Lindestam; Huang, Huang; Davis, Mark M.; McKinney, Denise M.; Scriba, Thomas Jens; Sidney, John; Peters, Bjoern; Sette, Alessandro

    2015-01-01

    Identification of the specific HLA locus and allele presenting an epitope for recognition by specific T cell receptors (HLA restriction) is necessary to fully characterize the immune response to antigens. Experimental determination of HLA restriction is complex and technically challenging. As an alternative, the restricting HLA locus and allele can be inferred by genetic association, utilizing response data in an HLA typed population. However, simple odds ratio calculations can be problematic when dealing with large numbers of subjects and antigens and because the same epitope can be presented by multiple alleles (epitope promiscuity). Here, we develop a tool, denominated Restrictor Analysis Tool for Epitopes (RATE), to extract inferred restriction from HLA class II -typed epitope responses. This automated method infers HLA class II restriction from large datasets of T cell responses in HLA class II typed subjects by calculating Odds Ratios and relative frequencies from simple data tables. The program is validated by 1. Analyzing data of previously determined HLA restrictions. 2. Experimentally determining in selected individuals new HLA restrictions using HLA transfected cell lines 3. Predicting HLA restriction of particular peptides, and showing that corresponding HLA class II tetramers efficiently bind to epitope specific T cells. We further design a specific iterative algorithm to account for promiscuous recognition by calculation of Odds Ratio values for combinations of different HLA molecules while incorporating predicted HLA binding affinity. The RATE program streamlines the prediction of HLA class II restriction across multiple T cell epitopes and HLA types. PMID:25948811

  3. HLA and Disease Associations in Koreans

    PubMed Central

    Ahn, Stephen; Choi, Hee-Back

    2011-01-01

    The human leukocyte antigen (HLA), the major histocompatibility complex (MHC) in humans has been known to reside on chromosome 6 and encodes cell-surface antigen-presenting proteins and many other proteins related to immune system function. The HLA is highly polymorphic and the most genetically variable coding loci in humans. In addition to a critical role in transplantation medicine, HLA and disease associations have been widely studied across the populations world-wide and are found to be important in prediction of disease susceptibility, resistance and of evolutionary maintenance of genetic diversity. Because recently developed molecular based HLA typing has several advantages like improved specimen stability and increased resolution of HLA types, the association between HLA alleles and a given disease could be more accurately quantified. Here, in this review, we have collected HLA association data on some autoimmune diseases, infectious diseases, cancers, drug responsiveness and other diseases with unknown etiology in Koreans and attempt to summarize some remarkable HLA alleles related with specific diseases. PMID:22346771

  4. A gene feature enumeration approach for describing HLA allele polymorphism.

    PubMed

    Mack, Steven J

    2015-12-01

    HLA genotyping via next generation sequencing (NGS) poses challenges for the use of HLA allele names to analyze and discuss sequence polymorphism. NGS will identify many new synonymous and non-coding HLA sequence variants. Allele names identify the types of nucleotide polymorphism that define an allele (non-synonymous, synonymous and non-coding changes), but do not describe how polymorphism is distributed among the individual features (the flanking untranslated regions, exons and introns) of a gene. Further, HLA alleles cannot be named in the absence of antigen-recognition domain (ARD) encoding exons. Here, a system for describing HLA polymorphism in terms of HLA gene features (GFs) is proposed. This system enumerates the unique nucleotide sequences for each GF in an HLA gene, and records these in a GF enumeration notation that allows both more granular dissection of allele-level HLA polymorphism and the discussion and analysis of GFs in the absence of ARD-encoding exon sequences. PMID:26416087

  5. HLA typing from RNA-Seq sequence reads.

    PubMed

    Boegel, Sebastian; Löwer, Martin; Schäfer, Michael; Bukur, Thomas; de Graaf, Jos; Boisguérin, Valesca; Türeci, Ozlem; Diken, Mustafa; Castle, John C; Sahin, Ugur

    2012-01-01

    We present a method, seq2HLA, for obtaining an individual's human leukocyte antigen (HLA) class I and II type and expression using standard next generation sequencing RNA-Seq data. RNA-Seq reads are mapped against a reference database of HLA alleles, and HLA type, confidence score and locus-specific expression level are determined. We successfully applied seq2HLA to 50 individuals included in the HapMap project, yielding 100% specificity and 94% sensitivity at a P-value of 0.1 for two-digit HLA types. We determined HLA type and expression for previously un-typed Illumina Body Map tissues and a cohort of Korean patients with lung cancer. Because the algorithm uses standard RNA-Seq reads and requires no change to laboratory protocols, it can be used for both existing datasets and future studies, thus adding a new dimension for HLA typing and biomarker studies. PMID:23259685

  6. Vaccines targeting tumor blood vessel antigens promote CD8(+) T cell-dependent tumor eradication or dormancy in HLA-A2 transgenic mice.

    PubMed

    Zhao, Xi; Bose, Anamika; Komita, Hideo; Taylor, Jennifer L; Chi, Nina; Lowe, Devin B; Okada, Hideho; Cao, Ying; Mukhopadhyay, Debabrata; Cohen, Peter A; Storkus, Walter J

    2012-02-15

    We have recently shown that effective cytokine gene therapy of solid tumors in HLA-A2 transgenic (HHD) mice lacking murine MHC class I molecule expression results in the generation of HLA-A2-restricted CD8(+) T effector cells selectively recognizing tumor blood vessel-associated pericytes and/or vascular endothelial cells. Using an HHD model in which HLA-A2(neg) tumor (MC38 colon carcinoma or B16 melanoma) cells are not recognized by the CD8(+) T cell repertoire, we now show that vaccines on the basis of tumor-associated blood vessel Ags (TBVA) elicit protective Tc1-dependent immunity capable of mediating tumor regression or extending overall survival. Vaccine efficacy was not observed if (HLA-A2(neg)) wild-type C57BL/6 mice were instead used as recipient animals. In the HHD model, effective vaccination resulted in profound infiltration of tumor lesions by CD8(+) (but not CD4(+)) T cells, in a coordinate reduction of CD31(+) blood vessels in the tumor microenvironment, and in the "spreading" of CD8(+) T cell responses to alternate TBVA that were not intrinsic to the vaccine. Protective Tc1-mediated immunity was durable and directly recognized pericytes and/or vascular endothelial cells flow-sorted from tumor tissue but not from tumor-uninvolved normal kidneys harvested from these same animals. Strikingly, the depletion of CD8(+), but not CD4(+), T cells at late time points after effective therapy frequently resulted in the recurrence of disease at the site of the regressed primary lesion. This suggests that the vaccine-induced anti-TBVA T cell repertoire can mediate the clinically preferred outcomes of either effectively eradicating tumors or policing a state of (occult) tumor dormancy. PMID:22246626

  7. Donor-Specific Anti-HLA Antibodies in Allogeneic Hematopoietic Stem Cell Transplantation

    PubMed Central

    Morin-Zorman, Sarah; Loiseau, Pascale; Taupin, Jean-Luc; Caillat-Zucman, Sophie

    2016-01-01

    Allogeneic hematopoietic stem cell transplantation (AHSCT) is a curative treatment for a wide variety of hematological diseases. In 30% of the cases, a geno-identical donor is available. Any other situation displays some level of human leukocyte antigen (HLA) incompatibility between donor and recipient. Deleterious effects of anti-HLA immunization have long been recognized in solid organ transplant recipients. More recently, anti-HLA immunization was shown to increase the risk of primary graft failure (PGF), a severe complication of AHSCT that occurs in 3–4% of matched unrelated donor transplantation and up to 15% in cord blood transplantation and T-cell depleted haplo-identical stem cell transplantation. Rates of PGF in patients with DSA were reported to be between 24 and 83% with the highest rates in haplo-identical and cord blood transplantation recipients. This led to the recommendation of anti-HLA antibody screening to detect donor-specific antibodies (DSA) in recipients prior to AHSCT. In this review, we highlight the role of anti-HLA antibodies in AHSCT and the mechanisms that may lead to PGF in patients with DSA, and discuss current issues in the field. PMID:27570526

  8. Donor-Specific Anti-HLA Antibodies in Allogeneic Hematopoietic Stem Cell Transplantation.

    PubMed

    Morin-Zorman, Sarah; Loiseau, Pascale; Taupin, Jean-Luc; Caillat-Zucman, Sophie

    2016-01-01

    Allogeneic hematopoietic stem cell transplantation (AHSCT) is a curative treatment for a wide variety of hematological diseases. In 30% of the cases, a geno-identical donor is available. Any other situation displays some level of human leukocyte antigen (HLA) incompatibility between donor and recipient. Deleterious effects of anti-HLA immunization have long been recognized in solid organ transplant recipients. More recently, anti-HLA immunization was shown to increase the risk of primary graft failure (PGF), a severe complication of AHSCT that occurs in 3-4% of matched unrelated donor transplantation and up to 15% in cord blood transplantation and T-cell depleted haplo-identical stem cell transplantation. Rates of PGF in patients with DSA were reported to be between 24 and 83% with the highest rates in haplo-identical and cord blood transplantation recipients. This led to the recommendation of anti-HLA antibody screening to detect donor-specific antibodies (DSA) in recipients prior to AHSCT. In this review, we highlight the role of anti-HLA antibodies in AHSCT and the mechanisms that may lead to PGF in patients with DSA, and discuss current issues in the field. PMID:27570526

  9. Comparison of Outcomes after Transplantation of G-CSF Stimulated Bone Marrow Grafts versus Bone Marrow or Peripheral Blood Grafts from HLA-Matched Sibling Donors for Patients with Severe Aplastic Anemia

    PubMed Central

    Chu, Roland; Brazauskas, Ruta; Kan, Fangyu; Bashey, Asad; Bredeson, Christopher; Camitta, Bruce; Chiang, Kuang-Yueh; Frangoul, Haydar; Gale, Robert Peter; Gee, Adrian; George, Biju; Goldman, Frederick D.; Gross, Thomas G.; Gupta, Vikas; Hale, Gregory A.; Isola, Luis; Ispizua, Alvaro Urbano; Lazarus, Hillard; Marsh, Judith; Russell, James; Sabloff, Mitchell; Waller, Edmund K.; Eapen, Mary

    2010-01-01

    We compared outcomes of patients with severe aplastic anemia (SAA) who received G-CSF stimulated bone marrow (G-BM) (n=78), unstimulated bone marrow (BM) (n=547), or peripheral blood progenitor cells (PBPC) (n=134) from an HLA-matched sibling. Transplantations occurred in 1997–2003. Rates of neutrophil and platelet recovery were not different among the three treatment groups. Grade 2–4 acute graft-versus-host disease (GVHD) (RR 0.82, p=0.539), grade 3–4 acute GVHD (RR 0.74, p=0.535) and chronic GVHD (RR 1.56, p=0.229) were similar after G-BM and BM transplants. Grade 2–4 acute GVHD (RR 2.37, p=0.012) but not grade 3–4 acute GVHD (RR 1.66, p=0.323) and chronic GVHD (RR 5.09, p<0.001) were higher after PBPC transplants compared to G-BM. Grade 2–4 (RR 2.90, p<0.001), grade 3–4 (RR 2.24, p=0.009) acute GVHD and chronic GVHD (RR 3.26, p<0.001) were higher after PBPC transplants compared to BM. Mortality risks were lower after transplantation of BM compared to G-BM (RR 0.63, p=0.05). These data suggest no advantage to using G-BM and the observed higher rates of acute and chronic GVHD in PBPC recipients warrants cautious use of this graft source for SAA. Taken together, BM is the preferred graft for HLA matched sibling transplants for SAA. PMID:21034842

  10. Molecular analysis of HLA-DQ A alleles in coeliac disease lack of a unique disease-associated sequence.

    PubMed Central

    Mantovani, V; Corazza, G R; Angelini, G; Delfino, L; Frisoni, M; Mirri, P; Valentini, R A; Barboni, P; Gasbarrini, G; Ferrara, G B

    1991-01-01

    Susceptibility to coeliac disease is strongly associated with some HLA class II antigens, encoded by the HLA-D region. Since the HLA-DQ locus seems to be primarily involved, we have analysed by polymerase chain reaction amplification and allele-specific oligonucleotide hybridization the most polymorphic region of the HLA-DQ A1 gene. No difference was observed between the 20 coeliac patients and 20 HLA-D-matched healthy controls who took part in the study. Furthermore, in patients and controls, the restriction fragment length polymorphism analysis of the HLA-DQ A gene using the restriction enzyme BglII did not disclose any specific disease-associated fragment. Our results are not consistent with a unique DQ A coeliac disease-associated sequence, but rather with the hypothesis that some polymorphic residues or allelic hypervariable regions, although found also in the normal population, can predispose to coeliac disease due to their higher frequency in this condition. Images Fig. 1 Fig. 2 PMID:1671007

  11. sHLA-G1 and HLA-G5 levels are decreased in Tunisian women with multiple abortion.

    PubMed

    Zidi, Inès; Rizzo, Roberta; Bouaziz, Aicha; Laaribi, Ahmed Baligh; Zidi, Nour; Di Luca, Dario; Tlili, Henda; Bortolotti, Daria

    2016-04-01

    Pregnancy is associated with increased levels of soluble (s) human leukocyte antigen (HLA)-G molecules, while during abortion these molecules are decreased. To date, little is known about the role of sHLA-G isoforms during abortion. In this study, we investigated the levels of total sHLA-G and its isoforms: HLA-G1 (membrane shedded isoform) and alternative spliced HLA-G5 in plasma samples obtained from 55 women who had experienced spontaneous abortion, 108 pregnant healthy women and 56 non pregnant healthy women. We found that pregnant women exhibited higher amounts of sHLA-G compared to either non pregnant women or women with abortion. Among women who had experienced spontaneous abortion, women with recurrent abortions (RSA) had lower sHLA-G than women with only one abortion. In particular, RSA women were characterized by the absence of sHLA-G1 isoform, suggesting a possible implication in abortion event. PMID:26812178

  12. Additive and interaction effects at three amino acid positions in HLA-DQ and HLA-DR molecules drive type 1 diabetes risk

    PubMed Central

    Hu, Xinli; Deutsch, Aaron J; Lenz, Tobias L; Onengut-Gumuscu, Suna; Han, Buhm; Chen, Wei-Min; Howson, Joanna M M; Todd, John A; de Bakker, Paul I W; Rich, Stephen S; Raychaudhuri, Soumya

    2016-01-01

    Variation in the human leukocyte antigen (HLA) genes accounts for one-half of the genetic risk in type 1 diabetes (T1D). Amino acid changes in the HLA-DR and HLA-DQ molecules mediate most of the risk, but extensive linkage disequilibrium complicates the localization of independent effects. Using 18,832 case-control samples, we localized the signal to 3 amino acid positions in HLA-DQ and HLA-DR. HLA-DQβ1 position 57 (previously known; P = 1 × 10−1,355) by itself explained 15.2% of the total phenotypic variance. Independent effects at HLA-DRβ1 positions 13 (P = 1 × 10−721) and 71 (P = 1 × 10−95) increased the proportion of variance explained to 26.9%. The three positions together explained 90% of the phenotypic variance in the HLA-DRB1–HLA-DQA1–HLA-DQB1 locus. Additionally, we observed significant interactions for 11 of 21 pairs of common HLA-DRB1–HLA-DQA1–HLA-DQB1 haplotypes (P = 1.6 × 10−64). HLA-DRβ1 positions 13 and 71 implicate the P4 pocket in the antigen-binding groove, thus pointing to another critical protein structure for T1D risk, in addition to the HLA-DQ P9 pocket. PMID:26168013

  13. Outcomes of pediatric bone marrow transplantation for leukemia and myelodysplasia using matched sibling, mismatched related, or matched unrelated donors

    PubMed Central

    Kan, Fangyu; Woo Ahn, Kwang; Spellman, Stephen R.; Aljurf, Mahmoud; Ayas, Mouhab; Burke, Michael; Cairo, Mitchell S.; Chen, Allen R.; Davies, Stella M.; Frangoul, Haydar; Gajewski, James; Gale, Robert Peter; Godder, Kamar; Hale, Gregory A.; Heemskerk, Martin B.A.; Horan, John; Kamani, Naynesh; Kasow, Kimberly A.; Chan, Ka Wah; Lee, Stephanie J.; Leung, Wing H.; Lewis, Victor A.; Miklos, David; Oudshoorn, Machteld; Petersdorf, Effie W.; Ringdén, Olle; Sanders, Jean; Schultz, Kirk R.; Seber, Adriana; Setterholm, Michelle; Wall, Donna A.; Yu, Lolie; Pulsipher, Michael A.

    2010-01-01

    Although some trials have allowed matched or single human leukocyte antigen (HLA)–mismatched related donors (mmRDs) along with HLA-matched sibling donors (MSDs) for pediatric bone marrow transplantation in early-stage hematologic malignancies, whether mmRD grafts lead to similar outcomes is not known. We compared patients < 18 years old reported to the Center for International Blood and Marrow Transplant Research with acute myeloid leukemia, acute lymphoblastic leukemia, chronic myeloid leukemia, and myelodysplastic syndrome undergoing allogeneic T-replete, myeloablative bone marrow transplantation between 1993 and 2006. In total, patients receiving bone marrow from 1208 MSDs, 266 8/8 allelic-matched unrelated donors (URDs), and 151 0-1 HLA-antigen mmRDs were studied. Multivariate analysis showed that recipients of MSD transplants had less transplantation-related mortality, acute graft-versus-host disease (GVHD), and chronic GVHD, along with better disease-free and overall survival than the URD and mmRD groups. No differences were observed in transplant-related mortality, acute and chronic GVHD, relapse, disease-free survival, or overall survival between the mmRD and URD groups. These data show that mmRD and 8/8 URD outcomes are similar, whereas MSD outcomes are superior to the other 2 sources. Whether allele level typing could identify mmRD recipients with better outcomes will not be known unless centers alter practice and type mmRD at the allele level. PMID:20671124

  14. Contribution of a Non-classical HLA Gene, HLA-DOA, to the Risk of Rheumatoid Arthritis.

    PubMed

    Okada, Yukinori; Suzuki, Akari; Ikari, Katsunori; Terao, Chikashi; Kochi, Yuta; Ohmura, Koichiro; Higasa, Koichiro; Akiyama, Masato; Ashikawa, Kyota; Kanai, Masahiro; Hirata, Jun; Suita, Naomasa; Teo, Yik-Ying; Xu, Huji; Bae, Sang-Cheol; Takahashi, Atsushi; Momozawa, Yukihide; Matsuda, Koichi; Momohara, Shigeki; Taniguchi, Atsuo; Yamada, Ryo; Mimori, Tsuneyo; Kubo, Michiaki; Brown, Matthew A; Raychaudhuri, Soumya; Matsuda, Fumihiko; Yamanaka, Hisashi; Kamatani, Yoichiro; Yamamoto, Kazuhiko

    2016-08-01

    Despite the progress in human leukocyte antigen (HLA) causal variant mapping, independent localization of major histocompatibility complex (MHC) risk from classical HLA genes is challenging. Here, we conducted a large-scale MHC fine-mapping analysis of rheumatoid arthritis (RA) in a Japanese population (6,244 RA cases and 23,731 controls) population by using HLA imputation, followed by a multi-ethnic validation study including east Asian and European populations (n = 7,097 and 23,149, respectively). Our study identified an independent risk of a synonymous mutation at HLA-DOA, a non-classical HLA gene, on anti-citrullinated protein autoantibody (ACPA)-positive RA risk (p = 1.4 × 10(-9)), which demonstrated a cis-expression quantitative trait loci (cis-eQTL) effect on HLA-DOA expression. Trans-ethnic comparison revealed different linkage disequilibrium (LD) patterns in HLA-DOA and HLA-DRB1, explaining the observed HLA-DOA variant risk heterogeneity among ethnicities, which was most evident in the Japanese population. Although previous HLA fine-mapping studies have identified amino acid polymorphisms of the classical HLA genes as driving genetic susceptibility to disease, our study additionally identifies the dosage contribution of a non-classical HLA gene to disease etiology. Our study contributes to the understanding of HLA immunology in human diseases and suggests the value of incorporating additional ancestry in MHC fine-mapping. PMID:27486778

  15. A catalog of HLA type, HLA expression, and neo-epitope candidates in human cancer cell lines

    PubMed Central

    Boegel, Sebastian; Löwer, Martin; Bukur, Thomas; Sahin, Ugur; Castle, John C

    2014-01-01

    Cancer cell lines are a tremendous resource for cancer biology and therapy development. These multipurpose tools are commonly used to examine the genetic origin of cancers, to identify potential novel tumor targets, such as tumor antigens for vaccine devel­opment, and utilized to screen potential therapies in preclinical studies. Mutations, gene expression, and drug sensitivity have been determined for many cell lines using next-generation sequencing (NGS). However, the human leukocyte antigen (HLA) type and HLA expression of tumor cell lines, characterizations necessary for the development of cancer vaccines, have remained largely incomplete and, such information, when available, has been distributed in many publications. Here, we determine the 4-digit HLA type and HLA expression of 167 cancer and 10 non-cancer cell lines from publically available RNA-Seq data. We use standard NGS RNA-Seq short reads from “whole transcriptome” sequencing, map reads to known HLA types, and statistically determine HLA type, heterozygosity, and expression. First, we present previously unreported HLA Class I and II genotypes. Second, we determine HLA expression levels in each cancer cell line, providing insights into HLA downregulation and loss in cancer. Third, using these results, we provide a fundamental cell line “barcode” to track samples and prevent sample annotation swaps and contamination. Fourth, we integrate the cancer cell-line specific HLA types and HLA expression with available cell-line specific mutation information and existing HLA binding prediction algorithms to make a catalog of predicted antigenic mutations in each cell line. The compilation of our results are a fundamental resource for all researchers selecting specific cancer cell lines based on the HLA type and HLA expression, as well as for the development of immunotherapeutic tools for novel cancer treatment modalities. PMID:25960936

  16. HLA Typing for the Next Generation.

    PubMed

    Mayor, Neema P; Robinson, James; McWhinnie, Alasdair J M; Ranade, Swati; Eng, Kevin; Midwinter, William; Bultitude, Will P; Chin, Chen-Shan; Bowman, Brett; Marks, Patrick; Braund, Henny; Madrigal, J Alejandro; Latham, Katy; Marsh, Steven G E

    2015-01-01

    Allele-level resolution data at primary HLA typing is the ideal for most histocompatibility testing laboratories. Many high-throughput molecular HLA typing approaches are unable to determine the phase of observed DNA sequence polymorphisms, leading to ambiguous results. The use of higher resolution methods is often restricted due to cost and time limitations. Here we report on the feasibility of using Pacific Biosciences' Single Molecule Real-Time (SMRT) DNA sequencing technology for high-resolution and high-throughput HLA typing. Seven DNA samples were typed for HLA-A, -B and -C. The results showed that SMRT DNA sequencing technology was able to generate sequences that spanned entire HLA Class I genes that allowed for accurate allele calling. Eight novel genomic HLA class I sequences were identified, four were novel alleles, three were confirmed as genomic sequence extensions and one corrected an existing genomic reference sequence. This method has the potential to revolutionize the field of HLA typing. The clinical impact of achieving this level of resolution HLA typing data is likely to considerable, particularly in applications such as organ and blood stem cell transplantation where matching donors and recipients for their HLA is of utmost importance. PMID:26018555

  17. HLA Typing for the Next Generation

    PubMed Central

    Mayor, Neema P.; Robinson, James; McWhinnie, Alasdair J. M.; Ranade, Swati; Eng, Kevin; Midwinter, William; Bultitude, Will P.; Chin, Chen-Shan; Bowman, Brett; Marks, Patrick; Braund, Henny; Madrigal, J. Alejandro; Latham, Katy; Marsh, Steven G. E.

    2015-01-01

    Allele-level resolution data at primary HLA typing is the ideal for most histocompatibility testing laboratories. Many high-throughput molecular HLA typing approaches are unable to determine the phase of observed DNA sequence polymorphisms, leading to ambiguous results. The use of higher resolution methods is often restricted due to cost and time limitations. Here we report on the feasibility of using Pacific Biosciences’ Single Molecule Real-Time (SMRT) DNA sequencing technology for high-resolution and high-throughput HLA typing. Seven DNA samples were typed for HLA-A, -B and -C. The results showed that SMRT DNA sequencing technology was able to generate sequences that spanned entire HLA Class I genes that allowed for accurate allele calling. Eight novel genomic HLA class I sequences were identified, four were novel alleles, three were confirmed as genomic sequence extensions and one corrected an existing genomic reference sequence. This method has the potential to revolutionize the field of HLA typing. The clinical impact of achieving this level of resolution HLA typing data is likely to considerable, particularly in applications such as organ and blood stem cell transplantation where matching donors and recipients for their HLA is of utmost importance. PMID:26018555

  18. HLA-G Molecules in Autoimmune Diseases and Infections

    PubMed Central

    Rizzo, Roberta; Bortolotti, Daria; Bolzani, Silvia; Fainardi, Enrico

    2014-01-01

    Human leukocyte antigen (HLA)-G molecule, a non-classical HLA-Ib molecule, is less polymorphic when compared to classical HLA class I molecules. Human leukocyte antigen-G (HLA-G) was first detected on cytotrophoblast cells at the feto-maternal interface but its expression is prevalent during viral infections and several autoimmune diseases. HLA-G gene is characterized by polymorphisms at the 3′ un-translated region and 5′ upstream regulatory region that regulate its expression and are associated with autoimmune diseases and viral infection susceptibility, creating an unbalanced and pathologic environment. This review focuses on the role of HLA-G genetic polymorphisms, mRNA, and protein expression in autoimmune conditions and viral infections. PMID:25477881

  19. Transancestral mapping of the MHC region in systemic lupus erythematosus identifies new independent and interacting loci at MSH5, HLA-DPB1 and HLA-G

    PubMed Central

    Fernando, Michelle M A; Freudenberg, Jan; Lee, Annette; Morris, David Lester; Boteva, Lora; Rhodes, Benjamin; Gonzalez-Escribano, María Francisca; Lopez-Nevot, Miguel Angel; Navarra, Sandra V; Gregersen, Peter K; Martin, Javier; Vyse, Timothy J

    2012-01-01

    Objectives Systemic lupus erythematosus (SLE) is a chronic multisystem genetically complex autoimmune disease characterised by the production of autoantibodies to nuclear and cellular antigens, tissue inflammation and organ damage. Genome-wide association studies have shown that variants within the major histocompatibility complex (MHC) region on chromosome 6 confer the greatest genetic risk for SLE in European and Chinese populations. However, the causal variants remain elusive due to tight linkage disequilibrium across disease-associated MHC haplotypes, the highly polymorphic nature of many MHC genes and the heterogeneity of the SLE phenotype. Methods A high-density case-control single nucleotide polymorphism (SNP) study of the MHC region was undertaken in SLE cohorts of Spanish and Filipino ancestry using a custom Illumina chip in order to fine-map association signals in these haplotypically diverse populations. In addition, comparative analyses were performed between these two datasets and a northern European UK SLE cohort. A total of 1433 cases and 1458 matched controls were examined. Results Using this transancestral SNP mapping approach, novel independent loci were identified within the MHC region in UK, Spanish and Filipino patients with SLE with some evidence of interaction. These loci include HLA-DPB1, HLA-G and MSH5 which are independent of each other and HLA-DRB1 alleles. Furthermore, the established SLE-associated HLA-DRB1*15 signal was refined to an interval encompassing HLA-DRB1 and HLA-DQA1. Increased frequencies of MHC region risk alleles and haplotypes were found in the Filipino population compared with Europeans, suggesting that the greater disease burden in non-European SLE may be due in part to this phenomenon. Conclusion These data highlight the usefulness of mapping disease susceptibility loci using a transancestral approach, particularly in a region as complex as the MHC, and offer a springboard for further fine-mapping, resequencing and

  20. Sex ratios and hormones in HLA related rheumatic diseases.

    PubMed Central

    James, W H

    1991-01-01

    The major diseases associated with HLA-B27 (Reiter's disease, ankylosing spondylitis, acute anterior uveitis, and psoriatic arthritis) all occur much more commonly in men. Published evidence indicates that the antigen HLA-B27 is associated with high testosterone concentrations in men. Moreover, the antigen HLA-B44 exerts a protective effect on one of these diseases (psoriatic arthritis), and there are external grounds for supposing that HLA-B44 indexes an antiandrogenic process. These data are interpreted as support for the hypothesis (first adumbrated nearly 20 years ago) that HLA antigens index unusual hormone concentrations, which in turn are causally related to the diseases. An examination of published reports suggests that sibs of probands with ankylosing spondylitis (and perhaps Reiter's disease) contain an excess of men, and that sibs of probands with rheumatoid arthritis contain an excess of women. These data lend further support to the hypothesis. PMID:2059084

  1. Clinical and immunological significance of HLA-E in stem cell transplantation and cancer.

    PubMed

    Wieten, L; Mahaweni, N M; Voorter, C E M; Bos, G M J; Tilanus, M G J

    2014-12-01

    Human leukocyte antigen-E (HLA-E) is a nonclassical HLA class I molecule that canonically binds peptides derived from the leader sequence of classical HLA class I. HLA-E can also bind peptides from stress protein [e.g. heat shock protein 60 (Hsp60)] and pathogens, illustrating the importance of HLA-E for anti-viral and anti-tumor immunity. Like classical HLA class I molecules, HLA-E is ubiquitously expressed, however, it is characterized by only a very limited sequence variability and two dominant protein forms have been described (HLA-E*01:01 and HLA-E*01:03). HLA-E influences both the innate and the adaptive arms of the immune system by the engagement of inhibitory (e.g. NKG2A) and activating receptors [e.g. αβ T cell receptor (αβTCR) or NKG2C] on NK cells and CD8 T cells. The effects of HLA-E on the cellular immune response are therefore complex and not completely understood yet. Here, we aim to provide an overview of the immunological and clinical relevance of HLA-E and HLA-E polymorphism in stem cell transplantation and in cancer. We review novel insights in the mechanism via which HLA-E expression levels are controlled and how the cellular immune response in transplantation and cancer is influenced by HLA-E. PMID:25413103

  2. The frequency of HLA alleles in the Romanian population.

    PubMed

    Constantinescu, Ileana; Boșcaiu, Voicu; Cianga, Petru; Dinu, Andrei-Antoniu; Gai, Elena; Melinte, Mihaela; Moise, Ana

    2016-03-01

    Knowledge of human leukocyte antigen (HLA) allele frequencies is essential for bone marrow and kidney donor searches. The Romanian Caucasian population is heterogeneous and information on HLA polymorphism has not been well studied. We characterized the HLA genetic profile and allele frequencies of regional populations in Romania. HLA-A, B and DRB1 alleles were examined in 8252 individuals, belonging to the four main regions of Romania. The most common alleles found in the Romanian population are the following: HLA-A*01, A*02, A*03, A*11, A*24; HLA-B*18, B*35, B*44, B*51 and HLA-DRB1*01, DRB1*03, DRB1*07, DRB1*11, DRB1*13, DRB1*15, DRB1*16. More than half of the alleles are non-homogeneously spread in Romania. These results provide a starting point for future analyses of genetic heterogeneity in Romania. PMID:26711124

  3. Clinically relevant interpretation of solid phase assays for HLA antibody

    PubMed Central

    Bettinotti, Maria P.; Zachary, Andrea A.; Leffell, Mary S.

    2016-01-01

    Purpose of review Accurate and timely detection and characterization of human leukocyte antigen (HLA) antibodies are critical for pre-transplant and post-transplant immunological risk assessment. Solid phase immunoassays have provided increased sensitivity and specificity, but test interpretation is not always straightforward. This review will discuss the result interpretation considering technical limitations; assessment of relative antibody strength; and the integration of data for risk stratification from complementary testing and the patient's immunological history. Recent findings Laboratory and clinical studies have provided insight into causes of test failures – false positive reactions because of antibodies to denatured HLA antigens and false negative reactions resulting from test interference and/or loss of native epitopes. Test modifications permit detection of complement-binding antibodies and determination of the IgG subclasses. The high degree of specificity of single antigen solid phase immunoassays has revealed the complexity and clinical relevance of antibodies to HLA-C, HLA-DQ, and HLA-DP antigens. Determination of antibody specificity for HLA epitopes enables identification of incompatible antigens not included in test kits. Summary Detection and characterization of HLA antibodies with solid phase immunoassays has led to increased understanding of the role of those antibodies in graft rejection, improved treatment of antibody-mediated rejection, and increased opportunities for transplantation. However, realization of these benefits requires careful and accurate interpretation of test results. PMID:27200498

  4. HLA-DPB1*04:01 Protects Genetically Susceptible Children from Celiac Disease Autoimmunity in the TEDDY Study

    PubMed Central

    Hadley, David; Hagopian, William; Liu, Edwin; She, Jin-Xiong; Simell, Olli; Akolkar, Beena; Ziegler, Anette-G.; Rewers, Marian; Krischer, Jeffrey P.; Chen, Wei-Min; Onengut-Gumuscu, Suna; Bugawan, Teodorica L.; Rich, Stephen S.; Erlich, Henry; Agardh, Daniel

    2015-01-01

    OBJECTIVES Tissue transglutaminase autoantibodies (tTGAs) represent the first evidence of celiac disease (CD) development. Associations of HLA-DR3-DQA1*05:01-DQB1*02:01 (i.e., DR3-DQ2) and, to a lesser extent, DR4-DQA1*03:01-DQB1*03:02 (i.e., DR4-DQ8) with the risk of CD differ by country, consistent with additional genetic heterogeneity that further refines risk. Therefore, we examined human leukocyte antigen (HLA) factors other than DR3-DQ2 for their contribution to developing tTGAs. METHODS The Environmental Determinants of Diabetes in the Young (TEDDY) study enrolled 8,676 infants at an increased HLA-DR-DQ risk for type 1 diabetes and CD into a 15-year prospective surveillance follow-up. Of those followed up, 21% ( n =1,813) carried DR3-DQ2/DR3-DQ2, 39% ( n =3,359) carried DR3-DQ2/DR4-DQ8, 20% ( n =1701) carried DR4-DQ8/DR4-DQ8, and 17% ( n =1,493) carried DR4-DQ8/DQ4. Within TEDDY, a nested case–control design of 248 children with CD autoimmunity (CDA) and 248 matched control children were genotyped for HLA-B, -DRB3, -DRB4, -DPA1, and -DPB1 genes, and the entire cohort was genotyped for single-nucleotide polymorphisms (SNPs) using the Illumina ImmunoChip. CDA was defined as a positive tTGA test at two consecutive clinic visits, whereas matching in those with no evidence of tTGAs was based on the presence of HLA-DQ2, country, and sex. RESULTS After adjustment for DR3-DQ2 and restriction to allele frequency (AF) ≥5%, HLA-DPB1*04:01 was inversely associated with CDA by conditional logistic regression (AF=44%, odds ratio=0.71, 95% confidence interval (CI)=0.53–0.96, P =0.025). This association of time to CDA and HLA-DPB1* 04:01 was replicated with statistical significance in the remainder of the cohort using imputation for specific HLA alleles based on SNP genotyping (hazard ratio=0.84, 95% CI= 0.73–0.96, P =0.013). CONCLUSIONS HLA-DPB1*04:01 may reduce the risk of tTGAs, an early marker of CD, among DR3-DQ2 children, confirming that additional variants in

  5. Human Leukocyte Antigen (HLA) B27 Allotype-Specific Binding and Candidate Arthritogenic Peptides Revealed through Heuristic Clustering of Data-independent Acquisition Mass Spectrometry (DIA-MS) Data.

    PubMed

    Schittenhelm, Ralf B; Sivaneswaran, Saranjah; Lim Kam Sian, Terry C C; Croft, Nathan P; Purcell, Anthony W

    2016-06-01

    Expression of HLA-B27 is strongly associated with ankylosing spondylitis (AS) and other spondyloarthropathies. While this is true for the majority of HLA-B27 allotypes, HLA-B*27:06 and HLA-B*27:09 are not associated with AS. These two subtypes contain polymorphisms that are ideally positioned to influence the bound peptide repertoire. The existence of disease-inducing peptides (so-called arthritogenic peptides) has therefore been proposed that are exclusively presented by disease-associated HLA-B27 allotypes. However, we have recently demonstrated that this segregation of allotype-bound peptides is not the case and that many peptides that display sequence features predicted to favor binding to disease-associated subtypes are also capable of being presented naturally by protective alleles. To further probe more subtle quantitative changes in peptide presentation, we have used a combination of data-independent acquisition (DIA) and multiple reaction monitoring (MRM) mass spectrometry to quantify the abundance of 1646 HLA-B27 restricted peptides across the eight most frequent HLA-B27 allotypes (HLA-B*27:02-HLA-B*27:09). We utilized K means cluster analysis to group peptides with similar allelic binding preferences across the eight HLA-B27 allotypes, which enabled us to identify the most-stringent binding characteristics for each HLA-B27 allotype and further refined their existing consensus-binding motifs. Moreover, a thorough analysis of this quantitative dataset led to the identification of 26 peptides, which are presented in lower abundance by HLA-B*27:06 and HLA-B*27:09 compared with disease-associated HLA-B27 subtypes. Although these differences were observed to be very subtle, these 26 peptides might encompass the sought-after arthritogenic peptide(s). PMID:26929215

  6. HLA-A, B and DR in Caucasians with transitional cell carcinoma of the bladder.

    PubMed

    Saunders, P H; Anderson, S A; Stogdill, V D; Lamm, D L

    1983-11-01

    When HLA-A, B and DR antigens in Caucasian patients with transitional cell carcinoma of the urinary bladder were compared with controls, no significant alterations in antigen frequencies were found. PMID:6581580

  7. Loss of Mismatched HLA on the Leukemic Blasts of Patients With Relapsed Lymphoid Malignancies Following Bone Marrow Transplantation From Related Donors With HLA Class II Mismatches in the Graft Versus Host Direction.

    PubMed

    Hirabayashi, Koichi; Kurata, Takashi; Horiuchi, Kazuki; Saito, Shoji; Shigemura, Tomonari; Tanaka, Miyuki; Yanagisawa, Ryu; Matsuda, Kazuyuki; Sakashita, Kazuo; Koike, Kenichi; Nakazawa, Yozo

    2016-04-01

    Mechanisms of relapse of acute lymphoblastic leukemia (ALL) after human leukocyte antigen (HLA) class II mismatched hematopoietic stem cell transplantation (HSCT) remain unclear. We report two children with relapsed ALL after HSCT from related donors with HLA-DRB1 and -DQB1 mismatches in the graft versus host direction. One lost HLA-DRB1, DQB1, and DPB1 alleles, and the other lost one HLA haplotype of the leukemic blasts at relapse. HLA class II loss may be a triggering event for ALL relapse after partially HLA-mismatched-related HSCT. In addition, HLA typing of relapsed leukemic blasts could be vital in the selection of retransplant donors. PMID:26544669

  8. Alpha/Beta T-Cell Depleted Grafts as an Immunological Booster to Treat Graft Failure after Hematopoietic Stem Cell Transplantation with HLA-Matched Related and Unrelated Donors

    PubMed Central

    Rådestad, E.; Wikell, H.; Engström, M.; Watz, E.; Sundberg, B.; Thunberg, S.; Uzunel, M.; Mattsson, J.; Uhlin, M.

    2014-01-01

    Allogeneic hematopoietic stem cell transplantation is associated with several complications and risk factors, for example, graft versus host disease (GVHD), viral infections, relapse, and graft rejection. While high levels of CD3+ cells in grafts can contribute to GVHD, they also promote the graft versus leukemia (GVL) effect. Infusions of extra lymphocytes from the original stem cell donor can be used as a treatment after transplantation for relapse or poor immune reconstitution but also they increase the risk for GVHD. In peripheral blood, 95% of T-cells express the αβ T-cell receptor and the remaining T-cells express the γδ T-cell receptor. As αβ T-cells are the primary mediators of GVHD, depleting them from the graft should reduce this risk. In this pilot study, five patients transplanted with HLA-matched related and unrelated donors were treated with αβ T-cell depleted stem cell boosts. The majority of γδ T-cells in the grafts expressed Vδ2 and/or Vγ9. Most patients receiving αβ-depleted stem cell boosts increased their levels of white blood cells, platelets, and/or granulocytes 30 days after infusion. No signs of GVHD or other side effects were detected. A larger pool of patients with longer follow-up time is needed to confirm the data in this study. PMID:25371909

  9. Widespread non-additive and interaction effects within HLA loci modulate the risk of autoimmune diseases

    PubMed Central

    Lenz, Tobias L.; Deutsch, Aaron J.; Han, Buhm; Hu, Xinli; Okada, Yukinori; Eyre, Stephen; Knapp, Michael; Zhernakova, Alexandra; Huizinga, Tom W.J.; Abecasis, Goncalo; Becker, Jessica; Boeckxstaens, Guy E.; Chen, Wei-Min; Franke, Andre; Gladman, Dafna D.; Gockel, Ines; Gutierrez-Achury, Javier; Martin, Javier; Nair, Rajan P.; Nöthen, Markus M.; Onengut-Gumuscu, Suna; Rahman, Proton; Rantapää-Dahlqvist, Solbritt; Stuart, Philip E.; Tsoi, Lam C.; Van Heel, David A.; Worthington, Jane; Wouters, Mira M.; Klareskog, Lars; Elder, James T.; Gregersen, Peter K.; Schumacher, Johannes; Rich, Stephen S.; Wijmenga, Cisca; Sunyaev, Shamil R.; de Bakker, Paul I.W.; Raychaudhuri, Soumya

    2015-01-01

    Human leukocyte antigen (HLA) genes confer strong risk for autoimmune diseases on a log-additive scale. Here we speculated that differences in autoantigen binding repertoires between a heterozygote’s two expressed HLA variants may result in additional non-additive risk effects. We tested non-additive disease contributions of classical HLA alleles in patients and matched controls for five common autoimmune diseases: rheumatoid arthritis (RA, Ncases=5,337), type 1 diabetes (T1D, Ncases=5,567), psoriasis vulgaris (Ncases=3,089), idiopathic achalasia (Ncases=727), and celiac disease (Ncases=11,115). In four out of five diseases, we observed highly significant non-additive dominance effects (RA: P=2.5×1012; T1D: P=2.4×10−10; psoriasis: P=5.9×10−6; celiac disease: P=1.2×10−87). In three of these diseases, the dominance effects were explained by interactions between specific classical HLA alleles (RA: P=1.8×10−3; T1D: P=8.6×1027; celiac disease: P=6.0×10−100). These interactions generally increased disease risk and explained moderate but significant fractions of phenotypic variance (RA: 1.4%, T1D: 4.0%, and celiac disease: 4.1%, beyond a simple additive model). PMID:26258845

  10. Identification of the new HLA-DRB1{sup *}0812 allele detected by sequencing based typing

    SciTech Connect

    Versluis, L.F.; Zwan, A.W. van der; Tilanus, M.G.J.; Savelkoul, P.H.M.; Berg-Loonen, E.M. van den

    1996-12-31

    HLA-DRB typing by polymerase chain reaction-sequence specific priming (PCR-SSP) and sequencing based typing (SBT) was studied within the framework of the Antigen and Haplotype Society 11 and the Sequencing Based Typing Component of the Twelfth International HLA workshop. Sequencing was performed as described by McGinnis and co-workers in 1995 on coded samples, including most DR2 subtypes, resulting in high resolution HLA-DR typing. Sequences were compared with a database containing 107 DRB1, four DRB3, and five DRB5 alleles in a similar way as described for HLA-DPB. One sample showed a new DR8 sequence, indicating the presence of a new allele. This individual (4390) is of Indonesian origin. The specific amplification of the DR8 allele and subsequent sequencing resulted in a sequence which did not match the database and new polymorphism was identified. The complementary strand was sequenced and confirmed the presence of a new DRB1 allele. Cloning and subsequent sequencing of the polymerase chain reaction fragment resulted in confirmation of the direct sequence data. Later this variant was officially named DRB1{sup *}0812. The complete nucleotide sequence of exon 2 of this new allele is shown. This allele differs from DRB1{sup *}0810 by one nucleotide at codon 85, resulting in an alanine (GTT), whereas DRB1{sup *}0810 carries a valine (GCT). 5 refs., 1 fig.

  11. Hematopoietic SCT from partially HLA-mismatched (HLA-haploidentical) related donors

    PubMed Central

    Symons, HJ; Fuchs, EJ

    2008-01-01

    Hematopoietic SCT from a partially HLA-mismatched (HLA-haploidentical) first-degree relative offers the benefits of rapid and near universal donor availability but also the risks that result from traversing the HLA barrier; namely, graft failure, severe GVHD and prolonged immunodeficiency. Improvements over the last 10 years in conditioning regimens, graft engineering and pharmacological immuno-prophylaxis of GVHD have substantially reduced the morbidity and mortality of HLA-haploidentical SCT. Highly immunosuppressive but nonmyeloablative conditioning extends the availability of HLA-haploidentical SCT to elderly hematologic malignancy patients lacking HLA-matched donors and permits recovery of autologous hematopoiesis in the event of graft failure. Current regimens for HLA-haploidentical SCT are associated with a 2-year non-relapse mortality of 20 ± 5%, relapse of 35 ± 15% and overall survival of 50 ± 20%. Major developmental areas include harnessing natural killer cell alloreactivity to reduce the risk of disease relapse and improving immune reconstitution by delayed infusions of lymphocytes selectively depleted of alloreactive cells. Hematologic malignancy patients who lack suitably matched related or unrelated donors can now be treated with HLA-haploidentical related donor or unrelated umbilical cord blood SCT. Future clinical trials will assess the relative risks and benefits of these two graft sources. PMID:18679375

  12. Narcolepsy-Associated HLA Class I Alleles Implicate Cell-Mediated Cytotoxicity

    PubMed Central

    Tafti, Mehdi; Lammers, Gert J.; Dauvilliers, Yves; Overeem, Sebastiaan; Mayer, Geert; Nowak, Jacek; Pfister, Corinne; Dubois, Valérie; Eliaou, Jean-François; Eberhard, Hans-Peter; Liblau, Roland; Wierzbicka, Aleksandra; Geisler, Peter; Bassetti, Claudio L.; Mathis, Johannes; Lecendreux, Michel; Khatami, Ramin; Heinzer, Raphaël; Haba-Rubio, José; Feketeova, Eva; Baumann, Christian R.; Kutalik, Zoltán; Tiercy, Jean-Marie

    2016-01-01

    Study Objectives: Narcolepsy with cataplexy is tightly associated with the HLA class II allele DQB1*06:02. Evidence indicates a complex contribution of HLA class II genes to narcolepsy susceptibility with a recent independent association with HLA-DPB1. The cause of narcolepsy is supposed be an autoimmune attack against hypocretin-producing neurons. Despite the strong association with HLA class II, there is no evidence for CD4+ T-cell-mediated mechanism in narcolepsy. Since neurons express class I and not class II molecules, the final effector immune cells involved might include class I-restricted CD8+ T-cells. Methods: HLA class I (A, B, and C) and II (DQB1) genotypes were analyzed in 944 European narcolepsy with cataplexy patients and in 4,043 control subjects matched by country of origin. All patients and controls were DQB1*06:02 positive and class I associations were conditioned on DQB1 alleles. Results: HLA-A*11:01 (OR = 1.49 [1.18–1.87] P = 7.0*10−4), C*04:01 (OR = 1.34 [1.10–1.63] P = 3.23*10−3), and B*35:01 (OR = 1.46 [1.13–1.89] P = 3.64*10−3) were associated with susceptibility to narcolepsy. Analysis of polymorphic class I amino-acids revealed even stronger associations with key antigen-binding residues HLA-A-Tyr9 (OR = 1.32 [1.15–1.52] P = 6.95*10−5) and HLA-C-Ser11 (OR = 1.34 [1.15–1.57] P = 2.43*10−4). Conclusions: Our findings provide a genetic basis for increased susceptibility to infectious factors or an immune cytotoxic mechanism in narcolepsy, potentially targeting hypocretin neurons. Citation: Tafti M, Lammers GJ, Dauvilliers Y, Overeem S, Mayer G, Nowak J, Pfister C, Dubois V, Eliaou JF, Eberhard HP, Liblau R, Wierzbicka A, Geisler P, Bassetti CL, Mathis J, Lecendreux M, Khatami R, Heinzer R, Haba-Rubio J, Feketeova E, Baumann CR, Kutalik Z, Tiercy JM. Narcolepsy-associated HLA class I alleles implicate cell-mediated cytotoxicity. SLEEP 2016;39(3):581–587. PMID:26518595

  13. KIR-HLA intercourse in HIV disease

    PubMed Central

    Carrington, Mary; Martin, Maureen P.; van Bergen, Jeroen

    2012-01-01

    Human leukocyte antigen (HLA) class I loci are essential to an effective immune response against a wide variety of pathogenic microorganisms, and they represent the prototypes for genetic polymorphism that are sustained through balancing selection. The functional significance of HLA class I variation is better exemplified by studies involving HIV type 1 (HIV-1) than any other infectious organism. HLA class I molecules are essential to the acquired immune response, but they are also important in innate immunity as ligands for the killer cell immunoglobulin-like receptors (KIR), which modulate natural killer cell activity. Here we concentrate on the interaction between the HLA-B and KIR3DL1/KIR3DS1 genes, describe the effects of these loci on HIV disease, and discuss questions that remain unresolved. PMID:18976921

  14. Distribution of HLA-DRB1 and HLA-DQB1 alleles in Lak population of Iran.

    PubMed

    Varzi, Ali Mohammad; Shahsavar, Farhad; Tarrahi, Mohammad Javad

    2016-07-01

    Human leukocyte antigen (HLA) genes are the most polymorphic loci in the human genome and encode the highly polymorphic molecules critically involved in immune responses. Anthropological studies based on highly polymorphic HLA genes provide useful information for bone marrow donor registry, forensic medicine, disease association studies, as well as designing peptide vaccines against tumors, and infectious or autoimmune diseases. The aim of this study was to determine the HLA-DRB1 and HLA-DQB1 allele frequencies in 100 unrelated Lak individuals from Lorestan province of Iran. Finally, we compared the results with those previously described in four other Iranian populations. Commercial HLA-Type kits were used for determination of the HLA-DRB1 and HLA-DQB1 allele frequencies. Differences between populations in the distribution of HLA-DRB1 and HLA-DQB1 alleles were estimated by χ2 test with Yate's correction and Fisher's exact test. The most frequent HLA-DRB1 alleles were (*)1103=4 (23%), (*)1502 (9.5%), (*)0701 (9%), (*)0301 (8.5%), (*)1101 (7.5%) and (*)1501 (6%) while HLA-DQB1(*)0301 (40%), (*)0201 (15%), (*)0502 (10.5%), (*)0303 (10%), (*)0602=3 (9.5%), and (*)0501 (7.5%) were the most frequent alleles in Lak population. HLA-DRB1(*)0409, (*)0804, (*)1102, (*)1112, (*)1405, and HLA-DQB1(*)0503, (*)0604 were the least observed frequencies in Lak population. Our results based on HLA-DRB1 and HLA-DQB1 allele frequencies showed that the Lak population possesses the previously reported general features of the Lur and Kurd populations but still with unique, decreased or increased frequencies of several alleles. In other words, the Lak population is close to Lurs Khorramabadi and Kurd but far from Lurs Kohkiloyeh/Boyerahmad and Bakhtiari. PMID:27189628

  15. HLA-DQ rather than HLA-DR region might be involved in dominant nonsusceptibility to diabetes.

    PubMed Central

    Sterkers, G; Zeliszewski, D; Chaussée, A M; Deschamps, I; Font, M P; Freidel, C; Hors, J; Betuel, H; Dausset, J; Levy, J P

    1988-01-01

    Since HLA-DRw15 (a subdivision of the HLA-DR2 specificity previously called DR2 long) is associated with dominant nonsusceptibility to insulin-dependent diabetes mellitus (IDDM), while HLA-DRw16 (another subdivision of HLA-DR2, previously called DR2 short) is positively associated with the disease, we looked for particular characteristics of HLA products encoded by the DR2 haplotypes of IDDM patients. The results show the following: (i) HLA-DQ molecules of HLA-DRw15-positive IDDM patients are different from those of HLA-DRw15-positive controls, suggesting that the HLA-DQ gene of DRw15 haplotypes is involved in a protective effect. (ii) HLA-DR and -DQ products of DRw16-positive IDDM are functionally indistinguishable from those of HLA-DRw16-positive controls. Furthermore, our data provide evidence that the residue at position 57 on the DQ beta chain could play a crucial biological role in antigen presentation to T cells as far as the DRw16 haplotype is concerned. This observation fits with the recent observation of correlation between DQ beta allelic polymorphism at position 57 and both susceptibility and resistance to IDDM. PMID:2901099

  16. Human leukocyte antigen-DRB1 polymorphism in childhood acute lymphoblastic leukemia

    PubMed Central

    EL ANSARY, MERVAT M.; MOHAMMED, LAMIAA A.; HASSAN, TAMER H.; BARAKA, AHMED; AHMED, ALSHYMAA A.

    2015-01-01

    Similar to autoimmune diseases, there are clear associations between resistance or susceptibility to cancer and the classic human leukocyte antigen (HLA) profile of an individual. HLA-associated susceptibility to childhood acute lymphoblastic leukemia (ALL) may provide clues to leukemogenesis in general and to the role of other risk factors. The present study aimed to determine the association between the HLA-DRB1 genotype and susceptibility to ALL in children and to assess the prognostic value of HLA-DRB1 alleles in these patients. This study included 50 ALL patients who were consecutively admitted to the Pediatric Oncology Unit of Zagazig University Hospital and 50 gender-matched healthy volunteers as a control group. The patients were subjected to full clinical history, thorough clinical examination and routine laboratory investigations. Molecular HLA-DRB1 typing for patients and controls using the reverse sequence-specific oligonucleotide probe technique was performed. HLA-DRB1*04 allele frequency was significantly higher in female patients compared to that in female controls (P=0.03) and in patients aged <10 years compared to those aged ≥10 years at the time of diagnosis (P=0.01). HLA-DRB1*11 allele frequency was significantly higher in high-risk compared to standard-risk patients (P=0.01) and in refractory patients compared to those who achieved remission (P=0.02). In conclusion, the HLA-DRB1*04 allele appears to be a female-specific susceptibility factor for the acquisition of childhood ALL and it may affect the age of onset of ALL. In addition, the HLA-DRB1*11 allele may be of prognostic significance in childhood ALL. However, further larger studies are required to support the conclusions drawn from this study. PMID:25798280

  17. Cloning of a new gene encoding an antigen recognized by melanoma-specific HLA-A24-restricted tumor-infiltrating lymphocytes

    SciTech Connect

    Robbins, P.F.; El-Gamil, M.; Li, Y.F.

    1995-06-01

    The role of tumor-specific T cells in mediating the regression of metastatic melanoma has been suggested by the clinical response of patients to treatment with tumor-infiltrating lymphocytes (TIL). A number of Ags recognized by class I-restricted melanoma-specific T cells have recently been isolated, raising the hope that this will lead to the development of improved therapies. In this study, we report the cloning of a tumor Ag recognized by T cells from melanoma patient 888. Previously, we reported that TIL 888, grown from the tumor of this patient, recognized tyrosinase in an HLA-A24 -restricted fashion. This line, when infused into the autologous patient, resulted in complete regression of multiple metastases. Three years later, a second TIL line, TIL 1290, was isolated from a recurrent pelvic tumor. Infusion of a mixture of TIL 888 and TIL 1290 cell lines into the patient resulted in complete regression of a residual abdominal mass and the patient remains disease-free 2 yr later. The TIL 1290 cell line, which recognized melanoma in an HLAA-A24-restricted manner, failed to recognize tyrosinase. TIL 1290 was then used to screen an 888 melanoma cDNA library, and an Ag was isolated that did not correspond to any found in sequence databases. This gene, termed p15, was found to be expressed in a variety of normal tissues, and a peptide epitope recognized by TIL 1290 was found to represent the product of an nonmutated gene. Screening of additional cDNA pools resulted in the isolation of a second clone which stimulated TIL 1290. This clone also appeared to represent a transcript of the p15 gene, indicating that this gene may encode the predominant Ag recognized by TIL 1290. 27 refs., 4 figs., 5 tabs.

  18. Endoplasmic Reticulum Aminopeptidase 1 (ERAP1) Polymorphism Relevant to Inflammatory Disease Shapes the Peptidome of the Birdshot Chorioretinopathy-Associated HLA-A*29:02 Antigen.

    PubMed

    Alvarez-Navarro, Carlos; Martín-Esteban, Adrian; Barnea, Eilon; Admon, Arie; López de Castro, José A

    2015-07-01

    Birdshot chorioretinopathy is a rare ocular inflammation whose genetic association with HLA-A*29:02 is the highest between a disease and a major histocompatibility complex (MHC) molecule. It belongs to a group of MHC-I-associated inflammatory disorders, also including ankylosing spondylitis, psoriasis, and Behçet's disease, for which endoplasmic reticulum aminopeptidases (ERAP) 1 and/or 2 have been identified as genetic risk factors. Since both enzymes are involved in the processing of MHC-I ligands, it seems reasonable that common peptide-mediated mechanisms may underlie the pathogenesis of these diseases. In this study, comparative immunopeptidomics was used to characterize >5000 A*29:02 ligands and quantify the effects of ERAP1 polymorphism and expression on the A*29:02 peptidome in human cells. The peptides predominant in an active ERAP1 context showed a higher frequency of nonamers and bulkier amino acid side chains at multiple positions, compared with the peptides predominant in a less active ERAP1 background. Thus, ERAP1 polymorphism has a large influence, shaping the A*29:02 peptidome through length-dependent and length-independent effects. These changes resulted in increased affinity and hydrophobicity of A*29:02 ligands in an active ERAP1 context. The results reveal the nature of the functional interaction between A*29:02 and ERAP1 and suggest that this enzyme may affect the susceptibility to birdshot chorioretinopathy by altering the A*29:02 peptidome. The complexity of these alterations is such that not only peptide presentation but also other potentially pathogenic features could be affected. PMID:25892735

  19. Development of a high-resolution NGS-based HLA-typing and analysis pipeline

    PubMed Central

    Wittig, Michael; Anmarkrud, Jarl A.; Kässens, Jan C.; Koch, Simon; Forster, Michael; Ellinghaus, Eva; Hov, Johannes R.; Sauer, Sascha; Schimmler, Manfred; Ziemann, Malte; Görg, Siegfried; Jacob, Frank; Karlsen, Tom H.; Franke, Andre

    2015-01-01

    The human leukocyte antigen (HLA) complex contains the most polymorphic genes in the human genome. The classical HLA class I and II genes define the specificity of adaptive immune responses. Genetic variation at the HLA genes is associated with susceptibility to autoimmune and infectious diseases and plays a major role in transplantation medicine and immunology. Currently, the HLA genes are characterized using Sanger- or next-generation sequencing (NGS) of a limited amplicon repertoire or labeled oligonucleotides for allele-specific sequences. High-quality NGS-based methods are in proprietary use and not publicly available. Here, we introduce the first highly automated open-kit/open-source HLA-typing method for NGS. The method employs in-solution targeted capturing of the classical class I (HLA-A, HLA-B, HLA-C) and class II HLA genes (HLA-DRB1, HLA-DQA1, HLA-DQB1, HLA-DPA1, HLA-DPB1). The calling algorithm allows for highly confident allele-calling to three-field resolution (cDNA nucleotide variants). The method was validated on 357 commercially available DNA samples with known HLA alleles obtained by classical typing. Our results showed on average an accurate allele call rate of 0.99 in a fully automated manner, identifying also errors in the reference data. Finally, our method provides the flexibility to add further enrichment target regions. PMID:25753671

  20. [The HLA system in the Moroccan population: General review].

    PubMed

    Brick, C; Atouf, O; Essakalli, M

    2015-01-01

    The Moroccan population is an interesting study model of Human Leukocyte Antigen (HLA) polymorphism given its ethnic and genetic diversity. Through an analysis of the literature, this work proposes to establish a balance of knowledge for this population in the field of histocompatibility: HLA diversity, anthropology, transplantation and HLA associations and diseases. This analysis shows that the HLA system has not been fully explored within the Moroccan population. However, the results obtained allowed us to initiate a database reflecting the specific healthy Moroccan population HLA polymorphism to identify immigration flows and relationships with different people of the world and to reveal the association of certain HLA alleles with frequent pathologies. We also propose to analyze the reasons hindering the development of this activity in Morocco and we will try to identify some perspectives. PMID:26597780

  1. Distinct assembly profiles of HLA-B molecules

    PubMed Central

    Rizvi, Syed Monem; Salam, Nasir; Geng, Jie; Qi, Ying; Bream, Jay H.; Duggal, Priya; Hussain, Shehnaz K.; Martinson, Jeremy; Wolinsky, Steven; Carrington, Mary; Raghavan, Malini

    2014-01-01

    Major histocompatibility complex (MHC) class I polymorphisms are known to influence outcomes in a number of infectious diseases, cancers and inflammatory diseases. Human MHC class I heavy chains are encoded by the HLA-A, HLA-B and HLA-C genes. These genes are highly polymorphic, with the HLA-B locus being the most variable. Each HLA class I protein binds to distinct set of peptide antigens, which are presented to CD8+ T cells. HLA-disease associations have been shown in some cases to link to the peptide binding characteristics of individual HLA class I molecules. Here we show that polymorphisms at the HLA-B locus profoundly influence the assembly characteristics of HLA-B molecules and the stabilities of their peptide-deficient forms. In particular, dependence on the assembly factor tapasin is highly variable, with frequent occurrence of strongly tapasin-dependent or independent allotypes. Several polymorphic HLA-B residues located near the C-terminal end of the peptide are key determinants of tapasin-independent assembly. In vitro refolded forms of tapasin-independent allotypes assemble more readily with peptides compared to tapasin-dependent allotypes that belong to the same supertype, and during refolding, reduced aggregation of tapasin-independent allotypes is observed. Paradoxically, in HIV-infected individuals, greater tapasin-independent HLA-B assembly confers more rapid progression to death, consistent with previous findings that some HLA-B allotypes shown to be tapasin-independent are associated with rapid progression to multiple AIDS outcomes. Together, these findings demonstrate significant variations in the assembly of HLA-B molecules, and indicate influences of HLA-B folding patterns upon infectious disease outcomes. PMID:24790147

  2. HLA-E polymorphism and soluble HLA-E plasma levels in chronic hepatitis B patients.

    PubMed

    Zidi, I; Laaribi, A B; Bortolotti, D; Belhadj, M; Mehri, A; Yahia, H B; Babay, W; Chaouch, H; Zidi, N; Letaief, A; Yacoub, S; Boukadida, J; Di Luca, D; Hannachi, N; Rizzo, R

    2016-03-01

    Chronic hepatitis B virus (HBV) infection occurs in association to a deregulation of immune system. Human leukocyte antigen E (HLA-E) is an immune-tolerant nonclassical HLA class I molecule that could be involved in HBV progression. To measure soluble (s) HLA-E in patients with chronic HBV hepatitis (CHB). We tested the potential association of HLA-E*01:01/01:03 A > G gene polymorphism to CHB. Our cohort consisted of 93 Tunisian CHB patients (stratified in CHB with high HBV DNA levels and CHB with low HBV DNA levels) and 245 healthy donors. Plasma sHLA-E was determined using enzyme-linked immunosorbent assay (ELISA). Genotyping was performed using polymerase chain reaction sequence-specific primer. No association between HLA-E*01:01/01:03 A > G polymorphism and HBV DNA levels in CHB patients was found. G/G genotype is less frequent in CHB patients without significance. sHLA-E is significantly enhanced in CHB patients compared with healthy controls (P = 0.0017). Stratification according to HBV DNA levels showed that CHB patients with low HBV DNA levels have higher sHLA-E levels compared with CHB patients with high HBV DNA levels. CHB patients with G/G genotype have enhanced sHLA-E levels compared with other genotypes (P = 0.037). This significant difference is maintained only for CHB women concerning G/G genotypes (P = 0.042). Finally, we reported enhanced sHLA-E in CHB patients with advanced stages of fibrosis (P = 0.032). We demonstrate, for the first time, the association of sHLA-E to CHB. Owing to the positive correlation of HLA-E*01:01/01:03 A > G polymorphism and the association of sHLA-E to advanced fibrosis stages, HLA-E could be a powerful predictor for CHB progression. Further investigations will be required to substantiate HLA-E role as a putative clinical biomarker of CHB. PMID:26956431

  3. Recognition of distinct HLA-DQA1 promoter elements by a single nuclear factor containing Jun and Fos or antigenically related proteins.

    PubMed Central

    Neve Ombra, M; Autiero, M; DeLerma Barbaro, A; Barretta, R; Del Pozzo, G; Guardiola, J

    1993-01-01

    The activity of MHC class II promoters depends upon conserved regulatory signals one of which, the extended X-box, contains in its X2 subregion a sequence related to the cAMP response element, CRE and to the TPA response element, TRE. Accordingly, X2 is recognized by the AP-1 factor and by other c-Jun or c-Fos containing heterodimers. We report that the X-box dependent promoter activity of the HLA-DQA1 gene is down-modulated by an array of DNA elements each of which represented twice either in an invertedly or directly repeated orientation. In this frame, we describe a nuclear binding factor, namely DBF, promiscuously interacting with two of these additional signals, delta and sigma, and with a portion of the X-box, namely the X-core, devoid of X2. The presence of a single factor recognizing divergent DNA sequences was indicated by the finding that these activities were co-eluted from a heparin-Sepharose column and from DNA affinity columns carrying different DNA binding sites as ligands. Competition experiments made with oligonucleotides representing wild type and mutant DNA elements showed that each DNA element specifically inhibited the binding of the others, supporting the contention that DBF is involved in recognition of different targets. Furthermore, we found that DBF also exhibits CRE/TRE binding activity and that this activity can be competed out by addition of an excess of sigma, delta and X-core oligonucleotides. Anti-Jun peptide and anti-Fos peptide antibodies blocked not only the binding activity of DBF, but also its X-core and sigma binding; this blockade was removed by the addition of the Jun or Fos peptides against which the antibodies had been raised. In vitro synthesized Jun/Fos was able to bind to all these boxes, albeit with seemingly different affinities. The cooperativity of DBF interactions may explain the modulation of the X-box dependent promoter activity mediated by the accessory DNA elements described here. Images PMID:8493100

  4. The Potential of HLA-G-Bearing Extracellular Vesicles as a Future Element in HLA-G Immune Biology.

    PubMed

    Rebmann, Vera; König, Lisa; Nardi, Fabiola da Silva; Wagner, Bettina; Manvailer, Luis Felipe Santos; Horn, Peter A

    2016-01-01

    The HLA-G molecule is a member of the non-classical HLA class I family. Its surface expression is physiologically restricted to the maternal-fetal interface and to immune privileged adult tissues. Despite the restricted tissue expression, HLA-G is detectable in body fluids as secreted soluble molecules. A unique feature of HLA-G is the structural diversity as surface expressed and as secreted molecules. Secreted HLA-G can be found in various body fluids either as free soluble HLA-G or as part of extracellular vesicles (EVs), which are composed of various antigens/ligands/receptors, bioactive lipids, cytokines, growth factors, and genetic information, such as mRNA and microRNA. Functionally, HLA-G and its secreted forms are considered to play a crucial role in the network of immune-regulatory tolerance mechanisms, preferentially interacting with the cognate inhibitory receptors LILRB1 and LILRB2. The HLA-G mediated tolerance is described in processes of pregnancy, inflammation, and cancer. However, almost all functional and clinical implications of HLA-G in vivo and in vitro have been established based on simple single ligand/receptor interactions at the cell surface, whereas HLA-G-bearing EVs were in minor research focus. Indeed, cytotrophoblast cells, mesenchymal stem cells, and cancer cells were recently described to secrete HLA-G-bearing EVs, displaying immunosuppressive effects and modulating the tumor microenvironment. However, numerous functional and clinical open questions persist. Here, we (i) introduce basic aspects of EVs biology, (ii) summarize the functional knowledge, clinical implications and open questions of HLA-G-bearing EVs, and (iii) discuss HLA-G-bearing EVs as a future element in HLA-G biology. PMID:27199995

  5. The Potential of HLA-G-Bearing Extracellular Vesicles as a Future Element in HLA-G Immune Biology

    PubMed Central

    Rebmann, Vera; König, Lisa; Nardi, Fabiola da Silva; Wagner, Bettina; Manvailer, Luis Felipe Santos; Horn, Peter A.

    2016-01-01

    The HLA-G molecule is a member of the non-classical HLA class I family. Its surface expression is physiologically restricted to the maternal–fetal interface and to immune privileged adult tissues. Despite the restricted tissue expression, HLA-G is detectable in body fluids as secreted soluble molecules. A unique feature of HLA-G is the structural diversity as surface expressed and as secreted molecules. Secreted HLA-G can be found in various body fluids either as free soluble HLA-G or as part of extracellular vesicles (EVs), which are composed of various antigens/ligands/receptors, bioactive lipids, cytokines, growth factors, and genetic information, such as mRNA and microRNA. Functionally, HLA-G and its secreted forms are considered to play a crucial role in the network of immune-regulatory tolerance mechanisms, preferentially interacting with the cognate inhibitory receptors LILRB1 and LILRB2. The HLA-G mediated tolerance is described in processes of pregnancy, inflammation, and cancer. However, almost all functional and clinical implications of HLA-G in vivo and in vitro have been established based on simple single ligand/receptor interactions at the cell surface, whereas HLA-G-bearing EVs were in minor research focus. Indeed, cytotrophoblast cells, mesenchymal stem cells, and cancer cells were recently described to secrete HLA-G-bearing EVs, displaying immunosuppressive effects and modulating the tumor microenvironment. However, numerous functional and clinical open questions persist. Here, we (i) introduce basic aspects of EVs biology, (ii) summarize the functional knowledge, clinical implications and open questions of HLA-G-bearing EVs, and (iii) discuss HLA-G-bearing EVs as a future element in HLA-G biology. PMID:27199995

  6. HLA-B27/microbial mimicry: an in vivo analysis.

    PubMed Central

    Kapasi, K; Chui, B; Inman, R D

    1992-01-01

    The association between three major spondyloarthritic diseases, ankylosing spondylitis, Reiter's syndrome, and reactive arthritis, and the major histocompatibility complex (MHC) class 1 antigen HLA-B27 is well documented. The hypothesis of cross-reactivity between HLA-B27 and the antecedent infection-causing Gram-negative pathogens such as Salmonella, Shigella and Yersinia has been suggested by in vitro studies employing monoclonal antibodies. We have examined the possibility of such cross-reactivity in vivo using various rabbit immune sera and patient sera as the source of cross-reacting antibody. Mouse L cells were transfected with HLA-A3 or HLA-B27 and used as a source of antigen. Western blot analysis employing denatured antigen, FACS analysis employing native antigen and immunoprecipitation studies were undertaken to detect cross-reacting antibodies generated in vivo to HLA-B27 antigen. Antibodies generated in vivo by infection in patients or immunization in animals against arthritogenic bacteria did not demonstrate any cross-reactivity with HLA-B27 by any of the methods used. As defined by the humoral immune response, molecular mimicry appears unlikely to explain the role of B27 in the pathogenesis of reactive arthritis. Images Figure 2 Figure 3 Figure 6 PMID:1478690

  7. Anti-tumor effect of the alphavirus-based virus-like particle vector expressing prostate-specific antigen in a HLA-DR transgenic mouse model of prostate cancer.

    PubMed

    Riabov, V; Tretyakova, I; Alexander, R B; Pushko, P; Klyushnenkova, E N

    2015-10-01

    The goal of this study was to determine if an alphavirus-based vaccine encoding human Prostate-Specific Antigen (PSA) could generate an effective anti-tumor immune response in a stringent mouse model of prostate cancer. DR2bxPSA F1 male mice expressing human PSA and HLA-DRB1(*)1501 transgenes were vaccinated with virus-like particle vector encoding PSA (VLPV-PSA) followed by the challenge with Transgenic Adenocarcinoma of Mouse Prostate cells engineered to express PSA (TRAMP-PSA). PSA-specific cellular and humoral immune responses were measured before and after tumor challenge. PSA and CD8 reactivity in the tumors was detected by immunohistochemistry. Tumor growth was compared in vaccinated and control groups. We found that VLPV-PSA could infect mouse dendritic cells in vitro and induce a robust PSA-specific immune response in vivo. A substantial proportion of splenic CD8 T cells (19.6 ± 7.4%) produced IFNγ in response to the immunodominant peptide PSA(65-73). In the blood of vaccinated mice, 18.4 ± 4.1% of CD8 T cells were PSA-specific as determined by the staining with H-2D(b)/PSA(65-73) dextramers. VLPV-PSA vaccination also strongly stimulated production of IgG2a/b anti-PSA antibodies. Tumors in vaccinated mice showed low levels of PSA expression and significant CD8+ T cell infiltration. Tumor growth in VLPV-PSA vaccinated mice was significantly delayed at early time points (p=0.002, Gehan-Breslow test). Our data suggest that TC-83-based VLPV-PSA vaccine can efficiently overcome immune tolerance to PSA, mediate rapid clearance of PSA-expressing tumor cells and delay tumor growth. The VLPV-PSA vaccine will undergo further testing for the immunotherapy of prostate cancer. PMID:26319744

  8. A web resource for mining HLA associations with adverse drug reactions: HLA-ADR.

    PubMed

    Ghattaoraya, Gurpreet S; Dundar, Yenal; González-Galarza, Faviel F; Maia, Maria Helena Thomaz; Santos, Eduardo José Melo; da Silva, Andréa Luciana Soares; McCabe, Antony; Middleton, Derek; Alfirevic, Ana; Dickson, Rumona; Jones, Andrew R

    2016-01-01

    Human leukocyte antigens (HLA) are an important family of genes involved in the immune system. Their primary function is to allow the host immune system to be able to distinguish between self and non-self peptides-e.g. derived from invading pathogens. However, these genes have also been implicated in immune-mediated adverse drug reactions (ADRs), presenting a problem to patients, clinicians and pharmaceutical companies. We have previously developed the Allele Frequency Net Database (AFND) that captures the allelic and haplotype frequencies for these HLA genes across many healthy populations from around the world. Here, we report the development and release of the HLA-ADR database that captures data from publications where HLA alleles and haplotypes have been associated with ADRs (e.g. Stevens-Johnson Syndrome/toxic epidermal necrolysis and drug-induced liver injury). HLA-ADR was created by using data obtained through systematic review of the literature and semi-automated literature mining. The database also draws on data already present in AFND allowing users to compare and analyze allele frequencies in both ADR patients and healthy populations. The HLA-ADR database provides clinicians and researchers with a centralized resource from which to investigate immune-mediated ADRs.Database URL: http://www.allelefrequencies.net/hla-adr/. PMID:27189608

  9. Relative expression levels of the HLA class-I proteins in normal and HIV-infected cells 1

    PubMed Central

    Apps, Richard; Meng, Zhaojing; Del Prete, Gregory Q.; Lifson, Jeffrey D.; Zhou, Ming; Carrington, Mary

    2015-01-01

    The expression level of human leukocyte antigens (HLA) is known to influence pathological outcomes: pathogens downregulate HLA to evade host immune responses, host inflammatory reactions upregulate HLA, and differences between people in steady-state expression levels of HLA associate with disease susceptibility. Yet precise quantification of relative expression levels of the various HLA loci is difficult due to the tremendous polymorphism of HLA. We report relative expression levels of HLA-A, HLA-B, HLA-C and HLA-E proteins for the specific haplotype A*02:01, B*44:02, C*05:01, characterized using two independent methods based on flow cytometry and mass spectrometry. Peripheral blood lymphocytes from normal donors showed that HLA-A and HLA-B proteins are expressed at similar levels, which are 13-18 times higher than HLA-C by flow cytometry and 4-5 times higher than HLA-C by mass spectrometry, differences that may reflect variation in the conformation or location of proteins detected. HLA-E was detected at a level 25 times lower than that of HLA-C by mass spectrometry. Primary CD4+ T cells infected with HIV in vitro were also studied since HIV downregulates selective HLA types. HLA-A and -B were reduced on HIV-infected cells by a magnitude that varied between cells in an infected culture. Averaging all infected cells from an individual showed HLA-A to be 1-3 and HLA-B to be 2-5 times higher than HLA-C for different individuals by flow cytometry. These results quantify substantial differences in expression levels of the proteins from different HLA loci, which are very likely physiologically significant on both uninfected and HIV-infected cells. PMID:25754738

  10. [Gene and haplotype frequencies for the loci HLA-A, B and DRB1 in 11755 north Chinese Han bone marrow registry donors].

    PubMed

    Wu, Qiang-Ju; Liu, Meng-Li; Qi, Jun; Liu, Sheng; Zhang, Yan; Wei, Xiao-Qian

    2007-04-01

    The study was aimed to investigate the human leukocyte antigen (HLA)-A, B, DRB1 alleles and haplotype frequencies and the characteristics of linkage disequilibrium in north Chinese Han bone marrow donors. HLA phenotype data of 11 755 north Chinese Han bone marrow donors were identified by PCR-SSP and PCR-SSO. HLA-A, B, DRB1 allele and haplotype frequencies were calculated by computer software named Arleguin which was based on Expectation-Maximization (EM) algorithms. The results showed that the population of 11755 unrelated-donors was tested by Hardy-Weinberg equilibrium, and 18,42 and 15 specificities of HLA alleles were identified on the HLA-A, B, DRB1 locus respectively, including HLA-A25, B42, B53, B73 and DR3 which were rarely reported in Han population. HLA-A36, A43, A80, B78, B82 and DR18 were not detected in this study. The most frequent alleles with a frequency of over 0.05 were HLA-A*02, A*11, A*24, A*33, A*30, A*01, A*03, A*13, B62, B*51, B*46, B60, B61, B*35, B*44, DRB1*15, DRB1*09, DRB1*04, DRB1*07, DRB1*12, DRB1*11, DRB1*14, DRB1*08, DRB1*13. There were a total of 2 026 kinds of HLA-A-B-DR haplotypes (with a frequency of over 10(-6)) to be obtained. The each frequency of 26 kinds of three-locus haplotypes including HLA-A30-B13-DR7, A2-B46-DR9, A33-B58-DR17 etc was higher than 0.005. A30-B13-DR7 was the most frequent haplotype in north Chinese Han population. There were a total of 538 kinds of haplotypes for HLA-A-B, 227 kinds for A-DR and 522 kinds for B-DR to be obtained, and there were 409, 195, 423 kinds of haplotypes respectively with a frequency higher than 10 - 6. There were 28 kinds of HLA-A-B haplotypes including A30-B13, A2-B46, A33-B58 etc, 26 kinds of HLA-A-DR haplotypes including A2-DR9, A2-DR15, A30-DR7 etc, and 24 kinds of HLA-B-DR haplotypes including B13-DR7, B46-DR9, B13-DR12 etc with a frequency higher than 0.01. 296 (72%) kinds of HLA-A-B, 130 (67%) kinds of A-DR and 308 (73%) kinds of B-DR haplotypes were statistical linkage

  11. HLA disease association and protection in HIV infection among African Americans and Caucasians.

    PubMed

    Cruse, J M; Brackin, M N; Lewis, R E; Meeks, W; Nolan, R; Brackin, B

    1991-01-01

    In a previous investigation, we demonstrated an increased progression of overt AIDS in the African American population compared to the Caucasian population as reflected by the significantly lower absolute number of CD4+ lymphocytes detected in the African American population in an earlier study. The present study elucidates some of the possible genetic factors which may contribute to disease association or protection against HIV infection. The HLA phenotypes expressed as A, B, C, DR and DQw antigens were revealed by the Amos-modified typing procedure. NIH scoring was utilized to designate positive cells taking up trypan blue. A test of proportion equivalent to the chi 2 approximation was used to compare the disease population (n = 62; 38 African Americans, 24 Caucasians) to race-matched normal heterosexual local controls (323 African Americans, 412 Caucasians). Significant p values were corrected for the number of HLA antigens tested. HLA markers associated with possible protection from infection for African Americans were Cw4 and DRw6, whereas Caucasians expressed none. Disease association markers present in the African American population were A31, B35, Cw6, Cw7, DR5, DR6, DRw11, DRw12, DQw6 and DQw7, whereas in the Caucasian population A28, Aw66, Aw48, Bw65, Bw70, Cw7, DRw10, DRw12, DQw6 and DQw7 were demonstrated. The highest phenotypic frequency for a disease association marker in the study was for HLA-DR5 (62.9%) in the HIV-infected African American population without Kaposi's sarcoma compared to a frequency of 28.9% for the regional control group (p = 0.0012). We conclude that genetic factors do have a role in HIV infection since only 50-60% of those exposed to the AIDS virus will become infected. PMID:1910527

  12. Susceptible and protective associations of HLA DRB1*/DQB1* alleles and haplotypes with ischaemic stroke.

    PubMed

    Murali, V; Rathika, C; Ramgopal, S; Padma Malini, R; Arun Kumar, M J; Neethi Arasu, V; Jeyaram Illiayaraja, K; Balakrishnan, K

    2016-06-01

    Stroke has emerged as the second commonest cause of mortality worldwide and is a major public health problem. For the first time, we present here the association of human leucocyte antigen (HLA)-DRB1*/DQB1* alleles and haplotypes with ischaemic stroke in South Indian patients. Ischaemic stroke (IS) cases and controls were genotyped for HLA-DRB1*/DQB1* alleles by polymerase chain reaction sequence-specific primers (PCR-SSP) method. The frequencies of HLA class II alleles such as DRB1*04, DRB1*07, DRB1*11, DRB1*12, DRB1*13, DQB1*02 and DQB1*07 were high in IS patients than in the age- and gender-matched controls, suggesting that the individuals with these alleles are susceptible to ischaemic stroke in South India. The frequencies of alleles such as DRB1*03, DRB1*10, DRB1*14, DQB1*04 and DQB1*05 were less in IS cases than in the controls, suggesting a protective association. Haplotypes DRB1*04-DQB1*0301, DRB1*07-DQB1*02, DRB1*07-DQB1*0301, DRB1*11-DQB1*0301 and DRB1*13-DQB1*06 were found to be high in IS patients conferring susceptibility. The frequency of haplotype DRB1*10-DQB1*05 was high in controls conferring protection. IS-LVD and gender-stratified analysis too confirmed these susceptible and protective associations. Thus, HLA-DRB1*/DQB1* alleles and haplotypes strongly predispose South Indian population to ischaemic stroke. Further studies in different populations with large sample size or the meta-analysis are needed to explain the exact mechanism of associations of HLA gene(s) with IS. PMID:27105925

  13. HLA ligandomics identifies histone deacetylase 1 as target for ovarian cancer immunotherapy

    PubMed Central

    Peper, Janet Kerstin; Bösmüller, Hans-Christian; Schuster, Heiko; Gückel, Brigitte; Hörzer, Helen; Roehle, Kevin; Schäfer, Richard; Wagner, Philipp; Rammensee, Hans-Georg; Stevanović, Stefan; Fend, Falko; Staebler, Annette

    2016-01-01

    abstract The recent approval of clincially effective immune checkpoint inhibitors illustrates the potential of cancer immunotherapy. A challenging task remains the identification of specific targets guiding immunotherapy. Facilitated by technical advances, the direct identification of physiologically relevant targets is enabled by analyzing the HLA ligandome of cancer cells. Since recent publications demonstrate the immunogenicity of ovarian cancer (OvCa), immunotherapies, including peptide-based cancer vaccines, represent a promising treatment approach. To identify vaccine peptides, we employed a combined strategy of HLA ligandomics in high-grade serous OvCa samples and immunogenicity analysis. Only few proteins were naturally presented as HLA ligands on all samples analyzed, including histone deacetylase (HDAC) 1 and 2. In vitro priming of CD8+ T cells demonstrated that two HDAC1/2-derived HLA ligands can induce T-cell responses, capable of killing HLA-matched tumor cells. High HDAC1 expression shown by immunohistochemistry in 136 high-grade serous OvCa patients associated with significantly reduced overall survival (OS), whereas patients with high numbers of CD3+ tumor-infiltrating lymphocytes (TILs) in the tumor epithelium and CD8+ TILs in the tumor stroma showed improved OS. However, correlating HDAC1 expression with TILs, high levels of TILs abrogated the impact of HDAC1 on OS. This study strengthens the role of HDAC1/2 as an important tumor antigen in OvCa, demonstrating its impact on OS in a large cohort of OvCa patients. We further identified two immunogenic HDAC1-derived peptides, which frequently induce multi-functional T-cell responses in many donors, suitable for future multi-peptide vaccine trials in OvCa patients.

  14. HLA-sharing, recurrent spontaneous abortion, and the genetic hypothesis

    SciTech Connect

    Hedrick, P.W.

    1988-05-01

    A number of studies indicates that there is a high sharing of HLA antigens in couples having recurrent spontaneous abortions. The genetic hypothesis to explain this phenomenon suggests that this fetal loss results from homozygosity of recessive lethal or deleterius alleles in gametic disequilibrium with HLA antigens. Theory predicting the lethality rate is derived when antigens are shared at one, two or three loci, given the disequilibrium is absolute. In addition, the effects of partial disequilibrium, inbreeding, and segregation distortion on the lethal proportion are examined.

  15. The HLA-DRB1 allele polymorphisms and nasopharyngeal carcinoma.

    PubMed

    Yang, Huimin; Yu, Kaihui; Zhang, Ruoheng; Li, Jiatong; Wei, Xiaomou; Zhang, Yuening; Zhang, Chengdong; Xiao, Feifan; Zhao, Dong; Lin, Xuandong; Wu, Huayu; Yang, Xiaoli

    2016-06-01

    Human leukocyte antigen (HLA)-DRB1 has been reported to influence individual's susceptibility to nasopharyngeal carcinoma (NPC) by many studies in recent years; however, these studies provided controversial results. The meta-analysis was thus conducted here to estimate the relationship between HLA-DRB1 polymorphisms and NPC. After an extensive review of journals from various databases (PubMed, the Web of Science, Embase, China National Knowledge Internet (CNKI), and Wanfang Database), 8 out of 69 case-control studies, including 778 cases and 1148 controls, were extracted. The results showed that 4 of 13 polymorphisms allele are statistically significantly associated with NPC, among them, HLA-DRB1*3, HLA-DRB1*9, and HLA-DRB1*10 may increase the risk of NPC while HLA-DRB1*01 has the opposite effect. The pooled odds ratio and 95 % confidence interval (CI) were 1.702 [95 % CI (1.047, 2.765)], 1.363 [95 % CI (1.029, 1.806)], 1.989 [95 % CI (1.042, 3.799)], and 0.461 [95 % CI (0.315, 0.676)], respectively. In a further ethnicity-based subgroup analysis, HLA-DRB1*08, HLA-DRB1*11, and HLA-DRB1*16 were found to be linked with NPC in Asian, Tunisian, and Caucasian, respectively. In Asian, HLA-DRB1*03, 08, and 10 may elevate the risk whereas HLA-DRB1*09 could lower it. In Tunisian, HLA-DRB1*01 and 11 are the protective factors while HLA-DRB1*03 is the only risk factor. In Caucasian, HLA-DRB1*01 and 03 increase the risk and HLA-DRB1*16 lowers it. The most frequent statistically associated gene is found to be HLA-DRB1*03 which has protective influence on Asian and Tunisian. In conclusion, HLA-DRB1*01, DRB1*03, DRB1*09, and DRB1*10 are related with NPC susceptibility, and the association of HLA-DRB1*08, DRB1*11, and DRB1*16 with NPC risk are significantly different in different ethnicities. PMID:27059731

  16. Is there a stronger graft-versus-leukemia effect using HLA-haploidentical donors compared with HLA-identical siblings?

    PubMed

    Ringdén, O; Labopin, M; Ciceri, F; Velardi, A; Bacigalupo, A; Arcese, W; Ghavamzadeh, A; Hamladji, R M; Schmid, C; Nagler, A; Mohty, M

    2016-02-01

    Haploidentical hematopoietic stem cell transplants (HSCTs) are increasingly used, but it is unknown whether they have a stronger graft-versus-leukemia (GVL) effect. We analyzed 10 679 acute leukemia patients who underwent HSCT from an HLA-matched sibling donor (MSD, n=9815) or a haploidentical donor (⩾2 HLA-antigen disparity, n=864) between 2007 and 2012, reported to the European Group for Blood and Marrow Transplantation. In a Cox regression model, acute and chronic graft-versus-host disease (GVHD) was added as time-dependent variables. There was no difference in probability of relapse between recipients of haploidentical and MSD grafts. Factors of importance for relapse after T-cell-replete grafts included remission status at HSCT, Karnofsky score ⩽80, acute GVHD of grade II or higher and chronic GVHD (P<10(-5)). Patients with post-transplant cyclophosphamide (n=194) had similar outcome as other T-cell-replete haploidentical transplants (n=369). Non-relapse mortality was significantly higher in the haploidentical group compared with that in MSD patients (P<10(-5)). Leukemia-free survival was superior in the MSD patients receiving T-cell-replete (P<10(-5)) or T-cell-depleted grafts (P=0.0006). The risk of relapse was the same in acute leukemia patients who received haploidentical donor grafts as in those given MSD transplants, suggesting a similar GVL effect. PMID:26293645

  17. Co-evolution of Human Leukocyte Antigen (HLA) Class I Ligands with Killer-Cell Immunoglobulin-Like Receptors (KIR) in a Genetically Diverse Population of Sub-Saharan Africans

    PubMed Central

    Norman, Paul J.; Hollenbach, Jill A.; Nemat-Gorgani, Neda; Guethlein, Lisbeth A.; Hilton, Hugo G.; Pando, Marcelo J.; Koram, Kwadwo A.; Riley, Eleanor M.; Abi-Rached, Laurent; Parham, Peter

    2013-01-01

    Interactions between HLA class I molecules and killer-cell immunoglobulin-like receptors (KIR) control natural killer cell (NK) functions in immunity and reproduction. Encoded by genes on different chromosomes, these polymorphic ligands and receptors correlate highly with disease resistance and susceptibility. Although studied at low-resolution in many populations, high-resolution analysis of combinatorial diversity of HLA class I and KIR is limited to Asian and Amerindian populations with low genetic diversity. At the other end of the spectrum is the West African population investigated here: we studied 235 individuals, including 104 mother-child pairs, from the Ga-Adangbe of Ghana. This population has a rich diversity of 175 KIR variants forming 208 KIR haplotypes, and 81 HLA-A, -B and -C variants forming 190 HLA class I haplotypes. Each individual we studied has a unique compound genotype of HLA class I and KIR, forming 1–14 functional ligand-receptor interactions. Maintaining this exceptionally high polymorphism is balancing selection. The centromeric region of the KIR locus, encoding HLA-C receptors, is highly diverse whereas the telomeric region encoding Bw4-specific KIR3DL1, lacks diversity in Africans. Present in the Ga-Adangbe are high frequencies of Bw4-bearing HLA-B*53:01 and Bw4-lacking HLA-B*35:01, which otherwise are identical. Balancing selection at key residues maintains numerous HLA-B allotypes having and lacking Bw4, and also those of stronger and weaker interaction with LILRB1, a KIR-related receptor. Correspondingly, there is a balance at key residues of KIR3DL1 that modulate its level of cell-surface expression. Thus, capacity to interact with NK cells synergizes with peptide binding diversity to drive HLA-B allele frequency distribution. These features of KIR and HLA are consistent with ongoing co-evolution and selection imposed by a pathogen endemic to West Africa. Because of the prevalence of malaria in the Ga-Adangbe and previous

  18. The human leukocyte antigen HLA DRB3*020/DQA1*0501 haplotype is associated with Graves' disease in African Americans.

    PubMed

    Chen, Q Y; Nadell, D; Zhang, X Y; Kukreja, A; Huang, Y J; Wise, J; Svec, F; Richards, R; Friday, K E; Vargas, A; Gomez, R; Chalew, S; Lan, M S; Tomer, Y; Maclaren, N K

    2000-04-01

    Information on genetic susceptibility to Graves' disease in African Americans is limited. We studied DRB1, DQB1, DRB3 subtypes, DQA1*0501, DQA1*0201, and CTLA-4 polymorphisms in 49 African American patients with adult onset Graves' disease and 47 racially-matched controls using PCR-based sequence-specific priming methods. There were no significant differences in DRB1 or DQB1 allelic frequencies or CTLA-4 polymorphisms between patients and controls. However, we found that the frequency of DRB3 was significantly increased in the patients (75.5% vs. 57.4%, P = 0.006, X2 = 3.52), especially for the DRB3*0202 subtype (53.1% vs. 23.4, P = 0.003, X2 = 8.91). In this one respect, the finding was in concordance with our previous observations in Caucasian patients with adult-onset Graves' disease. In addition, whereas the frequency of DQA1*0501 was increased (P = 0.018, X2 = 5.63) in our patients, the haplotype of DRB3/DQA1*0501, or DRB3*0202/DQA1*0501 was found to be more strongly associated (P = 0.008, X2 = 7.0; P = 0.0008, X2 = 11.34, respectively). These data suggest that DRB3*0202, particularly when found with DQA1*0501 in a haplotype is a susceptible gene(s) for Graves' disease in adult African Americans. Considering these data with those in Caucasian patients, our results would suggest that the primary Graves susceptible locus is likely DRB3 and not DRB1. PMID:10770195

  19. Clinical Profile and HLA Typing of Autoimmune Hepatitis From Pakistan

    PubMed Central

    Hassan, Nasir; Siddiqui, Adeelur Rehman; Abbas, Zaigham; Hassan, Syed Mujahid; Soomro, Ghous Bux; Mubarak, Muhammed; Anis, Sabiha; Muzaffar, Rana; Zafar, Mirza Naqi

    2013-01-01

    Background Human leukocyte antigen (HLA) typing in autoimmune hepatitis (AIH) has been investigated in different populations and ethnic groups, but no such data is available from Pakistan. Objectives The aim of this study was to evaluate the clinical profile of autoimmune hepatitis (AIH), and determine the associated antigens and alleles by performing HLA typing. Patients and Methods A total of 58 patients, diagnosed and treated as AIH in the last 10 years were reviewed. Diagnosis was based on International AIH Group criteria. Forty one patients underwent liver biopsy. HLA typing was performed in 44 patients and 912 controls by serological method for HLA A and B, and by PCR technique using sequence specific primers for DR alleles. Results Of 58 cases, 35 were females (60.3%). The median age was 14.5 (range 4-70 years), and AIH score was 14 (10-22). Thirty-six (62.0%) patients had type 1 AIH, 10 (17.2%) type 2, and the remaining 12 were seronegative with biopsy proven AIH. Forty-nine patients (84.4%) had cirrhosis. Twenty-four (41.4%) patients had ascites at the time of presentation. Among 41 patients who underwent liver biopsy, thirty-two had advance stages III and IV disease, and twenty had severe grade of inflammation. Fifteen patients had other associated autoimmune diseases and one developed hepatocellular carcinoma. HLA A2 (P = 0.036), HLA A9 (23) (P = 0.018), HLA A10 (25) (P = 0.000), HLA A19 (33) (P = 0.000), HLA B15 (63) (P = 0.007), HLA B40 (61) ( P = 0.002), HLA DR6 (P = 0.001) with its subtypes HLA-DRB1*13 (P = 0.032) and HLA-DRB1*14 (p = 0.017) were more prevalent in AIH with statistical significance than controls. Conclusions AIH in our region presents with advanced disease affecting predominantly children and adolescents. There is a genetic association of HLA DR6 along with other alleles and antigens in our patients with AIH. PMID:24358040

  20. A novel HLA-B allele, HLA-B*35:279, identified by sequencing-based typing in a Czech patient.

    PubMed

    Mrazek, F; Onderkova, J; Königova, N; Siffnerova, V; Vrana, M; Ambruzova, Z; Skoumalova, I; Petrek, M; Raida, L

    2016-08-01

    The identification of a novel HLA-B*35:279 allele in a Czech patient is described. This allele is identical to the B*35:03:01 variant except the G/A nucleotide exchange at position 652 of the HLA-B gene that corresponds to the amino acid substitution from valine to isoleucine in alpha 3 domain of the HLA-B antigen. PMID:27273911

  1. Genetic study confirms association of HLA-DPA1(∗)01:03 subtype with ankylosing spondylitis in HLA-B27-positive populations.

    PubMed

    Díaz-Peña, Roberto; Castro-Santos, Patricia; Aransay, Ana M; Brüges-Armas, Jacome; Pimentel-Santos, Fernando M; López-Larrea, Carlos

    2013-06-01

    The association of human leukocyte antigen (HLA)-B27 with ankylosing spondylitis (AS) has been known for over 38 years. However, it is not the only gene associated with AS. The aim of this study was to confirm the association of HLA markers around HLA-DPA1/DPB1 region with AS in HLA-B27 positive populations. Five SNPs (rs422544, rs6914849, rs92777535, rs3128968 and rs2295119) from the HLA-DPA1/DPB1 region were genotyped in 340 individuals HLA-B27-positive from Portugal (137 AS patients and 203 healthy controls). Characterizations of HLA-DPA1/DPB1 alleles were also performed. rs422544 revealed a significant association with AS (P<0.05) and sliding windows (SW) analysis showed association of some groups of adjacent SNPs within HLA-DPA1/DPB1 region with AS (P<0.05). We also found association of the HLA-DPA1(∗)01:03 allele with AS (P<0.05). This is the first study that confirms the association of HLA markers and haplotypes around HLA-DPA1 and HLA-DPB1 with AS. PMID:23459078

  2. High-Resolution Analyses of Human Leukocyte Antigens Allele and Haplotype Frequencies Based on 169,995 Volunteers from the China Bone Marrow Donor Registry Program

    PubMed Central

    Zhou, Xiao-Yang; Zhu, Fa-Ming; Li, Jian-Ping; Mao, Wei; Zhang, De-Mei; Liu, Meng-Li; Hei, Ai-Lian; Dai, Da-Peng; Jiang, Ping; Shan, Xiao-Yan; Zhang, Bo-Wei; Zhu, Chuan-Fu; Shen, Jie; Deng, Zhi-Hui; Wang, Zheng-Lei; Yu, Wei-Jian; Chen, Qiang; Qiao, Yan-Hui; Zhu, Xiang-Ming; Lv, Rong; Li, Guo-Ying; Li, Guo-Liang; Li, Heng-Cong; Zhang, Xu; Pei, Bin; Jiao, Li-Xin; Shen, Gang; Liu, Ying; Feng, Zhi-Hui; Su, Yu-Ping; Xu, Zhao-Xia; Di, Wen-Ying; Jiang, Yao-Qin; Fu, Hong-Lei; Liu, Xiang-Jun; Liu, Xiang; Zhou, Mei-Zhen; Du, Dan; Liu, Qi; Han, Ying; Zhang, Zhi-Xin; Cai, Jian-Ping

    2015-01-01

    Allogeneic hematopoietic stem cell transplantation is a widely used and effective therapy for hematopoietic malignant diseases and numerous other disorders. High-resolution human leukocyte antigen (HLA) haplotype frequency distributions not only facilitate individual donor searches but also determine the probability with which a particular patient can find HLA-matched donors in a registry. The frequencies of the HLA-A, -B, -C, -DRB1, and -DQB1 alleles and haplotypes were estimated among 169,995 Chinese volunteers using the sequencing-based typing (SBT) method. Totals of 191 HLA-A, 244 HLA-B, 146 HLA-C, 143 HLA-DRB1 and 47 HLA-DQB1 alleles were observed, which accounted for 6.98%, 7.06%, 6.46%, 9.11% and 7.91%, respectively, of the alleles in each locus in the world (IMGT 3.16 Release, Apr. 2014). Among the 100 most common haplotypes from the 169,995 individuals, nine distinct haplotypes displayed significant regionally specific distributions. Among these, three were predominant in the South China region (i.e., the 20th, 31st, and 81sthaplotypes), another three were predominant in the Southwest China region (i.e., the 68th, 79th, and 95th haplotypes), one was predominant in the South and Southwest China regions (the 18th haplotype), one was relatively common in the Northeast and North China regions (the 94th haplotype), and one was common in the Northeast, North and Northwest China (the 40th haplotype). In conclusion, this is the first to analyze high-resolution HLA diversities across the entire country of China, based on a detailed and complete data set that covered 31 provinces, autonomous regions, and municipalities. Specifically, we also evaluated the HLA matching probabilities within and between geographic regions and analyzed the regional differences in the HLA diversities in China. We believe that the data presented in this study might be useful for unrelated HLA-matched donor searches, donor registry planning, population genetic studies, and anthropogenesis

  3. Extensive HLA class I allele promiscuity among viral CTL epitopes

    PubMed Central

    Frahm, Nicole; Yusim, Karina; Suscovich, Todd J.; Adams, Sharon; Sidney, John; Hraber, Peter; Hewitt, Hannah S.; Linde, Caitlyn H.; Kavanagh, Daniel G.; Woodberry, Tonia; Henry, Leah M.; Faircloth, Kellie; Listgarten, Jennifer; Kadie, Carl; Jojic, Nebojsa; Sango, Kaori; Brown, Nancy V.; Pae, Eunice; Zaman, M. Tauheed; Bihl, Florian; Khatri, Ashok; John, Mina; Mallal, Simon; Marincola, Francesco M.; Walker, Bruce D.; Sette, Alessandro; Heckerman, David; Korber, Bette T.; Brander, Christian

    2008-01-01

    Summary Promiscuous binding of T helper epitopes to MHC class II molecules has been well established, but few examples of promiscuous class I restricted epitopes exist. To address the extent of promiscuity of HLA class I peptides, responses to 242 well-defined viral epitopes were tested in 100 subjects regardless of the individuals’ HLA type. Surprisingly, half of all detected responses were seen in the absence of the originally reported restricting HLA class I allele, and only 3% of epitopes were recognized exclusively in the presence of their original allele. Functional assays confirmed the frequent recognition of HLA class I-restricted T cell epitopes on several alternative alleles across HLA class I supertypes and encoded on different class I loci. These data have significant implications for the understanding of MHC class I restricted antigen presentation and vaccine development. PMID:17705138

  4. Interaction between HLA-B60 and HLA-B27 as a Better Predictor of Ankylosing Spondylitis in a Taiwanese Population

    PubMed Central

    Hsu, Yu-Wen; Wen, Ya-Feng; Wang, Wen-Chang; Wong, Ruey-Hong; Lu, Hsing-Fang; van Gaalen, Floris A.; Chang, Wei-Chiao

    2015-01-01

    Objective Ankylosing spondylitis (AS) is a form of chronic inflammatory spondyloarthritis (SpA) that causes pain and stiffness in spines or joints. Human leukocyte antigen B27 (HLA-B27) and B60 (HLA-B60) have been reported as major genetic risk factors of AS. In addition, rs13202464, located on major histocompatibility complex (MHC) region, showed high sensitivity (98.7%) and specificity (98.0%) for HLA-B27. Design The aim of our study is to test whether the interaction between HLA-B60 and HLA-B27 (rs13202464) can serve as a better predictor of AS. We have genotyped HLA-B60 and rs13202464 among 471 patients with AS and 557 healthy subjects. Combined risk factors were investigated to test the biological interaction. Results Our results indicated that the relative risk (RR) for HLA-B27+/HLA-B60− was 152 (95% CI 91 to 255) and it increased to 201 (95% CI 85 to 475) in HLA-B27+/HLA-B60+ patients (with HLA-B27−/HLA-B60− as reference). Combinational analysis of two risk factors (HLA-B27+/HLA-B60+) showed a relative excess risk due to interaction (RERI) of 46.79 (95% CI: -117.58 to 211.16), attributable proportion (AP) of 0.23 (95% CI: -0.41 to 0.88) and a synergy index (S) of 1.31 (95% CI: 0.56 to 3.04). Conclusion In conclusion, genetic interaction analysis revealed that the interaction between HLA-B60 and HLA-B27 is a better marker for the risk of AS susceptibility in a Taiwanese population. PMID:26469786

  5. Detection of 549 new HLA alleles in potential stem cell donors from the United States, Poland and Germany.

    PubMed

    Hernández-Frederick, C J; Cereb, N; Giani, A S; Ruppel, J; Maraszek, A; Pingel, J; Sauter, J; Schmidt, A H; Yang, S Y

    2016-01-01

    We characterized 549 new human leukocyte antigen (HLA) class I and class II alleles found in newly registered stem cell donors as a result of high-throughput HLA typing. New alleles include 101 HLA-A, 132 HLA-B, 105 HLA-C, 2 HLA-DRB1, 89 HLA-DQB1 and 120 HLA-DPB1 alleles. Mainly, new alleles comprised single nucleotide variations when compared with homologous sequences. We identified nonsynonymous nucleotide mutations in 70.7% of all new alleles, synonymous variations in 26.4% and nonsense substitutions in 2.9% (null alleles). Some new alleles (55, 10.0%) were found multiple times, HLA-DPB1 alleles being the most frequent among these. Furthermore, as several new alleles were identified in individuals from ethnic minority groups, the relevance of recruiting donors belonging to such groups and the importance of ethnicity data collection in donor centers and registries is highlighted. PMID:26812061

  6. Complete sequence of HLA-B27 cDNA identified through the characterization of structural markers unique to the HLA-A, -B, and -C allelic series.

    PubMed Central

    Szöts, H; Riethmüller, G; Weiss, E; Meo, T

    1986-01-01

    Antigen HLA-B27 is a high-risk genetic factor with respect to a group of rheumatoid disorders, especially ankylosing spondylitis. A cDNA library was constructed from an autozygous B-cell line expressing HLA-B27, HLA-Cw1, and the previously cloned HLA-A2 antigen. Clones detected with an HLA probe were isolated and sorted into homology groups by differential hybridization and restriction maps. Nucleotide sequencing allowed the unambiguous assignment of cDNAs to HLA-A, -B, and -C loci. The HLA-B27 mRNA has the structural features and the codon variability typical of an HLA class I transcript but it specifies two uncommon amino acid replacements: a cysteine in position 67 and a serine in position 131. The latter substitution may have functional consequences, because it occurs in a conserved region and at a position invariably occupied by a species-specific arginine in humans and lysine in mice. The availability of the complete sequence of HLA-B27 and of the partial sequence of HLA-Cw1 allows the recognition of locus-specific sequence markers, particularly, but not exclusively, in the transmembrane and cytoplasmic domains. Images PMID:3485286

  7. Natural micropolymorphism in human leukocyte antigens provides a basis for genetic control of antigen recognition

    SciTech Connect

    Archbold, Julia K.; Macdonald, Whitney A.; Gras, Stephanie; Ely, Lauren K.; Miles, John J.; Bell, Melissa J.; Brennan, Rebekah M.; Beddoe, Travis; Wilce, Matthew C.J.; Clements, Craig S.; Purcell, Anthony W.; McCluskey, James; Burrows, Scott R.; Rossjohn, Jamie

    2009-07-10

    Human leukocyte antigen (HLA) gene polymorphism plays a critical role in protective immunity, disease susceptibility, autoimmunity, and drug hypersensitivity, yet the basis of how HLA polymorphism influences T cell receptor (TCR) recognition is unclear. We examined how a natural micropolymorphism in HLA-B44, an important and large HLA allelic family, affected antigen recognition. T cell-mediated immunity to an Epstein-Barr virus determinant (EENLLDFVRF) is enhanced when HLA-B*4405 was the presenting allotype compared with HLA-B*4402 or HLA-B*4403, each of which differ by just one amino acid. The micropolymorphism in these HLA-B44 allotypes altered the mode of binding and dynamics of the bound viral epitope. The structure of the TCR-HLA-B*4405EENLLDFVRF complex revealed that peptide flexibility was a critical parameter in enabling preferential engagement with HLA-B*4405 in comparison to HLA-B*4402/03. Accordingly, major histocompatibility complex (MHC) polymorphism can alter the dynamics of the peptide-MHC landscape, resulting in fine-tuning of T cell responses between closely related allotypes.

  8. The distribution of KIR-HLA functional blocks is different from north to south of Italy.

    PubMed

    Fasano, M E; Rendine, S; Pasi, A; Bontadini, A; Cosentini, E; Carcassi, C; Capittini, C; Cornacchini, G; Espadas de Arias, A; Garbarino, L; Carella, G; Mariotti, M L; Mele, L; Miotti, V; Moscetti, A; Nesci, S; Ozzella, G; Piancatelli, D; Porfirio, B; Riva, M R; Romeo, G; Tagliaferri, C; Lombardo, C; Testi, M; Amoroso, A; Martinetti, M

    2014-03-01

    The killer cell immunoglobulin-like receptor (KIR)-human leukocyte antigen (HLA) interaction represents an example of genetic epistasis, where the concomitant presence of specific genes or alleles encoding receptor-ligand units is necessary for the activity of natural killer (NK) cells. Although KIR and HLA genes segregate independently, they co-evolved under environmental pressures to maintain particular KIR-HLA functional blocks for species survival. We investigated, in 270 Italian healthy individuals, the distribution of KIR and HLA polymorphisms in three climatic areas (from cold north to warm south), to verify their possible geographical stratification. We analyzed the presence of 13 KIR genes and genotyped KIR ligands belonging to HLA class I: HLA-C, HLA-B and HLA-A. We did not observe any genetic stratification for KIR genes and HLA-C ligands in Italy. By contrast, in a north-to-south direction, we found a decreasing trend for the HLA-A3 and HLA-A11 ligands (P = 0.012) and an increasing trend for the HLA-B ligands carrying the Bw4 epitope (P = 0.0003) and the Bw4 Ile80 epitope (P = 0.0005). The HLA-A and HLA-B KIR ligands were in negative linkage disequilibrium (correlation coefficient -0.1211), possibly as a consequence of their similar function in inhibiting NK cells. The distribution of the KIR-HLA functional blocks was different along Italy, as we observed a north-to-south ascending trend for KIR3DL1, when coupled with HLA-B Bw4 ligands (P = 0.0067) and with HLA-B Bw4 Ile80 (P = 0.0027), and a descending trend for KIR3DL2 when coupled with HLA-A3 and HLA-A11 ligands (P = 0.0044). Overall, people from South Italy preferentially use the KIR3DL1-HLA-B Bw4 functional unit, while those from the North Italy equally use both the KIR3DL2-HLA-A3/A11 and the KIR3DL1-HLA-B Bw4 functional units to fight infections. Thus, only KIR3DL receptors, which exert the unique role of microbial sensors through the specific D0 domain, and their cognate

  9. Utility of HLA Antibody Testing in Kidney Transplantation

    PubMed Central

    Konvalinka, Ana

    2015-01-01

    HLA antigens are polymorphic proteins expressed on donor kidney allograft endothelium and are critical targets for recipient immune recognition. HLA antibodies are risk factors for acute and chronic rejection and allograft loss. Solid-phase immunoassays for HLA antibody detection represent a major advance in sensitivity and specificity over cell-based methods and are widely used in organ allocation and pretransplant risk assessment. Post-transplant, development of de novo donor–specific HLA antibodies and/or increase in donor-specific antibodies from pretransplant levels are associated with adverse outcomes. Although single antigen bead assays have allowed sensitive detection of recipient HLA antibodies and their specificities, a number of interpretive considerations must be appreciated to understand test results in clinical and research contexts. This review, which is especially relevant for clinicians caring for transplant patients, discusses the technical aspects of single antigen bead assays, emphasizes their quantitative limitations, and explores the utility of HLA antibody testing in identifying and managing important pre- and post-transplant clinical outcomes. PMID:25804279

  10. The Relevance of HLA Sequencing in Population Genetics Studies

    PubMed Central

    Sanchez-Mazas, Alicia

    2014-01-01

    Next generation sequencing (NGS) is currently being adapted by different biotechnological platforms to the standard typing method for HLA polymorphism, the huge diversity of which makes this initiative particularly challenging. Boosting the molecular characterization of the HLA genes through efficient, rapid, and low-cost technologies is expected to amplify the success of tissue transplantation by enabling us to find donor-recipient matching for rare phenotypes. But the application of NGS technologies to the molecular mapping of the MHC region also anticipates essential changes in population genetic studies. Huge amounts of HLA sequence data will be available in the next years for different populations, with the potential to change our understanding of HLA variation in humans. In this review, we first explain how HLA sequencing allows a better assessment of the HLA diversity in human populations, taking also into account the methodological difficulties it introduces at the statistical level; secondly, we show how analyzing HLA sequence variation may improve our comprehension of population genetic relationships by facilitating the identification of demographic events that marked human evolution; finally, we discuss the interest of both HLA and genome-wide sequencing and genotyping in detecting functionally significant SNPs in the MHC region, the latter having also contributed to the makeup of the HLA molecular diversity observed today. PMID:25126587

  11. Identification of a novel HLA-A allele, HLA-A*01:195, in a UAE national.

    PubMed

    Abdrabou, Wael; Witzel, Ini-Isabée; Paduch, Agnieszka; Tay, Guan; Alsafar, Habiba

    2016-07-01

    A novel human leucocyte antigen (HLA)-A allele, HLA-A*01:195, was identified by sequence-based typing (SBT) in a UAE national subject. The novel allele is identical to its closest known allele, HLA-A*01:01:01:01, in exon 2, 3 and 4, except for a single nucleotide mutation of A to G at position 442 in exon 3 (codon 124 in the α2 domain of the α chain of the mature protein). This A to G mutation results in an amino acid change of isoleucine #124 to valine. PMID:27184862

  12. HLA-A Disparities Illustrate Challenges for Ranking the Impact of HLA Mismatches on Bone Marrow Transplant Outcomes in the United States

    PubMed Central

    Baxter-Lowe, Lee Ann; Maiers, Martin; Spellman, Stephen R.; Haagenson, Michael D.; Wang, Tao; Fernandez-Vina, Marcelo; Marsh, Steven G.E.; Horowitz, Mary; Hurley, Carolyn Katovich

    2009-01-01

    HLA disparity between hematopoietic stem cell donors and recipients is one of the most important factors influencing transplant outcomes, but there are no well accepted guidelines to aid in selecting the optimal donor amongst several HLA mismatched donors. In this report, HLA-A is used as a model to illustrate factors that are barriers to delineating the relationship between specific HLA mismatches and transplant outcomes in the United States. Patients in this investigation received transplants for hematological malignancies that were facilitated by the National Marrow Donor Program (NMDP) between 1990 and 2002 (n=4,226). High resolution HLA typing was performed for HLA-A, -B, -C, -DRB1, -DQA1, -DQB1, -DPA1 and -DPB1. HLA-A mismatches were observed in 745 donor-recipient pairs and 62% of these pairs also had disparities at HLA-B, -C and/or -DRB1. The HLA-A mismatches involved 190 different combinations of HLA-A alleles and 51% of these were observed in only one pair. Addition of a single HLA-A disparity when HLA-B, -C, and -DRB1 were matched (n=282) was associated with increased mortality (OR=1.32, CI 1.07-1.63). When HLA-B, -C, and DRB1 were matched, the most frequent HLA-A mismatches were HLAA*0201:0205 (n=28), HLA-A *0301:0302 (n=15), HLA-A *0201:0206 (n=15), HLAA *0201:6801 (n=12), HLA-A*0101:1101 (n=11) and HLA-A*0101:0201 (n=10). There were no statistically significant relationships between any of these disparities and transplant outcomes (engraftment, acute and chronic GVHD, relapse, transplant-related mortality or overall survival) when adjustments for multiple comparisons were considered. Achieving 80% power to detect an effect of any one of these six HLA-A disparities on survival is estimated to require a total transplant population of 11,000 to more than one million U.S. donor-recipient pairs depending upon the HLA disparity. Thus, alternative approaches are required to develop a clinically relevant ranking system for specific HLA disparities in the U

  13. New Developments in HLA-G in Cardiac Transplantation.

    PubMed

    Lazarte, Julieta; Tumiati, Laura C; Rao, Vivek; Delgado, Diego H

    2016-09-01

    Human Leukocyte Antigen-G (HLA-G) is a non-classical class 1b protein, whose gene is located on chromosome 6 (6p21.31). HLA-G inhibits the immune cells' cytotoxic activity by interacting with specific receptors on their membranes. Since it is a naturally occurring immune modulator, HLA-G has been investigated in transplantation. Indeed, a number of investigations reveal that HLA-G expression is influenced by genetic polymorphisms and in turn, those polymorphisms are associated with detrimental or beneficial outcomes in various pathological situations. The present review introduces the HLA-G molecule, the gene and its polymorphisms. It focuses on the expression of HLA-G and the role of polymorphisms primarily in heart transplant outcomes, secondarily in other transplant organs, as well as the role of the allograft and effect of medical therapy. We discuss the limitations in HLA-G transplant investigations and future directions. The immune inhibiting activity of HLA-G has a great deal of potential for its utilization in enhancing diagnostic, preventive and therapeutic strategies against rejection in the setting of transplantation. PMID:26707934

  14. The impact of next-generation sequencing technologies on HLA research

    PubMed Central

    Hosomichi, Kazuyoshi; Shiina, Takashi; Tajima, Atsushi; Inoue, Ituro

    2015-01-01

    In the past decade, the development of next-generation sequencing (NGS) has paved the way for whole-genome analysis in individuals. Research on the human leukocyte antigen (HLA), an extensively studied molecule involved in immunity, has benefitted from NGS technologies. The HLA region, a 3.6-Mb segment of the human genome at 6p21, has been associated with more than 100 different diseases, primarily autoimmune diseases. Recently, the HLA region has received much attention because severe adverse effects of various drugs are associated with particular HLA alleles. Owing to the complex nature of the HLA genes, classical direct sequencing methods cannot comprehensively elucidate the genomic makeup of HLA genes. Thus far, several high-throughput HLA-typing methods using NGS have been developed. In HLA research, NGS facilitates complete HLA sequencing and is expected to improve our understanding of the mechanisms through which HLA genes are modulated, including transcription, regulation of gene expression and epigenetics. Most importantly, NGS may also permit the analysis of HLA-omics. In this review, we summarize the impact of NGS on HLA research, with a focus on the potential for clinical applications. PMID:26311539

  15. The impact of next-generation sequencing technologies on HLA research.

    PubMed

    Hosomichi, Kazuyoshi; Shiina, Takashi; Tajima, Atsushi; Inoue, Ituro

    2015-11-01

    In the past decade, the development of next-generation sequencing (NGS) has paved the way for whole-genome analysis in individuals. Research on the human leukocyte antigen (HLA), an extensively studied molecule involved in immunity, has benefitted from NGS technologies. The HLA region, a 3.6-Mb segment of the human genome at 6p21, has been associated with more than 100 different diseases, primarily autoimmune diseases. Recently, the HLA region has received much attention because severe adverse effects of various drugs are associated with particular HLA alleles. Owing to the complex nature of the HLA genes, classical direct sequencing methods cannot comprehensively elucidate the genomic makeup of HLA genes. Thus far, several high-throughput HLA-typing methods using NGS have been developed. In HLA research, NGS facilitates complete HLA sequencing and is expected to improve our understanding of the mechanisms through which HLA genes are modulated, including transcription, regulation of gene expression and epigenetics. Most importantly, NGS may also permit the analysis of HLA-omics. In this review, we summarize the impact of NGS on HLA research, with a focus on the potential for clinical applications. PMID:26311539

  16. CD4+ T-cell clones recognizing human lymphoma-associated antigens: generation by in vitro stimulation with autologous Epstein-Barr virus-transformed B cells.

    PubMed

    Long, Heather M; Zuo, Jianmin; Leese, Alison M; Gudgeon, Nancy H; Jia, Hui; Taylor, Graham S; Rickinson, Alan B

    2009-07-23

    Epstein-Barr virus (EBV)-specific T-cell preparations, generated by stimulating immune donor lymphocytes with the autologous virus-transformed B-lymphoblastoid cell line (LCL) in vitro, can be used to target EBV-positive malignancies. Although these preparations are enriched for EBV antigen-specific CD8(+) T cells, most also contain a CD4(+) T-cell population whose specificity is unknown. Here, we show that, although CD4(+) T-cell clones derived from such cultures recognize HLA class II-matched LCLs but not mitogen-activated B lymphoblasts, many (1) do not map to any known EBV antigen, (2) can be raised from EBV-naive as well as EBV-immune persons, and (3) can recognize a broad range of human B lymphoma-derived cell lines irrespective of EBV genome status, providing those lines to express the relevant HLA class II-restricting allele. Importantly, such CD4(+) clones not only produce IFNgamma but are also cytotoxic and can control the outgrowth of HLA-matched lymphoma cells in cocultivation assays. We infer that such CD4(+) T cells recognize cellular antigens that are preferentially up-regulated in EBV-transformed but not mitogen-activated B lymphoblasts and that are also expressed in a range of B-cell malignancies. Such antigens are therefore of potential value as targets for CD4(+) T cell-based immunotherapy. PMID:19443664

  17. HLA-G coding region and 3'untranslated region (3'UTR) in two Chinese Han populations.

    PubMed

    Wang, Wen Yi; Tian, Wei; Liu, Xue Xiang; Li, Li Xin

    2016-08-01

    In this study, exons 2-4 and 3'untranslated region (3'UTR) of human leukocyte antigen (HLA)-G gene were investigated for 201 and 104 healthy unrelated Han samples recruited from Hunan Province, southern China and central Inner Mongolia Autonomous Region, northern China, respectively, using sequence-based typing and cloning methods. Totally 12 HLA-G alleles in the coding region, 9 variable sites in 3'UTR, 8 3'UTR haplotypes and 15 HLA-G extended haplotypes (EHs) incorporating the coding region and 3'UTR were observed. Very strong linkage disequilibrium (LD) was observed between HLA-A and HLA-G, and between HLA-G coding region and 3'UTR in each population (all global P=0.0000). Seven HLA-A-G haplotypes showed significant LD in both populations. Three HLA-G alleles in the coding region, 4 polymorphic sites in the 3'UTR, 3 3'UTR haplotypes and 4 HLA-G EHs differed significantly in their distributions between the 2 Chinese Han populations (all P≤0.0001). There was evidence for balancing selection acting on HLA-G 3'UTR positions +3010, +3142 and +3187 in the two populations. The NJ dendrograms demonstrated the existence of two basic HLA-G lineages and indicated that, HLA-G*01:01:01, the most common HLA-G allele, formed a separate lineage from other alleles. Our results shed new lights into HLA-G genetics among Chinese Han populations. The findings reported here are of importance for future studies related to post-transcriptional regulation of HLA-G allelic expression and the potential role of HLA-G in disease association in populations of Chinese ancestry. PMID:27262928

  18. CD3+/CD19+-depleted grafts in HLA-matched allogeneic peripheral blood stem cell transplantation lead to early NK cell cytolytic responses and reduced inhibitory activity of NKG2A.

    PubMed

    Eissens, D N; Schaap, N P M; Preijers, F W M B; Dolstra, H; van Cranenbroek, B; Schattenberg, A V M; Joosten, I; van der Meer, A

    2010-03-01

    Natural killer (NK) cells have an important function in the anti-tumor response early after stem cell transplantation (SCT). As part of a prospective randomized phase III study, directly comparing the use of CD3(+)/CD19(+)-depleted peripheral blood stem cell (PBSC) harvests with CD34(+)-selected PBSC harvests in allogeneic human leukocyte antigen-matched SCT, we here show that the use of CD3(+)/CD19(+)-depleted PBSC grafts leads to early NK cell repopulation and reconstitution of the CD56(dim) and CD56(bright) NK cell subsets, with concomitant high cytolytic capacity. In the CD34 group, this process took significantly longer. Moreover, in the CD3/19 group after reconstitution, a higher percentage of killer immunoglobulin-like receptor-positive NK cells was found. Although similar percentages of CD94-positive NK cells were found in both groups, in the CD34 group, almost all expressed the inhibitory CD94:NKG2A complex, whereas in the CD3/19 group, the inhibitory CD94:NKG2A and the activating CD94:NKG2C complex were equally distributed. This preferential development of NKG2C-expressing NK cells in the CD3/19 group was paralleled by a loss of NKG2A-mediated inhibition of NK cell degranulation. These results show that the use of CD3(+)/CD19(+)-depleted grafts facilitates strong NK cell cytolytic responses directly after SCT, and the rapid emergence of an NK cell receptor phenotype that is more prone to activation. PMID:20033055

  19. A rapid and efficient strategy to generate allele-specific anti-HLA monoclonal antibodies.

    PubMed

    Yamazaki, Satoshi; Suzuki, Nao; Saito, Tsuneyoshi; Ishii, Yumiko; Takiguchi, Masafumi; Nakauchi, Hiromitsu; Watanabe, Nobukazu

    2009-03-31

    That generation of allele-specific anti-human leukocyte antigen (HLA) monoclonal antibodies (ASHmAb) is very difficult is well known. This is thought to be due to the unique epitope structure, an assemblage of amino acid residues that lie separately in the amino acid sequence of human HLA, and to its low antigenicity compared with that of common epitopes recognized as xenogeneic determinants by mice. Here we report a rapid and efficient strategy to generate ASHmAb. Different from usual immunization methods is that we suppressed the production of non-allele-specific anti-HLA antibodies against xenogeneic determinants of HLA molecules by immunizing human HLA-B51 transgenic mice against non-HLA-B51 HLA tetramers. In addition, HLA-coated beads enabled rapid and efficient screening for ASHmAb. ASHmAb generated by this strategy will be useful for HLA typing and for clinical diagnosis, such as flow cytometry-based chimerism analysis for early detection of graft failure and relapse of leukemia after HLA-mismatched hematopoietic stem cell transplantation. PMID:19187783

  20. MHC microsatellite diversity and linkage disequilibrium among common HLA-A, HLA-B, DRB1 haplotypes: implications for unrelated donor hematopoietic transplantation and disease association studies.

    PubMed

    Malkki, M; Single, R; Carrington, M; Thomson, G; Petersdorf, E

    2005-08-01

    Twenty-two human major histocompatibility complex (MHC) region microsatellite (Msat) markers were studied for diversity and linkage disequilibrium (LD) with HLA loci in hematopoietic cell transplant recipients and their HLA-A, HLA-B, HLA-C, HLA-DRB1, and HLA-DQB1 allele-matched unrelated donors. These Msats showed highly significant LD over much of the MHC region. The Msat diversity of five common Caucasian haplotypes (HLA-A1-B8-DR3, A3-B7-DR15, A2-B44-DR4, A29-B44-DR7, and A2-B7-DR15) was examined using a new measure called 'haplotype specific heterozygosity' (HSH). Each of the five haplotypes had at least one Msat marker with an HSH value of zero indicating that only one Msat allele was observed for the particular HLA haplotype. In addition, the ability of Msats to predict HLA-A-B-DRB1 haplotypes was studied. Over 90% prediction probability of two common haplotypes (HLA-A1-B8-DR3 and HLA-A3-B7-DR15) was achieved with information from three Msats (D6S265/D6S2787/D6S2894 and D6S510/D6S2810/D6S2876, respectively). We demonstrate how the HSH index can be used in the selection of informative Msats for transplantation and disease association studies. Markers with low HSH values can be used to predict specific HLA haplotypes or multilocus genotypes to supplement the screening of HLA-matched donors for transplantation. Markers with high HSH values will be most informative in studies investigating MHC region disease-susceptibility genes where HLA haplotypic effects are known to exist. PMID:16029431

  1. Live attenuated influenza vaccine strains elicit a greater innate immune response than antigenically-matched seasonal influenza viruses during infection of human nasal epithelial cell cultures.

    PubMed

    Fischer, William A; Chason, Kelly D; Brighton, Missy; Jaspers, Ilona

    2014-03-26

    Influenza viruses are global pathogens that infect approximately 10-20% of the world's population each year. Vaccines, including the live attenuated influenza vaccine (LAIV), are the best defense against influenza infections. The LAIV is a novel vaccine that actively replicates in the human nasal epithelium and elicits both mucosal and systemic protective immune responses. The differences in replication and innate immune responses following infection of human nasal epithelium with influenza seasonal wild type (WT) and LAIV viruses remain unknown. Using a model of primary differentiated human nasal epithelial cell (hNECs) cultures, we compared influenza WT and antigenically-matched cold adapted (CA) LAIV virus replication and the subsequent innate immune response including host cellular pattern recognition protein expression, host innate immune gene expression, secreted pro-inflammatory cytokine production, and intracellular viral RNA levels. Growth curves comparing virus replication between WT and LAIV strains revealed significantly less infectious virus production during LAIV compared with WT infection. Despite this disparity in infectious virus production the LAIV strains elicited a more robust innate immune response with increased expression of RIG-I, TLR-3, IFNβ, STAT-1, IRF-7, MxA, and IP-10. There were no differences in cytotoxicity between hNEC cultures infected with WT and LAIV strains as measured by basolateral levels of LDH. Elevated levels of intracellular viral RNA during LAIV as compared with WT virus infection of hNEC cultures at 33°C may explain the augmented innate immune response via the up-regulation of pattern recognition receptors and down-stream type I IFN expression. Taken together our results suggest that the decreased replication of LAIV strains in human nasal epithelial cells is associated with a robust innate immune response that differs from infection with seasonal influenza viruses, limits LAIV shedding and plays a role in the silent

  2. Single antigen flow beads for identification of human leukocyte antigen antibody specificities in hypersensitized patients with chronic renal failure

    PubMed Central

    Kılıçaslan-Ayna, Tülay; Özkızılcık-Koçyiğit, Aslı; Güleç, Derya; Pirim, İbrahim

    2016-01-01

    Aims of this study Aims of this study were to identify class I and class II antibodies in highly sensitized patients by flow cytometry single antigen bead (FC-SAB) assay and to evaluate according to donor HLA type in order to increase their kidney transplantation chance. Material and methods We analyzed 60 hypersensitive patients of 351 individuals, who applied to our laboratory for PRA test in November 2013-December 2014. Flow cytometric PRA screening and single antigen bead commercial kits were used for these analyses. Results In our study group, 19 (31.7%) of these patients were male while 41 (68.3%) patients were female. The most common acceptable antigens were A*02 (10.11%), HLA-A*23 (10.11%), HLA-B*38 (8.79%) and HLA-DRB1*03 (7.83%) in hypersensitive patients. The highest antibody reactivity on SAB was observed against HLA-A*25, HLA-B*45, HLA-DRB1*04 and HLA-DRB1*08 antigens. Conclusions The determination of these acceptable and unacceptable antigens may increase their transplantation chance. Pre-transplant HLA antibody identifications provide prognostic information with respect to the determination of patients who are at increased risk of graft loss. PMID:27095928

  3. Analysis of HLA-B15 and HLA-B27 in spondyloarthritis with peripheral and axial clinical patterns

    PubMed Central

    Londono, John; Santos, Ana Maria; Peña, Paola; Calvo, Enrique; Espinosa, Luis R; Reveille, John D; Vargas-Alarcon, Gilberto; Jaramillo, Carlos A; Valle-Oñate, Rafael; Avila, Mabel; Romero, Consuelo; Medina, Juan F

    2015-01-01

    Objective Human leucocyte antigen (HLA) B27 and HLA-B15 are associated with spondyloarthritis (SpA). Recent Assessment of SpondyloArthritis international Society (ASAS) criteria emphasise a distinction between SpA with axial and peripheral patterns. We analysed whether HLA-A, HLA-B and HLA-DRB1 alleles could associate with these patterns. Methods We studied 100 healthy individuals and 178 patients with SpA according to European Spondyloarthropathy Study Group (ESSG) criteria. Patients were then classified according to ASAS criteria, the axial spondyloarthritis pattern (axSpA) being defined by ascertained sacroiliitis and the peripheral pattern (pSpA) by enthesitis and/or arthritis in extremities. A combined ax/p pattern was also considered. Results Only HLA-B27 and HLA-B15 alleles were associated with SpA. ASAS criteria for axSpA were met in 152 patients (12 with isolated axSpA and 140 with a combined ax/p patterns). When the ASAS peripheral criteria were applied, 161 patients met these criteria (13 with isolated pSpA and 148 with a combined ax/p pattern). HLA-B27 was found in 83% of patients with axSpA and 43% of ax/pSpA patients according to axASAS. HLA-B27 occurred in 7% controls but not in any patient with isolated pSpA. HLA-B15 was encountered in 31% of patients with isolated pSpA and 20% of ax/pSpA patients according to pASAS criteria. Moreover, 2 healthy controls, but none of our patients with isolated axSpA were positive for HLA-B15. Conclusions Our data suggest that the presence of HLA-B15 favours the development of isolated/combined peripheral rather than isolated axSpA, while HLA-B27 promotes an isolated/combined axial disease and excludes a peripheral pattern. HLA-B15 should be considered in addition to HLA-B27 when diagnosing patients with SpA according to ASAS criteria. PMID:26560062

  4. Neutrophil elastase enhances antigen presentation by upregulating human leukocyte antigen class I expression on tumor cells.

    PubMed

    Chawla, Akhil; Alatrash, Gheath; Philips, Anne V; Qiao, Na; Sukhumalchandra, Pariya; Kerros, Celine; Diaconu, Iulia; Gall, Victor; Neal, Samantha; Peters, Haley L; Clise-Dwyer, Karen; Molldrem, Jeffrey J; Mittendorf, Elizabeth A

    2016-06-01

    Neutrophil elastase (NE) is an innate immune cell-derived inflammatory mediator that we have shown increases the presentation of tumor-associated peptide antigens in breast cancer. In this study, we extend these observations to show that NE uptake has a broad effect on enhancing antigen presentation by breast cancer cells. We show that NE increases human leukocyte antigen (HLA) class I expression on the surface of breast cancer cells in a concentration and time-dependent manner. HLA class I upregulation requires internalization of enzymatically active NE. Western blots of NE-treated breast cancer cells confirm that the expression of total HLA class I as well as the antigen-processing machinery proteins TAP1, LMP2, and calnexin does not change following NE treatment. This suggests that NE does not increase the efficiency of antigen processing; rather, it mediates the upregulation of HLA class I by stabilizing and reducing membrane recycling of HLA class I molecules. Furthermore, the effects of NE extend beyond breast cancer since the uptake of NE by EBV-LCL increases the presentation of HLA class I-restricted viral peptides, as shown by their increased sensitivity to lysis by EBV-specific CD8+ T cells. Together, our results show that NE uptake increases the responsiveness of breast cancer cells to adaptive immunity by broad upregulation of membrane HLA class I and support the conclusion that the innate inflammatory mediator NE enhances tumor cell recognition and increases tumor sensitivity to the host adaptive immune response. PMID:27129972

  5. Charting improvements in US registry HLA typing ambiguity using a typing resolution score.

    PubMed

    Paunić, Vanja; Gragert, Loren; Schneider, Joel; Müller, Carlheinz; Maiers, Martin

    2016-07-01

    Unrelated stem cell registries have been collecting HLA typing of volunteer bone marrow donors for over 25years. Donor selection for hematopoietic stem cell transplantation is based primarily on matching the alleles of donors and patients at five polymorphic HLA loci. As HLA typing technologies have continually advanced since the beginnings of stem cell transplantation, registries have accrued typings of varied HLA typing ambiguity. We present a new typing resolution score (TRS), based on the likelihood of self-match, that allows the systematic comparison of HLA typings across different methods, data sets and populations. We apply the TRS to chart improvement in HLA typing within the Be The Match Registry of the United States from the initiation of DNA-based HLA typing to the current state of high-resolution typing using next-generation sequencing technologies. In addition, we present a publicly available online tool for evaluation of any given HLA typing. This TRS objectively evaluates HLA typing methods and can help define standards for acceptable recruitment HLA typing. PMID:27163154

  6. Pathogen selection drives nonoverlapping associations between HLA loci

    PubMed Central

    Penman, Bridget S.; Ashby, Ben; Buckee, Caroline O.; Gupta, Sunetra

    2013-01-01

    Pathogen-mediated selection is commonly invoked as an explanation for the exceptional polymorphism of the HLA gene cluster, but its role in generating and maintaining linkage disequilibrium between HLA loci is unclear. Here we show that pathogen-mediated selection can promote nonrandom associations between HLA loci. These associations may be distinguished from linkage disequilibrium generated by other population genetic processes by virtue of being nonoverlapping as well as nonrandom. Within our framework, immune selection forces the pathogen population to exist as a set of antigenically discrete strains; this then drives nonoverlapping associations between the HLA loci through which recognition of these antigens is mediated. We demonstrate that this signature of pathogen-driven selection can be observed in existing data, and propose that analyses of HLA population structure can be combined with laboratory studies to help us uncover the functional relationships between HLA alleles. In a wider coevolutionary context, our framework also shows that the inclusion of memory immunity can lead to robust cyclical dynamics across a range of host–pathogen systems. PMID:24225852

  7. Methylome-wide Analysis of Chronic HIV Infection Reveals Five-Year Increase in Biological Age and Epigenetic Targeting of HLA.

    PubMed

    Gross, Andrew M; Jaeger, Philipp A; Kreisberg, Jason F; Licon, Katherine; Jepsen, Kristen L; Khosroheidari, Mahdieh; Morsey, Brenda M; Swindells, Susan; Shen, Hui; Ng, Cherie T; Flagg, Ken; Chen, Daniel; Zhang, Kang; Fox, Howard S; Ideker, Trey

    2016-04-21

    HIV-infected individuals are living longer on antiretroviral therapy, but many patients display signs that in some ways resemble premature aging. To investigate and quantify the impact of chronic HIV infection on aging, we report a global analysis of the whole-blood DNA methylomes of 137 HIV+ individuals under sustained therapy along with 44 matched HIV- individuals. First, we develop and validate epigenetic models of aging that are independent of blood cell composition. Using these models, we find that both chronic and recent HIV infection lead to an average aging advancement of 4.9 years, increasing expected mortality risk by 19%. In addition, sustained infection results in global deregulation of the methylome across >80,000 CpGs and specific hypomethylation of the region encoding the human leukocyte antigen locus (HLA). We find that decreased HLA methylation is predictive of lower CD4 / CD8 T cell ratio, linking molecular aging, epigenetic regulation, and disease progression. PMID:27105112

  8. HLA supertype variation across populations: new insights into the role of natural selection in the evolution of HLA-A and HLA-B polymorphisms.

    PubMed

    Dos Santos Francisco, Rodrigo; Buhler, Stéphane; Nunes, José Manuel; Bitarello, Bárbara Domingues; França, Gustavo Starvaggi; Meyer, Diogo; Sanchez-Mazas, Alicia

    2015-11-01

    Supertypes are groups of human leukocyte antigen (HLA) alleles which bind overlapping sets of peptides due to sharing specific residues at the anchor positions-the B and F pockets-of the peptide-binding region (PBR). HLA alleles within the same supertype are expected to be functionally similar, while those from different supertypes are expected to be functionally distinct, presenting different sets of peptides. In this study, we applied the supertype classification to the HLA-A and HLA-B data of 55 worldwide populations in order to investigate the effect of natural selection on supertype rather than allelic variation at these loci. We compared the nucleotide diversity of the B and F pockets with that of the other PBR regions through a resampling procedure and compared the patterns of within-population heterozygosity (He) and between-population differentiation (G ST) observed when using the supertype definition to those estimated when using randomized groups of alleles. At HLA-A, low levels of variation are observed at B and F pockets and randomized He and G ST do not differ from the observed data. By contrast, HLA-B concentrates most of the differences between supertypes, the B pocket showing a particularly high level of variation. Moreover, at HLA-B, the reassignment of alleles into random groups does not reproduce the patterns of population differentiation observed with supertypes. We thus conclude that differently from HLA-A, for which supertype and allelic variation show similar patterns of nucleotide diversity within and between populations, HLA-B has likely evolved through specific adaptations of its B pocket to local pathogens. PMID:26459025

  9. HLA non-class II genes may confer type I diabetes susceptibility in a Mapuche (Amerindian) affected family.

    PubMed

    Pérez-Bravo, Francisco; Martinez-Laso, Jorge; Martin-Villa, Jose M; Moscoso, Juan; Moreno, Almudena; Serrano-Vela, Juan I; Zamora, Jorge; Asenjo, Silvia; Gleisner, Andrea; Arnaiz-Villena, Antonio

    2006-01-01

    A rare case of type I diabetes is studied in an Amerindian (Mapuche) family from Chile, analyzing glutamic acid decarboxylase, islet-cell autoantibodies and human leukocyte antigen (HLA) genes. The affected sib is the only one that has one specific HLA haplotype combination that differs from the other sibs only in the HLA class I genes. It is concluded that HLA diabetes susceptibility factors may be placed outside the class II region or even that susceptibility factors do not exist in the HLA region in this Amerindian family. PMID:16473308

  10. Nonmyeloablative HLA-Haploidentical BMT with High-Dose Posttransplantation Cyclophosphamide: Effect of HLA Disparity on Outcome

    PubMed Central

    Kasamon, Yvette L.; Luznik, Leo; Leffell, Mary S.; Kowalski, Jeanne; Tsai, Hua-Ling; Bolanos-Meade, Javier; Morris, Lawrence E.; Crilley, Pamela A.; O’Donnell, Paul V.; Rossiter, Nancy; Huff, Carol Ann; Brodsky, Robert A.; Matsui, William H.; Swinnen, Lode J.; Borrello, Ivan; Powell, Jonathan D.; Ambinder, Richard F.; Jones, Richard J.; Fuchs, Ephraim J.

    2010-01-01

    Although some reports have found increasing HLA disparity between donor and recipient to be associated with fewer relapses after allogeneic blood or marrow transplantation (BMT), this potential benefit has been offset by more graft-versus-host disease (GVHD) and nonrelapse mortality. However, the type of GVHD prophylaxis could influence the balance between GVHD toxicity and relapse. We analyzed the impact of greater HLA disparity on outcomes of a specific platform for nonmyeloablative, HLA-haploidentical transplantation. A retrospective analysis was performed on 185 patients with hematologic malignancies enrolled on three similar trials of nonmyeloablative, related donor, haploidentical BMT incorporating high-dose posttransplantation cyclophosphamide for GVHD prophylaxis. No significant association was found between the number of HLA mismatches (HLA-A, -B, -Cw, and -DRB1 combined) and risk of acute grade II–IV GVHD (hazard ratio .89, P = .68 for 3–4 versus fewer antigen mismatches). More mismatching also had no detrimental effect on event-free survival (on multivariate analysis, hazard ratio .60, P = .03 for 3–4 versus fewer antigen mismatches; hazard ratio .55, P = .03 for 3–4 versus fewer allele mismatches). Thus, greater HLA disparity does not appear to worsen overall outcomes after nonmyeloablative haploidentical BMT with high-dose posttransplantation cyclophosphamide. PMID:19925877

  11. The heterogeneous HLA genetic composition of the Brazilian population and its relevance to the optimization of hematopoietic stem cell donor recruitment.

    PubMed

    Fabreti-Oliveira, R A; Nascimento, E; Fonseca, C G; Santos, M A

    2014-08-01

    The aim of this study was to investigate the human leukocyte antigen (HLA) molecular variation across the Brazilian population in order to determine possible regional differences, which would be highly relevant to optimizing donor recruitment strategies in hematopoietic stem cell transplantation (HSCT) and understanding the population genetic background of this heterogeneous country. HLA data of 551 HSCT donors from five Brazilian regions were characterized by high-resolution DNA alleles at the HLA-A, -B, -C, -DRB1 and -DQB1 loci and compared with other populations in Brazil and worldwide populations. Allele and haplotype frequencies were estimated. The analysis was performed to assess Hardy-Weinberg equilibrium (HWE) and linkage disequilibrium (LD) among different loci in each recruitment center. Genetic variation was explored through genetic distance analyzed by using a new algorithm based on linear algebra, taking into account geographic regions of Brazil. The results indicated a heterogeneous genetic composition of the Brazilian population, such that HLA allele and haplotype frequencies exhibit different distributions among Brazilian regions, which has important implications for donor matching. In addition, a pronounced differentiation was observed by the absence of clustering of the regional populations in the reduced-dimension space. These data may be useful for increasing donor recruitment with more genetic representativeness in the Brazilian Volunteer Bone Marrow Donors Registry (REDOME). PMID:24724906

  12. Gene Map of the HLA Region, Graves' Disease and Hashimoto Thyroiditis, and Hematopoietic Stem Cell Transplantation.

    PubMed

    Sasazuki, Takehiko; Inoko, Hidetoshi; Morishima, Satoko; Morishima, Yasuo

    2016-01-01

    The human leukocyte antigen (HLA) genomic region spanning about 4 Mb is the most gene dense and the polymorphic stretches in the human genome. A total of the 269 loci were identified, including 145 protein coding genes mostly important for immunity and 50 noncoding RNAs (ncRNAs). Biological function of these ncRNAs remains unknown, becoming hot spot in the studies of HLA-associated diseases. The genomic diversity analysis in the HLA region facilitated by next-generation sequencing will pave the way to molecular understanding of linkage disequilibrium structure, population diversity, histocompatibility in transplantation, and associations with autoimmune diseases. The 4-digit DNA genotyping of HLA for six HLA loci, HLA-A through DP, in the patients with Graves' disease (GD) and Hashimoto thyroiditis (HT) identified six susceptible and three resistant HLA alleles. Their epistatic interactions in controlling the development of these diseases are shown. Four susceptible and one resistant HLA alleles are shared by GD and HT. Two HLA alleles associated with GD or HT control the titers of autoantibodies to thyroid antigens. All these observations led us to propose a new model for the development of GD and HT. Hematopoietic stem cell transplantation from unrelated donor (UR-HSCT) provides a natural experiment to elucidate the role of allogenic HLA molecules in immune response. Large cohort studies using HLA allele and clinical outcome data have elucidated that (1) HLA locus, allele, and haplotype mismatches between donor and patient, (2) specific amino acid substitution at specific positions of HLA molecules, and (3) ethnic background are all responsible for the immunological events related to UR-HSCT including acute graft-versus-host disease (GVHD), chronic GVHD, graft-versus-leukemia (GvL) effect, and graft failure. PMID:26791860

  13. HLA-C and HIV-1: friends or foes?

    PubMed Central

    2012-01-01

    The major histocompatibility complex class I protein HLA-C plays a crucial role as a molecule capable of sending inhibitory signals to both natural killer (NK) cells and cytotoxic T lymphocytes (CTL) via binding to killer cell Ig-like receptors (KIR). Recently HLA-C has been recognized as a key molecule in the immune control of HIV-1. Expression of HLA-C is modulated by a microRNA binding site. HLA-C alleles that bear substitutions in the microRNA binding site are more expressed at the cell surface and associated with the control of HIV-1 viral load, suggesting a role of HLA-C in the presentation of antigenic peptides to CTLs. This review highlights the role of HLA-C in association with HIV-1 viral load, but also addresses the contradiction of the association between high cell surface expression of an inhibitory molecule and strong cell-mediated immunity. To explore additional mechanisms of control of HIV-1 replication by HLA-C, we address specific features of the molecule, like its tendency to be expressed as open conformer upon cell activation, which endows it with a unique capacity to associate with other cell surface molecules as well as with HIV-1 proteins. PMID:22571741

  14. Does Rh Immune Globulin Suppress HLA Sensitization in Pregnancy?

    PubMed Central

    Kaufman, Richard M.; Schlumpf, Karen S.; Wright, David J.; Triulzi, Darrell J.

    2012-01-01

    BACKGROUND How Rh immune globulin (RhIG) prevents sensitization to D antigen is unclear. If RhIG Fc delivers a nonspecific immunosuppressive signal, then RhIG may inhibit sensitization to antigens other than D. HLA antibody prevalence was compared in previously pregnant RhD negative versus RhD positive women to investigate whether RhIG suppresses HLA sensitization. STUDY DESIGN AND METHODS In the Leukocyte Antibody Prevalence Study (LAPS)1, 7,920 volunteer blood donors were screened for anti-HLA antibodies and surveyed about prior pregnancies and transfusions. A secondary analysis of the LAPS database was performed. RESULTS RhD negative women ≤40 years old (presumed to have received antenatal ± postpartum RhIG in all pregnancies) had a significantly lower HLA sensitization rate than RhD positive women (RR 0.58, 95% CI 0.40–0.83). When stratified by deliveries (1, 2, 3, or ≥4), RhD negative women ≤40 were HLA sensitized less often than RhD positive women in every case. In contrast, a clear relationship between RhD type and HLA sensitization was not seen in older previously pregnant women whose childbearing years are presumed to have preceded the use of routine RhIG prophylaxis. In a multivariable logistic regression model, RhD negative women ≤40 years old remained significantly less likely to be HLA sensitized compared with RhD positive women after adjusting for parity, time from last pregnancy, lost pregnancies, and transfusions (OR 0.55, 95% CI 0.34–0.88). CONCLUSION Consistent with a nonspecific immunosuppressive effect of RhIG, younger previously pregnant RhD negative women were less likely than previously pregnant RhD positive women to be HLA sensitized. PMID:23252646

  15. Carfilzomib alters the HLA-presented peptidome of myeloma cells and impairs presentation of peptides with aromatic C-termini

    PubMed Central

    Kowalewski, D J; Walz, S; Backert, L; Schuster, H; Kohlbacher, O; Weisel, K; Rittig, S M; Kanz, L; Salih, H R; Rammensee, H-G; Stevanović, S; Stickel, J S

    2016-01-01

    Recent studies suggest that multiple myeloma is an immunogenic disease, which might be effectively targeted by antigen-specific T-cell immunotherapy. As standard of care in myeloma includes proteasome inhibitor therapy, it is of great importance to characterize the effects of this treatment on HLA-restricted antigen presentation and implement only robustly presented targets for immunotherapeutic intervention. Here, we present a study that longitudinally and semi-quantitatively maps the effects of the proteasome inhibitor carfilzomib on HLA-restricted antigen presentation. The relative presentation levels of 4780 different HLA ligands were quantified in an in vitro model employing carfilzomib treatment of MM.1S and U266 myeloma cells, which revealed significant modulation of a substantial fraction of the HLA-presented peptidome. Strikingly, we detected selective down-modulation of HLA ligands with aromatic C-terminal anchor amino acids. This particularly manifested as a marked reduction in the presentation of HLA ligands through the HLA allotypes A*23:01 and A*24:02 on MM.1S cells. These findings implicate that carfilzomib mediates a direct, peptide motif-specific inhibitory effect on HLA ligand processing and presentation. As a substantial proportion of HLA allotypes present peptides with aromatic C-termini, our results may have broad implications for the implementation of antigen-specific treatment approaches in patients undergoing carfilzomib treatment. PMID:27058226

  16. Race, Ethnicity and Ancestry in Unrelated Transplant Matching for the National Marrow Donor Program: A Comparison of Multiple Forms of Self-Identification with Genetics

    PubMed Central

    Hollenbach, Jill A.; Saperstein, Aliya; Albrecht, Mark; Vierra-Green, Cynthia; Parham, Peter; Norman, Paul J.; Maiers, Martin

    2015-01-01

    We conducted a nationwide study comparing self-identification to genetic ancestry classifications in a large cohort (n = 1752) from the National Marrow Donor Program. We sought to determine how various measures of self-identification intersect with genetic ancestry, with the aim of improving matching algorithms for unrelated bone marrow transplant. Multiple dimensions of self-identification, including race/ethnicity and geographic ancestry were compared to classifications based on ancestry informative markers (AIMs), and the human leukocyte antigen (HLA) genes, which are required for transplant matching. Nearly 20% of responses were inconsistent between reporting race/ethnicity versus geographic ancestry. Despite strong concordance between AIMs and HLA, no measure of self-identification shows complete correspondence with genetic ancestry. In certain cases geographic ancestry reporting matches genetic ancestry not reflected in race/ethnicity identification, but in other cases geographic ancestries show little correspondence to genetic measures, with important differences by gender. However, when respondents assign ancestry to grandparents, we observe sub-groups of individuals with well- defined genetic ancestries, including important differences in HLA frequencies, with implications for transplant matching. While we advocate for tailored questioning to improve accuracy of ancestry ascertainment, collection of donor grandparents’ information will improve the chances of finding matches for many patients, particularly for mixed-ancestry individuals. PMID:26287376

  17. Killer Cell Immunoglobulin-Like Receptor-Ligand Matching and Outcomes after Unrelated Cord Blood Transplantation in Acute Myeloid Leukemia.

    PubMed

    Rocha, Vanderson; Ruggeri, Annalisa; Spellman, Stephen; Wang, Tao; Sobecks, Ronald; Locatelli, Franco; Askar, Medhat; Michel, Gerard; Arcese, William; Iori, Anna Paola; Purtill, Duncan; Danby, Robert; Sanz, Guillermo F; Gluckman, Eliane; Eapen, Mary

    2016-07-01

    The effect of killer cell immunoglobulin-like receptor (KIR)-ligand matching on outcomes after unrelated cord blood (CB) transplantation was studied in 461 patients with acute myeloid leukemia, categorizing KIR ligand for HLA-C groups C1 and C2 and Bw4. Donor-recipient HLA matching considered allele-level matching at HLA-A, -B, -C, and -DRB1. Separate analyses were conducted for 6-7/8 HLA-matched and 3-5/8 HLA-matched transplants because HLA matching confounded KIR-ligand matching (ie, KIR-ligand mismatching was less likely with better HLA matching). All patients received single CB unit and myeloablative conditioning. There were no significant differences in nonrelapse mortality (NRM), relapse, and overall mortality by KIR-ligand match status. However, among recipients of 3-5/8 HLA-matched transplants, NRM (HR, 2.26; P = .008) and overall mortality (HR, 1.78; P = .008) but not relapse were higher with KIR-ligand mismatched (host-versus-graft direction) compared with KIR-ligand matched transplants. These data do not support selecting CB units based on KIR-ligand match status for transplants mismatched at 1 or 2 HLA loci. Although transplants mismatched at 3 or more HLA loci are not recommended, avoiding KIR-ligand mismatching in this setting lowers mortality risks. PMID:27090957

  18. Recent developments in HLA-haploidentical transplantations

    PubMed Central

    Showel, Margaret; Fuchs, Ephraim J.

    2016-01-01

    While allogeneic hematopoietic stem cell transplantations have a curative potential, several patients with hematologic malignancies cannot avail themselves of this therapeutic option due to lack of matched donor availability. Although HLA-haploidentical transplantations were previously associated with poor outcomes, recent evidence with use of post transplantation cyclophosphamide indicate improved safety and efficacy. The following paper discusses the most recent developments in this area. PMID:26590771

  19. Association between HLA-A1 and -A2 types and Epstein-Barr virus status of post-transplant lymphoproliferative disorder.

    PubMed

    Kinch, Amelie; Sundström, Christer; Tufveson, Gunnar; Glimelius, Ingrid

    2016-10-01

    The susceptibility to Epstein-Barr virus (EBV)-related post-transplant lymphoproliferative disorder (PTLD) may be affected by the human leukocyte antigen (HLA) type. We investigated HLA-A and HLA-B allele frequencies, focusing on HLA-A1 and -A2, in a population-based case series of EBV + (n = 60) and EBV- (n = 44) PTLD after solid organ transplantation. The proportion of EBV + PTLD was highest in HLA-A1 homozygotes (100%), lower in carriers of HLA-A1/AX (79%), HLA-A1/A2 (55%), HLA-A2/AX (54%), and lowest in HLA-A2 homozygotes (37%). HLA-A1 type was overrepresented (22% versus 7%, p = 0.05) and HLA-A2 type underrepresented (57% versus 80%, p = 0.01) in patients with EBV + compared with EBV - PTLD. EBV + PTLD in HLA-A1 carriers developed almost exclusively in already EBV-seropositive individuals. EBV status of PTLD was not related to any other HLA-A or HLA-B type. Our findings suggest that HLA-A1 carriers may have an increased risk of EBV + PTLD due to a decreased ability to control the latent EBV infection. PMID:27104753

  20. Increased epithelial expression of HLA-DQ and HLA-DP molecules in salivary glands from patients with Sjögren's syndrome compared with obstructive sialadenitis.

    PubMed Central

    Thrane, P S; Halstensen, T S; Haanaes, H R; Brandtzaeg, P

    1993-01-01

    Salivary gland specimens from 10 patients with primary Sjögren's syndrome (pSS) were examined by two-colour immunofluorescence with various combinations of monoclonal and polyclonal antibody reagents of the following specificities: human leucocyte antigen (HLA) class I and II (DR, DP and DQ), CD3, CD45 (leucocyte common antigen), various cytokeratins, and factor VIII-related antigen. Tissue specimens from 10 normal glands and 10 glands with obstructive sialadenitis (no known autoimmunity) served as controls. Only some intercalated ducts and scattered acini of the normal major glands expressed HLA class II determinants (< 5% of total epithelial area); the relative proportion of positive elements indicated differential expression (DR > DP > DQ). SS glands contained substantial T cell infiltrates and increased numbers of activated (DR+) T cells; adjacent epithelium showed extensive differential expression of HLA class II determinants (DR > DP > DQ). Glands with obstructive sialadenitis showed similarly increased epithelial expression of HLA-DR but with surprisingly small amounts of concomitant HLA-DP and -DQ expression. Epithelial HLA class II expression probably depends on cytokines as an inductive event, which is not unique for SS but particularly prominent in this disorder. Our results suggest that epithelial expression of HLA-DP or -DQ, rather than -DR, might be a prerequisite for the autoimmune process of SS to develop in genetically susceptible individuals. Images Fig. 2 PMID:8485911

  1. Identification of the HLA-DM/HLA-DR interface.

    PubMed

    Davies, Matthew N; Lamikanra, Abigail; Sansom, Clare E; Flower, Darren R; Moss, David S; Travers, Paul J

    2008-02-01

    Human leukocyte antigen (HLA)-DM is a critical participant in antigen presentation that catalyzes the dissociation of the Class II-associated Invariant chain-derived Peptide (CLIP) from the major histocompatibility complex (MHC) Class II molecules. There is competition amongst peptides for access to an MHC Class II groove and it has been hypothesised that DM functions as a 'peptide editor' that catalyzes the replacement of one peptide for another within the groove. It is established that the DM catalyst interacts directly with the MHC Class II but the precise location of the interface is unknown. Here, we combine previously described mutational data with molecular docking and energy minimisation simulations to identify a putative interaction site of >4000A2 which agrees with known point mutational data for both the DR and DM molecule. The docked structure is validated by comparison with experimental data and previously determined properties of protein-protein interfaces. A possible dissociation mechanism is suggested by the presence of an acidic cluster near the N terminus of the bound peptide. PMID:17870168

  2. The Perfect Storm: HLA Antibodies, Complement, FcγRs and Endothelium in Transplant Rejection

    PubMed Central

    Thomas, Kimberly A.; Valenzuela, Nicole M.; Reed, Elaine F.

    2015-01-01

    The pathophysiology of antibody-mediated rejection (AMR) in solid organ transplants is multi-faceted and predominantly caused by antibodies directed against polymorphic donor human leukocyte antigens (HLA). Despite the clearly detrimental impact of HLA antibodies (HLA-Ab) on graft function and survival, the prevention, diagnosis and treatment of AMR remain a challenge. Histological manifestations of AMR reflect signatures of HLA-Ab-triggered injury, specifically endothelial changes, recipient leukocytic infiltrate, and complement deposition. We review the interconnected mechanisms of HLA-Ab-mediated injury that might synergize in a “perfect storm” of inflammation. Characterization of antibody features that are critical for effector functions may help identify HLA-Ab more likely to cause rejection. We also highlight recent advancements that may pave the way for new, more effective therapeutics. PMID:25801125

  3. An Object-Oriented Regression for Building Disease Predictive Models with Multiallelic HLA Genes.

    PubMed

    Zhao, Lue Ping; Bolouri, Hamid; Zhao, Michael; Geraghty, Daniel E; Lernmark, Åke

    2016-05-01

    Recent genome-wide association studies confirm that human leukocyte antigen (HLA) genes have the strongest associations with several autoimmune diseases, including type 1 diabetes (T1D), providing an impetus to reduce this genetic association to practice through an HLA-based disease predictive model. However, conventional model-building methods tend to be suboptimal when predictors are highly polymorphic with many rare alleles combined with complex patterns of sequence homology within and between genes. To circumvent this challenge, we describe an alternative methodology; treating complex genotypes of HLA genes as "objects" or "exemplars," one focuses on systemic associations of disease phenotype with "objects" via similarity measurements. Conceptually, this approach assigns disease risks base on complex genotype profiles instead of specific disease-associated genotypes or alleles. Effectively, it transforms large, discrete, and sparse HLA genotypes into a matrix of similarity-based covariates. By the Kernel representative theorem and machine learning techniques, it uses a penalized likelihood method to select disease-associated exemplars in building predictive models. To illustrate this methodology, we apply it to a T1D study with eight HLA genes (HLA-DRB1, HLA-DRB3, HLA-DRB4, HLA-DRB5, HLA-DQA1, HLA-DQB1, HLA-DPA1, and HLA-DPB1) to build a predictive model. The resulted predictive model has an area under curve of 0.92 in the training set, and 0.89 in the validating set, indicating that this methodology is useful to build predictive models with complex HLA genotypes. PMID:27080919

  4. The HLA genomic loci map: expression, interaction, diversity and disease.

    PubMed

    Shiina, Takashi; Hosomichi, Kazuyoshi; Inoko, Hidetoshi; Kulski, Jerzy K

    2009-01-01

    The human leukocyte antigen (HLA) super-locus is a genomic region in the chromosomal position 6p21 that encodes the six classical transplantation HLA genes and at least 132 protein coding genes that have important roles in the regulation of the immune system as well as some other fundamental molecular and cellular processes. This small segment of the human genome has been associated with more than 100 different diseases, including common diseases, such as diabetes, rheumatoid arthritis, psoriasis, asthma and various other autoimmune disorders. The first complete and continuous HLA 3.6 Mb genomic sequence was reported in 1999 with the annotation of 224 gene loci, including coding and non-coding genes that were reviewed extensively in 2004. In this review, we present (1) an updated list of all the HLA gene symbols, gene names, expression status, Online Mendelian Inheritance in Man (OMIM) numbers, including new genes, and latest changes to gene names and symbols, (2) a regional analysis of the extended class I, class I, class III, class II and extended class II subregions, (3) a summary of the interspersed repeats (retrotransposons and transposons), (4) examples of the sequence diversity between different HLA haplotypes, (5) intra- and extra-HLA gene interactions and (6) some of the HLA gene expression profiles and HLA genes associated with autoimmune and infectious diseases. Overall, the degrees and types of HLA super-locus coordinated gene expression profiles and gene variations have yet to be fully elucidated, integrated and defined for the processes involved with normal cellular and tissue physiology, inflammatory and immune responses, and autoimmune and infectious diseases. PMID:19158813

  5. HLA-E coding and 3' untranslated region variability determined by next-generation sequencing in two West-African population samples.

    PubMed

    Castelli, Erick C; Mendes-Junior, Celso T; Sabbagh, Audrey; Porto, Iane O P; Garcia, André; Ramalho, Jaqueline; Lima, Thálitta H A; Massaro, Juliana D; Dias, Fabrício C; Collares, Cristhianna V A; Jamonneau, Vincent; Bucheton, Bruno; Camara, Mamadou; Donadi, Eduardo A

    2015-12-01

    HLA-E is a non-classical Human Leucocyte Antigen class I gene with immunomodulatory properties. Whereas HLA-E expression usually occurs at low levels, it is widely distributed amongst human tissues, has the ability to bind self and non-self antigens and to interact with NK cells and T lymphocytes, being important for immunosurveillance and also for fighting against infections. HLA-E is usually the most conserved locus among all class I genes. However, most of the previous studies evaluating HLA-E variability sequenced only a few exons or genotyped known polymorphisms. Here we report a strategy to evaluate HLA-E variability by next-generation sequencing (NGS) that might be used to other HLA loci and present the HLA-E haplotype diversity considering the segment encoding the entire HLA-E mRNA (including 5'UTR, introns and the 3'UTR) in two African population samples, Susu from Guinea-Conakry and Lobi from Burkina Faso. Our results indicate that (a) the HLA-E gene is indeed conserved, encoding mainly two different protein molecules; (b) Africans do present several unknown HLA-E alleles presenting synonymous mutations; (c) the HLA-E 3'UTR is quite polymorphic and (d) haplotypes in the HLA-E 3'UTR are in close association with HLA-E coding alleles. NGS has proved to be an important tool on data generation for future studies evaluating variability in non-classical MHC genes. PMID:26187162

  6. Non-HLA antibodies against endothelial targets bridging allo- and autoimmunity.

    PubMed

    Dragun, Duska; Catar, Rusan; Philippe, Aurélie

    2016-08-01

    Detrimental actions of donor-specific antibodies (DSAs) directed against both major histocompatibility antigens (human leukocyte antigen [HLA]) and specific non-HLA antigens expressed on the allograft endothelium are a flourishing research area in kidney transplantation. Newly developed solid-phase assays enabling detection of functional non-HLA antibodies targeting G protein-coupled receptors such as angiotensin type I receptor and endothelin type A receptor were instrumental in providing long-awaited confirmation of their broad clinical relevance. Numerous recent clinical studies implicate angiotensin type I receptor and endothelin type A receptor antibodies as prognostic biomarkers for earlier occurrence and severity of acute and chronic immunologic complications in solid organ transplantation, stem cell transplantation, and systemic autoimmune vascular disease. Angiotensin type 1 receptor and endothelin type A receptor antibodies exert their pathophysiologic effects alone and in synergy with HLA-DSA. Recently identified antiperlecan antibodies are also implicated in accelerated allograft vascular pathology. In parallel, protein array technology platforms enabled recognition of new endothelial surface antigens implicated in endothelial cell activation. Upon target antigen recognition, non-HLA antibodies act as powerful inducers of phenotypic perturbations in endothelial cells via activation of distinct intracellular cell-signaling cascades. Comprehensive diagnostic assessment strategies focusing on both HLA-DSA and non-HLA antibody responses could substantially improve immunologic risk stratification before transplantation, help to better define subphenotypes of antibody-mediated rejection, and lead to timely initiation of targeted therapies. Better understanding of similarities and dissimilarities in HLA-DSA and distinct non-HLA antibody-related mechanisms of endothelial damage should facilitate discovery of common downstream signaling targets and pave the

  7. The detection of donor-directed, HLA-specific alloantibodies in recipients of unrelated hematopoietic cell transplantation is predictive of graft failure

    PubMed Central

    Bray, Robert; Rosen-Bronson, Sandra; Haagenson, Michael; Klein, John; Flesch, Susan; Vierra-Green, Cynthia; Anasetti, Claudio

    2010-01-01

    Donor-directed human leukocyte antigen (HLA)–specific allo-antibodies (DSAs) cause graft failure in animal models of hematopoietic stem cell transplantation (HCT). Archived pretransplantation sera from graft failure patients (n = 37) and a matched case-control cohort (n = 78) were tested to evaluate the role of DSAs in unrelated donor HCT. Controls were matched for disease, disease status, graft type, patient age, and transplantation year. Patients had acute myeloid leukemia, acute lymphoblastic leukemia, chronic myelogenous leukemia, or myelodysplastic syndrome; 98% received myeloablative conditioning regimens 100% received T-replete grafts, 97% received marrow, 95% HLA-mismatched, and 97% received calcineurin-based graft-versus-host disease prophylaxis. Among the 37 failed transplantations, 9 (24%) recipients possessed DSAs against HLA-A, B, and/or DP, compared with only 1 (1%) of 78 controls. Therefore, the presence of DSAs was significantly associated with graft failure (odds ratio = 22.84; 95% confidence interval, 3.57-∞; P < .001). These results indicate that the presence of pretransplantation DSAs in recipients of unrelated donor HCT is associated with failed engraftment and should be considered in HCT donor selection. PMID:20089963

  8. Impact of HLA-G analysis in prevention, diagnosis and treatment of pathological conditions

    PubMed Central

    Bortolotti, Daria; Gentili, Valentina; Rotola, Antonella; Cassai, Enzo; Rizzo, Roberta; Luca, Dario Di

    2014-01-01

    Human leukocyte antigen-G (HLA-G) is a non-classical HLA class I molecule that differs from classical HLA class I molecules by low polymorphism and tissue distribution. HLA-G is a tolerogenic molecule with an immune-modulatory and anti-inflammatory function on both innate and adaptative immunity. This peculiar characteristic of HLA-G has led to investigations of its role in pathological conditions in order to define possible uses in diagnosis, prevention and treatment. In recent years, HLA-G has been shown to have an important implication in different inflammatory and autoimmune diseases, pregnancy complications, tumor development and aggressiveness, and susceptibility to viral infections. In fact, HLA-G molecules have been reported to alternate at both genetic and protein level in different disease situations, supporting its crucial role in pathological conditions. Specific pathologies show altered levels of soluble (s)HLA-G and different HLA-G gene polymorphisms seem to correlate with disease. This review aims to update scientific knowledge on the contribution of HLA-G in managing pathological conditions. PMID:25237627

  9. HLA-G Expression and Role in Advanced-Stage Classical Hodgkin Lymphoma

    PubMed Central

    Caocci, G.; Greco, M.; Fanni, D.; Senes, G.; Littera, R.; Lai, S.; Risso, P.; Carcassi, C.; Faa, G.; La Nasa, G.

    2016-01-01

    Non-classical human leucocyte antigen (HLA)-G class I molecules have an important role in tumor immune escape mechanisms. We investigated HLA-G expression in lymphonode biopsies taken from 8 controls and 20 patients with advanced-stage classical Hodgkin lymphoma (cHL), in relationship to clinical outcomes and the HLA-G 14-basepair (14-bp) deletion-insertion (del-ins) polymorphism. Lymphnode tissue sections were stained using a specific murine monoclonal HLA-G antibody. HLA-G protein expression was higher in cHL patients than controls. In the group of PET-2 positive (positron emission tomography carried out after 2 cycles of standard chemotherapy) patients with a 2-year progression-free survival rate (PFS) of 40%, we observed high HLA-G protein expression within the tumor microenvironment with low expression on Hodgkin and Reed-Sternberg (HRS) cells. Conversely, PET-2 negative patients with a PFS of 86% had higher HLA-G protein expression levels on HRS cells compared to the microenvironment. Lower expression on HRS cells was significantly associated with the HLA-G 14-bp ins/ins genotype. These preliminary data suggest that the immunohistochemical pattern of HLA-G protein expression may represent a useful tool for a tailored therapy in patients with cHL, based on the modulation of HLA-G expression in relation to achievement of negative PET-2. PMID:27349312

  10. HLA Class Ib Molecules and Immune Cells in Pregnancy and Preeclampsia

    PubMed Central

    Djurisic, Snezana; Hviid, Thomas Vauvert F.

    2014-01-01

    Despite decades of research, the highly prevalent pregnancy complication preeclampsia, “the disease of theories,” has remained an enigma. Indeed, the etiology of preeclampsia is largely unknown. A compiling amount of studies indicates that the pathological basis involves a complex array of genetic predisposition and immunological maladaptation, and that a contribution from the mother, the father, and the fetus is likely to be important. The Human Leukocyte Antigen (HLA)-G is an increasing focus of research in relation to preeclampsia. The HLA-G molecule is primarily expressed by the extravillous trophoblast cells lining the placenta together with the two other HLA class Ib molecules, HLA-E and HLA-F. Soluble isoforms of HLA-G have been detected in the early endometrium, the matured cumulus–oocyte complex, maternal blood of pregnant women, in umbilical cord blood, and lately, in seminal plasma. HLA-G is believed to be involved in modulating immune responses in the context of vascular remodeling during pregnancy as well as in dampening potential harmful immune attacks raised against the semi-allogeneic fetus. In addition, HLA-G genetic variants are associated with both membrane-bound and soluble forms of HLA-G, and, in some studies, with preeclampsia. In this review, a genetic contribution from the mother, the father, and the fetus, together with the presence and function of various immune cells of relevance in pregnancy are reviewed in relation to HLA-G and preeclampsia. PMID:25566263

  11. Directed selection of influenza virus produces antigenic variants that match circulating human virus isolates and escape from vaccine-mediated immune protection.

    PubMed

    DeDiego, Marta L; Anderson, Christopher S; Yang, Hongmei; Holden-Wiltse, Jeanne; Fitzgerald, Theresa; Treanor, John J; Topham, David J

    2016-06-01

    Influenza vaccination does not provide 100% protection from infection, partly due to antigenic drift of the haemagglutinin (HA) protein. Low serum antibody titres increase the risk of infection. To determine whether there were additional correlates of risk, we examined the relationship between human serum immunity and antigenic variation in seasonal H3N2 influenza viruses. Seasonal H3N2 vaccine strains grown in the presence of heterogeneous human or mono-specific ferret antisera selected variants with mutations in the HA antigenic sites. Surprisingly, circulating strains infecting human subjects in the same seasons displayed mutations in the same positions, although only in one case did the change correspond to the same amino acid. Serum antibody titres were lower against both the in vitro selected and clinical isolates compared with the vaccine strains, suggesting that the mutations are relevant to vaccine failure. Antibody titres were also significantly lower in sera from infected subjects than in non-infected subjects, suggesting relatively poor responses to vaccination in the infected subjects. Collectively, the data suggest that risk from influenza infection is a result of poor response to vaccination, as well as encounter with drifted seasonal influenza virus antigenic variants. The results also show that directed selection under human immune pressure could reveal antigenic variants relevant to real-world drifted viruses, helping in annual vaccine re-formulation. PMID:26854888

  12. Enhanced Expression of Interferon-γ-Induced Antigen-Processing Machinery Components in a Spontaneously Occurring Cancer1

    PubMed Central

    Cerruti, Fulvia; Martano, Marina; Petterino, Claudio; Bollo, Enrico; Morello, Emanuela; Bruno, Renato; Buracco, Paolo; Cascio, Paolo

    2007-01-01

    In human tumors, changes in the surface expression and/or function of major histocompatibility complex (MHC) class I antigens are frequently found and may provide malignant cells with a mechanism to escape control of the immune system. This altered human lymphocyte antigen (HLA) class I phenotype can be caused by either structural alterations or dysregulation of genes encoding subunits of HLA class I antigens and/or components of the MHC class I antigen-processing machinery (APM). Herein we analyze the expression of several proteins involved in the generation of MHC class I epitopes in feline injection site sarcoma, a spontaneously occurring tumor in cats that is an informativemodel for the study of tumor biology in other species, including humans. Eighteen surgically removed primary fibrosarcoma lesions were analyzed, and an enhanced expression of two catalytic subunits of immunoproteasomes, PA28 and leucine aminopeptidase, was found in tumors compared to matched normal tissues. As a functional counterpart of these changes in protein levels, proteasomal activities were increased in tissue extracts from fibrosarcomas. Taken together, these results suggest that alterations in the APM system may account for reduced processing of selected tumor antigens and may potentially provide neoplastic fibroblasts with a mechanism for escape from T-cell recognition and destruction. PMID:18030364

  13. HLA Allele Frequencies in 5802 Koreans: Varied Allele Types Associated with SJS/TEN According to Culprit Drugs

    PubMed Central

    Park, Hye Jung; Kim, Young Joo; Kim, Dong Hyun; Kim, Junho; Park, Kyung Hee; Park, Jung-Won

    2016-01-01

    Purpose Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are very serious forms of drug-induced cutaneous adverse reaction. SJS/TEN induced by certain drug is well known to be associated with some human leukocyte antigen (HLA) gene type. We aimed to explore HLA allele frequencies and their association with SJS/TEN according to culprit drugs in Korea. Materials and Methods We enrolled 5802 subjects who had results of HLA typing test from August 2005 to July 2014. Total 28 SJS/TEN patients were categorized based on culprit drugs (allopurinol, lamotrigine, carbamazepine) and identified the presence of HLA-B*58:01, HLA-B*44:03, HLA-B*15:02, and HLA-A*31:01. Results HLA-A*24:02 (20.5%), HLA-B*44:03 (10.0%), and HLA-Cw*01:02 (17.1%) were the most frequent type in HLA-A, -B, and -C genes, respectively. Allele frequencies of HLA-B*58:01, HLA-B*44:03, HLA-A*31:01, and HLA-B*15:02 were 7.0%, 10.0%, 5.0%, and 0.3%, respectively. In 958 allopurinol users, 9 subjects (0.9%) were diagnosed with SJS/TEN. Among them, 8 subjects possessed HLA-B*58:01 allele. SJS/TEN induced by allopurinol was more frequently developed in subjects with HLA-B*58:01 than in subjects without it [odds ratio: 57.4; confidence interval (CI) 7.12-463.50; p<0.001]. Allopurinol treatment, based on screening by HLA-B*58:01 genotyping, could be more cost-effective than that not based on screening. HLA-B*44:03 may be associated with lamotrigine-induced SJS/TEN (odds ratio: 12.75; CI 1.03-157.14; p=0.053). Among carbamazepine users, only two patients experienced SJS/TEN and possessed neither HLA-B*15:02 nor HLA-A*31:03. Conclusion HLA gene frequencies varied in Korea. Screening of HLA-B*58:01 before the use of allopurinol might be needed to anticipate probability of SJS/TEN. PMID:26632391

  14. Identification of a novel HLA-G+ regulatory population in blood: expansion after allogeneic transplantation and de novo HLA-G expression at graft-versus-host disease sites

    PubMed Central

    Lazana, Ioanna; Zoudiari, Anastasia; Kokkinou, Dimitra; Themeli, Maria; Liga, Maria; Papadaki, Helen; Papachristou, Dionysios; Spyridonidis, Alexandros

    2012-01-01

    Background The human leukocyte antigen-G (HLA-G) has been considered to be an important tolerogeneic molecule playing an essential role in maternal-fetal tolerance, which constitutes the perfect example of successful physiological immunotolerance of semi-allografts. In this context, we investigated the putative role of this molecule in the allogeneic hematopoietic cell transplantation setting. Design and Methods The percentage of HLA-G+ cells in peripheral blood of healthy donors and allo-transplanted patients was evaluated by flow cytometry. Their immunoregulatory and tolerogeneic properties were investigated in in vitro immunostimulatory and immunosuppression assays. Immunohistochemical analysis for HLA-G expression was performed in skin biopsies from allo-transplanted patients and correlated with the occurrence of graft-versus-host disease. Results We identified a CD14+HLA-Gpos population with an HLA-DRlow phenotype and decreased in vitro immunostimulatory capacity circulating in peripheral blood of healthy individuals. Naturally occurring CD14+HLA-Gpos cells suppressed T-cell responses and exerted an immunotolerogenic action on T cells by rendering them hyporesponsive and immunosuppressive in vitro. After allogeneic hematopoietic cell transplantation, HLA-Gpos cells increase in blood. Interestingly, besides an increase in CD14+HLA-Gpos cells, there was also a pronounced expansion of CD3+HLA-Gpos cells. Of note, CD3+HLA-Gpos and CD14+HLA-Gpos cells from transplanted patients were suppressive in in vitro lymphoproliferation assays. Furthermore, we found an upregulation of HLA-G expression in skin specimens from transplanted patients that correlated with graft-versus-host disease. Inflammatory cells infiltrating the dermis of transplanted patients were also HLA-Gpos. Conclusions We report the presence of naturally occurring HLA-Gpos monocytic cells with in vitro suppressive properties. HLA-G expressing regulatory blood cells were found in increased numbers after

  15. HLA and fertility

    SciTech Connect

    Ober, C.

    1995-11-01

    The recent paper by Jin et al., reporting that class 11 region major histocompatibility complex genes may influence embryonic loss in outbred couples supports previous results of our studies of HLA and fertility in the Hutterites. However, the authors have incorrectly cited our work and have omitted the reference that is most relevant to their results. The paper by Kostyu et al. is incorrectly referred to in the introduction as providing evidence for HLA sharing being associated with recurrent spontaneous abortion. The Kostyu et al. paper does not include any data on fertility or reproduction but reports frequencies of individuals who are homozygous at the HLA-A, -C, -B, -DR, and -DQ loci in the Hutterite population. In fact, recurrent spontaneous abortion has not been observed in any of the couples in our sample of >500 Hutterite couples. References more appropriate to the association between HLA sharing and recurrent miscarriage are those by Komlos et al., Schacter et al., Gerencer and Kastelan, and Beer et al. It might also be worth pointing out that many studies of recurrent miscarriage in outbred couples have not found an association with HLA sharing; examples include the studies of Ergolu et al., Oksenberg et al., and Christiansen et al., among others. 11 refs.

  16. The diversity of the HLA-E-restricted peptide repertoire explains the immunological impact of the Arg107Gly mismatch.

    PubMed

    Celik, Alexander A; Kraemer, Thomas; Huyton, Trevor; Blasczyk, Rainer; Bade-Döding, Christina

    2016-01-01

    Human leukocyte antigen (HLA)-E molecules are potent inhibitors of NK cell-mediated killing. Low in polymorphisms, two alleles are widely expressed among diverse populations: HLA-E*01:01 and HLA-E*01:03. Both alleles are distinguished by one SNP resulting in the substitution Arg107Gly. Both alleles present a limited set of peptides derived from class I leader sequences physiologically; however, HLA-E*01:01 presents non-canonical peptides in the absence of HLA class I molecules. To further assess the functional differences between both alleles, we analyzed the peptide repertoire of HLA-E*01:03 by applying soluble HLA technology followed by mass-spectrometric peptide sequencing. HLA-E*01:03 restricted peptides showed a length of 9-17 amino acids and differed in their biophysical properties, no overlap in the peptide repertoire of both allelic variants could be observed; however, both alleles shared marginal peptides from the same proteomic content. Artificial APCs expressing empty HLA-E*01:01 or E*01:03 molecules were generated and stabilized using cognate HLA class I-derived peptide ligands to analyze the impact of residue 107 within the HLA-E heavy chain on the NKG2/CD94 receptor engagement. Differences in peptide stabilization could be translated to the density and half-life time of peptide-HLA-E molecules on the cell surface that subsequently impacted NK cell inhibition as verified by cytotoxicity assays. Taken together, these data illustrate functional differences of HLA-E allelic variants induced by a single amino acid. Furthermore, the function of HLA-E in pathophysiologic situations when the HLA processing machinery is interrupted seems to be more emphasized than previously described, implying a crucial role for HLA-E in tumor or viral immune episodes. PMID:26552660

  17. HLA-B alleles of the Cayapa of Ecuador: New B39 and B15 alleles

    SciTech Connect

    Garber, T.L.; Butler, L.M.; Watkins, D.I.

    1995-05-01

    Recent data suggest that HLA-B locus alleles can evolve quickly in native South American populations. To investigate further this phenomenon of new HLA-B variants among Amerindians, we studied samples from another South American tribe, the Cayapa from Ecuador. We selected individuals for HLA-B molecular typing based upon their HLA class II typing results. Three new variants of HLA-B39 and one new variant of HLA-B15 were found in the Cayapa: HLA-B*3905, HLA-B*3906, HLA-B*3907, and HLA-B*1522. A total of thirteen new HLA-B alleles have now been found in the four South American tribes studied. Each of these four tribes studied, including the Cayapa, had novel alleles that were not found in any of the other tribes, suggesting that many of these new HLA-B alleles may have evolved since the Paleo-Indians originally populated South America. Each of these 13 new alleles contained predicted amino acid replacements that were located in the peptide binding site. These amino acid replacements may affect the sequence motif of the bound peptides, suggesting that these new alleles have been maintained by selection. New allelic variants have been found for all common HLA-B locus antigenic groups present in South American tribes with the exception of B48. In spite of its high frequency in South American tribes, no evidence for variants of B48 has been found in all the Amerindians studied, suggesting that B48 may have unique characteristics among the B locus alleles. 70 refs., 2 figs., 2 tabs.

  18. HLA-G and MHC Class II Protein Expression in Diffuse Large B-Cell Lymphoma.

    PubMed

    Jesionek-Kupnicka, Dorota; Bojo, Marcin; Prochorec-Sobieszek, Monika; Szumera-Ciećkiewicz, Anna; Jabłońska, Joanna; Kalinka-Warzocha, Ewa; Kordek, Radzisław; Młynarski, Wojciech; Robak, Tadeusz; Warzocha, Krzysztof; Lech-Maranda, Ewa

    2016-06-01

    The expression of human leukocyte antigen-G (HLA-G) and HLA class II protein was studied by immunohistochemical staining of lymph nodes from 148 patients with diffuse large B-cell lymphoma (DLBCL) and related to the clinical course of the disease. Negative HLA-G expression was associated with a lower probability of achieving a complete remission (p = 0.04). Patients with negative HLA-G expression tended towards a lower 3-year overall survival (OS) rate compared to those with positive expression of HLA-G (p = 0.08). When restricting the analysis to patients receiving chemotherapy with rituximab, the estimated 3-year OS rate of patients with positive HLA-G expression was 73.3 % compared with 47.5 % (p = 0.03) in those with negative expression. Patients with negative HLA class II expression presented a lower 3-year OS rate compared to subjects with positive expression (p = 0.04). The loss of HLA class II expression (p = 0.05) and belonging to the intermediate high/high IPI risk group (p = 0.001) independently increased the risk of death. HLA class II expression also retained its prognostic value in patients receiving rituximab; the 3-year OS rate was 65.3 % in patients with positive HLA class II expression versus 29.6 % (p = 0.04) in subjects that had loss of HLA class II expression. To our knowledge, for the first time, the expression of HLA-G protein in DLBCL and its association with the clinical course of the disease was demonstrated. Moreover, the link between losing HLA class II protein expression and poor survival of patients treated with immunochemotherapy was confirmed. PMID:26667793

  19. Association between HLA-E gene polymorphism and unexplained recurrent spontaneous abortion (RSA) in Iranian women

    PubMed Central

    Fotoohi, Maryam; Ghasemi, Nasrin; Mirghanizadeh, Seyed Ali; Vakili, Mahmood; Samadi, Morteza

    2016-01-01

    Background: Human leukocyte antigen-E (HLA-E)is a non-classical major histocompatibility complex (MHC) class I antigens which expressed on extra villous cytotrophoblast, which interacts with NKG2A, is an inhibitory receptor on natural killer (NK) cells and leading to down regulation of immune response in the maternal-fetal interface and provides maternal immune tolerance of the fetus. Objective: This study was designated to investigate the gene frequencies of E0101 and E0103 in HLA-E gene in Iranian women with recurrent spontaneous abortion (RSA). Materials and Methods: Amplification Refractory Mutation System (ARMS-PCR) technique was carried out to detect polymorphism in exon 3 of the HLA-E gene in women with RSA and controls (n=200). Differences between groups were analyzed by SPSS19 software using 2 test. Results: There was no significant difference in the allele frequencies of the HLA-E polymorphism between RSA and fertile controls but HLA-E 0101/0103 heterozygous genotype was found to be significantly higher in RSA group (p=0.006, OR=1.73), so this genotype might confer susceptibility to RSA. Conclusion: Our results suggest that HLA-E 0101/0103 heterozygous genotype leads to increase of RSA risk. It seems that by genotyping of HLA-E polymorphism, we can predict the risk of RSA in infertile women. PMID:27525333

  20. Significant association of HLA-DQ5 with autoimmune hepatitis in Taiwan.

    PubMed

    Koay, Lok-Beng; Sun, Chi-Shu; Tsai, Sun-Lung; Lin, Ching-Yih

    2007-12-01

    Genetic predisposition is known to be an important etiopathogenic factor of autoimmune hepatitis (AIH). HLA antigens associated with AIH have been well studied in Western countries and Japan, but there is no HLA typing data of AIH patients in Taiwan. We therefore investigated HLA phenotypes and their association with AIH patients and compared the results with those of normal subjects and patients with chronic liver disease. Group 1 consisted of 22 AIH patients. All were born in Taiwan with no history of blood transfusion. Group 2 consisted of 19 chronic liver disease patients. Group 3 consisted of 81 unrelated healthy subjects who were normal blood donors. All three groups were tested for HLA phenotypes (HLAA, B, C, DR, DQ) using the polymerase chain reaction-sequence specific probe method. The statistical method used was Fisher's exact test. We found that HLA-DQ5 was significantly more frequent in the AIH group compared to the control group (RR, 2.03; p = 0.034). Low frequency of A1 (n = 2/22), B8 (n = 1/22) and DR3 (n = 0/22) were noted compared to results from the West; only HLA-DR4 showed a higher rate in our AIH patients (n = 8/22). This is a preliminary report of our study of HLA antigens in AIH patients. Further investigation to characterize AIH patients into HLA allelic subgroups is being done. PMID:18194915

  1. HLA Class I and Class II Associations with ESRD in Saudi Arabian Population

    PubMed Central

    Hamdi, Nuha Mahmoud; Al-Hababi, Fadel Hassan; Eid, Amr Ekhlas

    2014-01-01

    Background Chronic renal failure (CRF) leads in the majority of instances to end stage renal disease (ESRD) requiring renal replacement therapy. Our interest was to evaluate the possible associations of HLA class I and class II antigens with ESRD independent of other factors, in Saudi Arabia population. Methodology A retrospective study to determine the HLA class I and class II polymorphisms and their association with ESRD, was performed on 350 patients with ESRD, and 105 healthy unrelated control. Patients and control groups were typed by SSOP lumenix techniques. The alleles positively associated to the ESRD were: HLA-B*15, B*18, B*49 - DRB1*03, negatively associated alleles were A*26, HLA-B*39, B*50. The haplotypes positively associated with ESRD were: HLA-A*01-DRB1*13 and HLA-A*30-DRBI*03. The negatively associated haplotypes were: HLA-A*02-B*39, A*02-B*50, A*24-B*35, A*24-B*58, A*24-DRB1*16, A*68-DRB1*04, A*02-DQB1*03, A*29-DQB1*02, A*29-DOB1*05 and B*27-DRB1*07 and the last one is the most significant protective haplotypes. Conclusion The high Relative Risk (RR) observed and its statistical correlation reflect the strength of the described association between HLA antigens and ESRD. PMID:25380295

  2. Update of the HLA class I eplet database in the website based registry of antibody-defined HLA epitopes.

    PubMed

    Duquesnoy, R J

    2014-06-01

    Eplets are small configurations of polymorphic amino acid residues on human leukocyte antigen (HLA) molecules and are considered as essential components of HLA epitopes recognized by antibodies. This report describes a new design of the eplet repertoire in HLA-ABC alleles used in Luminex kits for antibody testing. There were three steps (1): identify all combinations of polymorphic residues with HLA molecular modeling within a 3-Å radius, (2) determine polymorphic residue compositions of 3 Å patches from amino acid sequences of HLA alleles in Luminex panels and (3) annotate eplets from one or more patches present on one allele or shared by the same group of alleles. There are now 270 HLA-ABC eplets in the Registry, of which 219 are in antibody-accessible positions on the molecular surface and 51 are defined solely by residue polymorphisms located below the molecular surface. Each eplet has a list of Luminex and non-Luminex alleles for which mismatch acceptability can be determined. PMID:24828055

  3. Regulation and trafficking of the HLA-E molecules during monocyte-macrophage differentiation.

    PubMed

    Camilli, Giorgio; Cassotta, Antonino; Battella, Simone; Palmieri, Gabriella; Santoni, Angela; Paladini, Fabiana; Fiorillo, Maria Teresa; Sorrentino, Rosa

    2016-01-01

    HLA-E is a nonclassical HLA-class I molecule whose best known role is to protect from the natural killer cells. More recently, an additional function more similar to that of classical HLA-class I molecules, i.e., antigen presentation to T cells, is emerging. However, much remains to be explored about the intracellular trafficking of the HLA-E molecules. With the use of 3 different cellular contexts, 2 monocytic cell lines, U937 and THP1, and peripheral blood monocytes, we show here a remarkable increase of HLA-E during monocyte-macrophage differentiation. This goes independently from the classical HLA-class I, the main source of HLA-E-specific peptides, which is found strongly up-regulated upon differentiation of peripheral blood monocytes but not at all in the case of U937 and THP1 cell lines. Although in all cases, there was a moderate increase of HLA-E expressed in the cell surface, lysis by natural killer cells is comparably restored by an anti-NKG2A antibody in untreated as well as in PMA-differentiated U937 cells. Instead, the great majority of the HLA-E is retained in the vesicles of the autophagy-lysosome network, where they colocalize with the microtubule-associated protein light chain 3, as well as with the lysosomal-associated membrane protein 1. We conclude that differently from the classical HLA-class I molecules, the primary destination of the newly synthesized HLA-E molecules in macrophages is, rather than the cell membrane, the intracellular autophagy-lysosomal vesicles where they are stored and where they can encounter the exogenous antigens. PMID:26310830

  4. Cross-Allele Cytotoxic T Lymphocyte Responses against 2009 Pandemic H1N1 Influenza A Virus among HLA-A24 and HLA-A3 Supertype-Positive Individuals

    PubMed Central

    Liu, Jun; Zhang, Shihong; Tan, Shuguang; Yi, Yong; Wu, Bin; Cao, Bin; Zhu, Fengcai; Wang, Chen; Wang, Hua; Qi, Jianxun

    2012-01-01

    Lack of a universal vaccine against all serotypes of influenza A viruses and recent progress on T cell-related vaccines against influenza A virus illuminate the important role of human leukocyte antigen (HLA)-restricted cytotoxic T lymphocytes (CTLs) in anti-influenza virus immunity. However, the diverse HLA alleles among humans complicate virus-specific cellular immunity research, and elucidation of cross-HLA allele T cell responses to influenza virus specificity requires further detailed work. An ideal CTL epitope-based vaccine would cover a broad spectrum of epitope antigens presented by most, if not all, of the HLAs. Here, we evaluated the 2009 pandemic influenza A (H1N1) virus-specific T cell responses among the HLA-A24+ population using a rationally designed peptide pool during the 2009 pandemic. Unexpectedly, cross-HLA allele T cell responses against the influenza A virus peptides were detected among both HLA-A11+ and HLA-A24+ donors. Furthermore, we found cross-responses in the entire HLA-A3 supertype population (including HLA-A11, -A31, -A33, and -A30). The cross-allele antigenic peptides within the peptide pool were identified and characterized, and the crystal structures of the major histocompatibility complex (MHC)-peptide complexes were determined. The subsequent HLA-A24-defined cross-allele peptides recognized by the HLA-A11+ population were shown to mildly bind to the HLA-A*1101 molecule. Together with the structural models, these results partially explain the cross-allele responses. Our findings elucidate the promiscuity of the cross-allele T cell responses against influenza A viruses and are beneficial for the development of a T cell epitope-based vaccine applied in a broader population. PMID:23015716

  5. The IMGT/HLA and IPD databases.

    PubMed

    Robinson, James; Waller, Matthew J; Fail, Sylvie C; Marsh, Steven G E

    2006-12-01

    The IMGT/HLA database (www.ebi.ac.uk/imgt/hla) has provided a centralized repository for the sequences of the alleles named by the WHO Nomenclature Committee for Factors of the HLA System since 1998. Since its initial release, the database has rapidly grown in size and is recognized as the primary source of information for the study of sequences of the human major histocompatibility complex. The Immuno Polymorphism Database (IPD; www.ebi.ac.uk/ipd) is a set of specialist databases related to the study of polymorphic genes in the immune system. The IPD currently consists of four databases: IPD-KIR contains the allelic sequences of killer-cell immunoglobulin-like receptors; IPD-MHC is a database of sequences of the major histocompatibility complex of different species; IPD-HPA contains alloantigens expressed only on platelets (human platelet antigens or HPA); and IPD-ESTDAB provides access to the European Searchable Tumour Cell-Line Database, a cell bank of immunologically characterized melanoma cell lines. PMID:16944494

  6. THE PREVALENCE OF HLA DQ2 AND DQ8 IN PATIENTS WITH CELIAC DISEASE, IN FAMILY AND IN GENERAL POPULATION

    PubMed Central

    CECILIO, Lucila Arantes; BONATTO, Mauro W.

    2015-01-01

    Background: Celiac disease is an enteropathy characterized by gluten sensitivity and broad clinical aspect. Has a multifactorial cause and depends on genetic, immunological and environmental factors for its development. The genetic influence is given mostly by the human leukocyte antigens HLA DQ2 and DQ8. Aim: To evaluate the prevalence of human leukocyte antigens DQ2 and DQ8 in three different groups: patients with celiac disease, first-degree relatives and the general population. Method: Retrospective analysis that evaluated serologic and endoscopic data of 74 patients with celiac disease and 109 non-celiac, which were subdivided into two subgroups: non-celiac who had first-degree relatives with celiac and non-celiac who did not. All patients underwent laboratory examination for screening genetic sensitivity given by HLA DQ2 and HLA DQ8 by. Results: The presence of HLA DQ2 and DQ8 was identified in 98,4% of 74 celiac patients, of which 79,7% had only HLA DQ2; 8,1% had only HLA DQ8 and 10,8% had both antigens histocompatibility. In the group of relatives of celiac patients, were included 29 patients; among them, 89,6% had HLA DQ2 and/or DQ8; 76% only the HLA DQ2, 10,3% only HLA DQ8 and 3,4% presented both human leukocyte antigens (HLA). Conclusion: HLA DQ2/DQ8 was present in 98,4% of celiac patients; 89,6% relatives of celiac family and in 55,4% of people from the general population without family celiac. PMID:26537142

  7. Genetic Association of HLA-A*26, -A*31, and -B*51 with Behcet’s Disease in Saudi Patients

    PubMed Central

    Al-Okaily, Fahda; Al-Rashidi, Seham; Al-Balawi, Maysoon; Mustafa, Md.; Arfin, Misbahul; Al-Asmari, Abdulrahman

    2016-01-01

    BACKGROUND HLA-B*51 has been universally associated with Behcet’s disease (BD) susceptibility, while different alleles of HLA-A have also been identified as independent BD susceptibility loci in various ethnic populations. The objective of this study was to investigate associations of HLA-A and -B alleles with BD in Saudi patients. MATERIALS AND METHODS Genotyping for HLA-A and HLA-B was performed using HLA genotyping kit (Lab type(R) SSO) in 120 Saudi subjects, including 60 BD patients and 60 matched healthy controls. RESULTS Our results revealed that frequencies of HLA-A*26, -A*31, and -B*51 were significantly higher in BD patients than in controls, suggesting that HLA-A*26, -A*31, and -B*51 are associated with BD. The frequency of HLA-B*15 was significantly lower in BD patients than in controls. Stratification of genotyping results into active and nonactive forms of BD revealed that the frequency of HLA-A*31 was significantly higher in the nonactive form than in the active form of BD, while there was no significant difference in the distribution of other alleles between the two forms of BD. CONCLUSION This study suggests that HLA-A*26, -A*31, and -B*51 are associated with susceptibility risk to BD, while HLA-B*15 may be protective in Saudi patients. However, larger scale studies are needed to confirm these findings. PMID:27547040

  8. Genetic analysis of HLA in the U.S. Schmiedenleut Hutterites.

    PubMed Central

    Kostyu, D D; Ober, C L; Dawson, D V; Ghanayem, M; Elias, S; Martin, A O

    1989-01-01

    The Hutterites are an Anabaptist population, highly inbred, with large family sizes and extensively documented pedigrees. As part of genetic-epidemiologic studies of the impact of HLA on fertility, HLA-A, -B, -C, -DR, and -DQ typing was performed on a total of 650 Schmiedenleut Hutterities in South Dakota. An extraordinary degree of homogeneity was found. HLA-A1, -A2, -A3, -A24, and -A26 accounted for 83%, HLA-B8, -B27, -B35, -B51, -Bw60, and -Bw62 for 75%, and HLA-DR1, -DR2, -DR3, and -DR4 for 66% of the antigens at the respective HLA-A, -B, and -DR loci. All Hutterites characterized for HLA were descendants of no more than 78 ancestors. However, family analysis identified only 45 unique HLA haplotypes thought to reflect the original gene pool. Eight haplotypes were particularly frequent, accounting for nearly 50% of all observed haplotypes; four of these were consistent with a European ancestry. Coefficients measuring linkage disequilibrium were computed from haplotypes identified by family analysis. Overall, HLA analysis portrayed the Schmiedenleut Hutterities as a homogeneous and unique population, with disequilibrium among particular alleles and a spectrum of common and uncommon European haplotypes. PMID:2757031

  9. Adenovirus expressing β2-microglobulin recovers HLA class I expression and antitumor immunity by increasing T-cell recognition.

    PubMed

    Del Campo, A B; Carretero, J; Muñoz, J A; Zinchenko, S; Ruiz-Cabello, F; González-Aseguinolaza, G; Garrido, F; Aptsiauri, N

    2014-08-01

    Optimal tumor cell surface expression of human leukocyte antigen (HLA) class I molecules is essential for the presentation of tumor-associated peptides to T-lymphocytes. However, a hallmark of many types of tumor is the loss or downregulation of HLA class I expression associated with ineffective tumor antigen presentation to T cells. Frequently, HLA loss can be caused by structural alterations in genes coding for HLA class I complex, including the light chain of the complex, β2-microglobulin (β2m). Its best-characterized function is to interact with HLA heavy chain and stabilize the complex leading to a formation of antigen-binding cleft recognized by T-cell receptor on CD8+ T cells. Our previous study demonstrated that alterations in the β2m gene are frequently associated with cancer immune escape leading to metastatic progression and resistance to immunotherapy. These types of defects require genetic transfer strategies to recover normal expression of HLA genes. Here we characterize a replication-deficient adenoviral vector carrying human β2m gene, which is efficient in recovering proper tumor cell surface HLA class I expression in β2m-negative tumor cells without compromising the antigen presentation machinery. Tumor cells transduced with β2m induced strong activation of T cells in a peptide-specific HLA-restricted manner. Gene therapy using recombinant adenoviral vectors encoding HLA genes increases tumor antigen presentation and represents a powerful tool for modulation of tumor cell immunogenicity by restoration of missing or altered HLA genes. It should be considered as part of cancer treatment in combination with immunotherapy. PMID:24971583

  10. The Structure and Stability of the Monomorphic HLA-G Are Influenced by the Nature of the Bound Peptide

    SciTech Connect

    Walpole, Nicholas G.; Kjer-Nielsen, Lars; Kostenko, Lyudmila; McCluskey, James; Brooks, Andrew G.; Rossjohn, Jamie; Clements, Craig S.

    2010-03-26

    The highly polymorphic major histocompatibility complex class Ia (MHC-Ia) molecules present a broad array of peptides to the clonotypically diverse {alpha}{beta} T-cell receptors. In contrast, MHC-Ib molecules exhibit limited polymorphism and bind a more restricted peptide repertoire, in keeping with their major role in innate immunity. Nevertheless, some MHC-Ib molecules do play a role in adaptive immunity. While human leukocyte antigen E (HLA-E), the MHC-Ib molecule, binds a very restricted repertoire of peptides, the peptide binding preferences of HLA-G, the class Ib molecule, are less stringent, although the basis by which HLA-G can bind various peptides is unclear. To investigate how HLA-G can accommodate different peptides, we compared the structure of HLA-G bound to three naturally abundant self-peptides (RIIPRHLQL, KGPPAALTL and KLPQAFYIL) and their thermal stabilities. The conformation of HLA-G{sup KGPPAALTL} was very similar to that of the HLA-G{sup RIIPRHLQL} structure. However, the structure of HLA-G{sup KLPQAFYIL} not only differed in the conformation of the bound peptide but also caused a small shift in the {alpha}2 helix of HLA-G. Furthermore, the relative stability of HLA-G was observed to be dependent on the nature of the bound peptide. These peptide-dependent effects on the substructure of the monomorphic HLA-G are likely to impact on its recognition by receptors of both innate and adaptive immune systems.

  11. HLA-E expression by gynecological cancers restrains tumor-infiltrating CD8⁺ T lymphocytes.

    PubMed

    Gooden, Marloes; Lampen, Margit; Jordanova, Ekaterina S; Leffers, Ninke; Trimbos, J Baptist; van der Burg, Sjoerd H; Nijman, Hans; van Hall, Thorbald

    2011-06-28

    HLA-E is a nonclassical HLA class I molecule, which differs from classical HLA molecules by its nonpolymorphic, conserved nature. Expression and function of HLA-E in normal tissues and solid tumors is not fully understood. We investigated HLA-E protein expression on tissue sections of 420 ovarian and cervical cancers and found equal or higher levels than normal counterpart epithelia in 80% of the tumors. Expression was strongly associated with components of the antigen presentation pathway, e.g., transporter associated with antigen processing (TAP), endoplasmic reticulum aminopeptide (ERAP), β2 microglobulin (β2m), HLA classes I and II, and for ovarian cancer with tumor infiltrating CD8(+) T lymphocytes (CTLs). This association argues against the idea that HLA-E would compensate for the loss of classical HLA in tumors. In situ detection of HLA-E interacting receptors revealed a very low infiltrate of natural killer (NK) cells, but up to 50% of intraepithelial CTLs expressed the inhibiting CD94/NKG2A receptor. In cervical cancer, HLA-E expression did not alter the prognostic effect of CTLs, most likely due to very high infiltrating CTL numbers in this virus-induced tumor. Overall survival of ovarian cancer patients, however, was strongly influenced by HLA-E, because the beneficial effect of high CTL infiltration was completely neutralized in the subpopulation with strong HLA-E expression. Interestingly, these results indicate that CTL infiltration in ovarian cancer is associated with better survival only when HLA-E expression is low and that intratumoral CTLs are inhibited by CD94/NKG2A receptors on CTLs in the tumor microenvironment. PMID:21670276

  12. HLA-G expression and role in advanced-stage classical Hodgkin lymphoma.

    PubMed

    Caocci, G; Greco, M; Fanni, D; Senes, G; Littera, R; Lai, S; Risso, P; Carcassi, C; Faa, G; La Nasa, G

    2016-01-01

    Non-classical human leucocyte antigen (HLA)-G class I molecules have an important role in tumor immune escape mechanisms. We investigated HLA-G expression in lymphonode biopsies taken from 8 controls and 20 patients with advanced-stage classical Hodgkin lymphoma (cHL), in relationship to clinical outcomes and the HLA-G 14-basepair (14-bp) deletion-insertion (del-ins) polymorphism. Lymphnode tissue sections were stained using a specific murine monoclonal HLA-G antibody. HLA-G protein expression was higher in cHL patients than controls. In the group of PET-2 positive (positron emission tomography carried out after 2 cycles of standard chemotherapy) patients with a 2-year progression-free survival rate (PFS) of 40%, we observed high HLA-G protein expression within the tumor microenvironment with low expression on Hodgkin and Reed-Sternberg (HRS) cells. Conversely, PET-2 negative patients with a PFS of 86% had higher HLA-G protein expression levels on HRS cells compared to the microenvironment. Lower expression on HRS cells was significantly associated with the HLA-G 14-bp ins/ins genotype. These preliminary data suggest that the immunohistochemical pattern of HLA-G protein expression may represent a useful tool for a tailored therapy in patients with cHL, based on the modulation of HLA-G expression in relation to achievement of negative PET-2.These preliminary data suggest that the immunohistochemical pattern of HLA-G protein expression may represent a useful tool for a tailored therapy in patients with cHL, based on the modulation of HLA-G expression in relation to achievement of negative PET-2. PMID:27349312

  13. Neonatal alloimmune thrombocytopenia caused by human leucocyte antigen-B27 antibody.

    PubMed

    Thude, H; Schorner, U; Helfricht, C; Loth, M; Maak, B; Barz, D

    2006-04-01

    Neonatal alloimmune thrombocytopenia (NAIT) occurs when maternal alloantibodies to antigens presented on foetal platelets cause their immune destruction. Whether human leucocyte antigen (HLA) antibodies can cause NAIT is controversial. Here, a patient was described who suffered from a NAIT caused by an HLA-B27 antibody. Sera from the mother and the newborn were tested for human platelet antigen antibodies and HLA antibodies by monoclonal antibody-specific immobilization of platelet antigens (MAIPA) assay, solid phase-linked immunosorbent assay (ELISA), lymphocytotoxicity assay (LCT) and flow cytometric analysis. No antibodies against cluster designation (CD)109 and platelet glycoproteins of the father were found in patient's and mother's serum. However, HLA ELISA was used to identify HLA antibody in both sera. The antibody was specified as HLA-B27 antibody. Typing results showed that the father descended HLA-B27 antigen on patient and his brother. The mother was HLA-B27 negative. It is most conceivable that the previous pregnancy of the mother induced the production of anti-HLA-B27 antibody, which crossed the placenta and subsequently caused an NAIT in the case presented. PMID:16623921

  14. The IMGT/HLA database.

    PubMed

    Robinson, James; Halliwell, Jason A; McWilliam, Hamish; Lopez, Rodrigo; Parham, Peter; Marsh, Steven G E

    2013-01-01

    It is 14 years since the IMGT/HLA database was first released, providing the HLA community with a searchable repository of highly curated HLA sequences. The HLA complex is located within the 6p21.3 region of human chromosome 6 and contains more than 220 genes of diverse function. Of these, 21 genes encode proteins of the immune system that are highly polymorphic. The naming of these HLA genes and alleles and their quality control is the responsibility of the World Health Organization Nomenclature Committee for Factors of the HLA System. Through the work of the HLA Informatics Group and in collaboration with the European Bioinformatics Institute, we are able to provide public access to these data through the website http://www.ebi.ac.uk/imgt/hla/. Regular updates to the website ensure that new and confirmatory sequences are dispersed to the HLA community and the wider research and clinical communities. This article describes the latest updates and additional tools added to the IMGT/HLA project. PMID:23080122

  15. A study of the occurrence of HLA DR2 in 124 narcoleptics: clinical aspects.

    PubMed

    Roth, B; Nevsímalová, S; Sonka, K; Docekal, P; Schulz, H; Geisler, P; Pollmächer, T; Andreas-Zietz, A; Keller, E; Scholz, S

    1988-01-01

    The authors examined HLA antigens in 124 narcoleptics. In addition to narcolepsy, 122 patients suffered also from cataplexy. The two patients without cataplexy suffered also from sleep paralysis and hypnagogic hallucinations. These two symptoms were also present in many of the other patients. HLA group DR2 was found in 120 patients including all six symptomatic cases. In four patients HLA DR2 was not present. Two of these were fully pronounced narcolepsy-cataplexy cases whereas the two other did not suffer from cataplexy. Since several other cases with negative DR2 have already been published it is necessary to admit the existence of DR2-negative narcolepsy, albeit very rare. Among 5 patients with isolated sleep paralysis HLA DR2 was present in one familial and 1 sporadic case. The authors further discuss some aspects of the classification of narcolepsies in the light of recent HLA studies as well as their delimitation from idiopathic hypersomnia. PMID:2459761

  16. Expression of classical HLA class I molecules: regulation and clinical impacts: Julia Bodmer Award Review 2015.

    PubMed

    René, C; Lozano, C; Eliaou, J-F

    2016-05-01

    Human leukocyte antigen (HLA) class I genes are ubiquitously expressed, but in a tissue specific-manner. Their expression is primarily regulated at the transcriptional level and can be modulated both positively and negatively by different stimuli. Advances in sequencing technologies led to the identification of new regulatory variants located in the untranslated regions (UTRs), which could influence the expression. After a brief description of the mechanisms underlying the transcriptional regulation of HLA class I genes expression, we will review how the expression levels of HLA class I genes could affect biological and pathological processes. Then, we will discuss on the differential expression of HLA class I genes according to the locus, allele and UTR polymorphisms and its clinical impact. This interesting field of study led to a new dimension of HLA typing, going beyond a qualitative aspect. PMID:27060357

  17. Predicting HLA Class I Non-Permissive Amino Acid Residues Substitutions

    PubMed Central

    Binkowski, T. Andrew; Marino, Susana R.; Joachimiak, Andrzej

    2012-01-01

    Prediction of peptide binding to human leukocyte antigen (HLA) molecules is essential to a wide range of clinical entities from vaccine design to stem cell transplant compatibility. Here we present a new structure-based methodology that applies robust computational tools to model peptide-HLA (p-HLA) binding interactions. The method leverages the structural conservation observed in p-HLA complexes to significantly reduce the search space and calculate the system’s binding free energy. This approach is benchmarked against existing p-HLA complexes and the prediction performance is measured against a library of experimentally validated peptides. The effect on binding activity across a large set of high-affinity peptides is used to investigate amino acid mismatches reported as high-risk factors in hematopoietic stem cell transplantation. PMID:22905104

  18. Mapping the HLA ligandome landscape of acute myeloid leukemia: a targeted approach toward peptide-based immunotherapy.

    PubMed

    Berlin, C; Kowalewski, D J; Schuster, H; Mirza, N; Walz, S; Handel, M; Schmid-Horch, B; Salih, H R; Kanz, L; Rammensee, H-G; Stevanović, S; Stickel, J S

    2015-03-01

    Identification of physiologically relevant peptide vaccine targets calls for the direct analysis of the entirety of naturally presented human leukocyte antigen (HLA) ligands, termed the HLA ligandome. In this study, we implemented this direct approach using immunoprecipitation and mass spectrometry to define acute myeloid leukemia (AML)-associated peptide vaccine targets. Mapping the HLA class I ligandomes of 15 AML patients and 35 healthy controls, more than 25 000 different naturally presented HLA ligands were identified. Target prioritization based on AML exclusivity and high presentation frequency in the AML cohort identified a panel of 132 LiTAAs (ligandome-derived tumor-associated antigens), and 341 corresponding HLA ligands (LiTAPs (ligandome-derived tumor-associated peptides)) represented subset independently in >20% of AML patients. Functional characterization of LiTAPs by interferon-γ ELISPOT (Enzyme-Linked ImmunoSpot) and intracellular cytokine staining confirmed AML-specific CD8(+) T-cell recognition. Of note, our platform identified HLA ligands representing several established AML-associated antigens (e.g. NPM1, MAGED1, PRTN3, MPO, WT1), but found 80% of them to be also represented in healthy control samples. Mapping of HLA class II ligandomes provided additional CD4(+) T-cell epitopes and potentially synergistic embedded HLA ligands, allowing for complementation of a multipeptide vaccine for the immunotherapy of AML. PMID:25092142

  19. LILRB2 interaction with HLA class I correlates with control of HIV-1 infection.

    PubMed

    Bashirova, Arman A; Martin-Gayo, Enrique; Jones, Des C; Qi, Ying; Apps, Richard; Gao, Xiaojiang; Burke, Patrick S; Taylor, Craig J; Rogich, Jerome; Wolinsky, Steven; Bream, Jay H; Duggal, Priya; Hussain, Shehnaz; Martinson, Jeremy; Weintrob, Amy; Kirk, Gregory D; Fellay, Jacques; Buchbinder, Susan P; Goedert, James J; Deeks, Steven G; Pereyra, Florencia; Trowsdale, John; Lichterfeld, Mathias; Telenti, Amalio; Walker, Bruce D; Allen, Rachel L; Carrington, Mary; Yu, Xu G

    2014-03-01

    Natural progression of HIV-1 infection depends on genetic variation in the human major histocompatibility complex (MHC) class I locus, and the CD8+ T cell response is thought to be a primary mechanism of this effect. However, polymorphism within the MHC may also alter innate immune activity against human immunodeficiency virus type 1 (HIV-1) by changing interactions of human leukocyte antigen (HLA) class I molecules with leukocyte immunoglobulin-like receptors (LILR), a group of immunoregulatory receptors mainly expressed on myelomonocytic cells including dendritic cells (DCs). We used previously characterized HLA allotype-specific binding capacities of LILRB1 and LILRB2 as well as data from a large cohort of HIV-1-infected individuals (N = 5126) to test whether LILR-HLA class I interactions influence viral load in HIV-1 infection. Our analyses in persons of European descent, the largest ethnic group examined, show that the effect of HLA-B alleles on HIV-1 control correlates with the binding strength between corresponding HLA-B allotypes and LILRB2 (p = 10(-2)). Moreover, overall binding strength of LILRB2 to classical HLA class I allotypes, defined by the HLA-A/B/C genotypes in each patient, positively associates with viral replication in the absence of therapy in patients of both European (p = 10(-11)-10(-9)) and African (p = 10(-5)-10(-3)) descent. This effect appears to be driven by variations in LILRB2 binding affinities to HLA-B and is independent of individual class I allelic effects that are not related to the LILRB2 function. Correspondingly, in vitro experiments suggest that strong LILRB2-HLA binding negatively affects antigen-presenting properties of DCs. Thus, we propose an impact of LILRB2 on HIV-1 disease outcomes through altered regulation of DCs by LILRB2-HLA engagement. PMID:24603468

  20. Dynamic characterization of HLA-B*44 Alleles: A comparative molecular dynamics simulation study.

    PubMed

    Ozbek, Pemra

    2016-06-01

    Human Leukocyte Antigens (HLA) are highly polymorphic proteins that play a key role in the immune system. HLA molecule is present on the cell membrane of antigen-presenting cells of the immune system and presents short peptides, originating from the proteins of invading pathogens or self-proteins, to the T-cell Receptor (TCR) molecule of the T-cells. In this study, peptide-binding characteristics of HLA-B*44:02, 44:03, 44:05 alleles bound to three nonameric peptides were studied using molecular dynamics simulations. Polymorphisms among these alleles (Asp116Tyr and Asp156Leu) result in major differences in the allele characteristics. While HLA-B*44:02 (Asp116, Asp156) and HLA-B*44:03 (Asp116, Leu156) depend on tapasin for efficient peptide loading, HLA-B*44:05 (Tyr116, Asp156) is tapasin independent. On the other hand, HLA-B*44:02 and HLA-B*44:03 mismatch is closely related to transplant rejection and acute-graft-versus-host disease. In order to understand the dynamic characteristics, the simulation trajectories were analyzed by applying Root Mean Square Deviation (RMSD) and Root Mean Square Fluctuation (RMSF) calculations and hydrogen bonding analysis. Binding dynamics of the three HLA-B*44 alleles and peptide sequences are comparatively discussed. In general, peptide binding stability is found to depend on the peptide rather than the allele type for HLA-B*44 alleles. PMID:27016630

  1. The in vitro generation of multi-tumor antigen-specific cytotoxic T cell clones: Candidates for leukemia adoptive immunotherapy following allogeneic stem cell transplantation.

    PubMed

    Mohamed, Yehia S; Bashawri, Layla A; Vatte, Chittibabu; Abu-Rish, Eman Y; Cyrus, Cyril; Khalaf, Wafaa S; Browning, Michael J

    2016-09-01

    Adoptive T-cell immunotherapy is a promising approach to manage and maintain relapse-free survival of leukemia patients, especially following allogeneic stem cell transplantation. Post-transplant adoptive immunotherapy using cytotoxic T lymphocytes (CTLs) of the donor origin provide graft-versus-tumor effects, with or without graft-versus-host disease. Myeloid leukemias express immunogenic leukemia associated antigens (LAAs); such as WT-1, PRAME, MAGE, h-TERT and others, most of them are able to induce specific T cell responses whenever associated with the proper co-stimulation. We investigated the ability of a LAA-expressing hybridoma cell line to induce CTL clones in PBMCs of HLA-matched healthy donors in vitro. The CTL clones were induced by repetitive co-culture with LAAs-expressing, HLA-A*0201(+) hybrid cell line, generated by fusion of leukemia blasts to human immortalized APC (EBV-sensitized B-lymphoblastoid cell line; HMy2). The induced cytotoxic T cell clones were phenotypically and functionally characterized by pentamer analysis, IFN-γ release ELISPOT and cellular cytotoxicity assays. All T cell lines showed robust peptide recognition and functional activity when sensitized with HLA-A*0201-restricted WT-1235-243, hTERT615-624 or PRAME100-108 peptides-pulsed T2 cells, in addition to partially HLA-matched leukemia blasts. This study demonstrates the feasibility of developing multi-tumor antigen-specific T cell lines in allogeneic PBMCs in vitro, using LAA-expressing tumor/HMy2 hybrid cell line model, for potential use in leukemia adoptive immunotherapy in partially matched donor-recipient setting. PMID:27490939

  2. Frequency of HLA-DRB1 and HLA-DQB1 Alleles and Haplotype Association in Syrian Population.

    PubMed

    Jazairi, Batoul; Khansaa, Issam; Ikhtiar, Adnan; Murad, Hossam

    2016-02-01

    The study of Human Leukocyte Antigen (HLA) system is very important in health and diseases. As the HLA loci are the most polymorphic in the human genome, it plays a very important role in the immune responses to self and nonself antigens. In the light of the growing importance of typing the HLA alleles in transplantation, autoimmune diseases, cancer, and many other diseases, we studied 225 unrelated healthy Syrian subjects for their HLA class II genotypes in an attempt to reveal the distribution of the HLA (DRB1-DQB1) alleles in the general Syrian population. Our results revealed that the most common alleles for the DRB1 locus were DRB1*11 (26.4%), DRB1*04 (14%), and DRB1*07 (12%). However, the most frequent alleles for the DQB1 locus were DQB1*03 (40.9%) and DQB1*05 (25.1%). The frequent of two-locus haplotypes carry the most frequent alleles at these loci. The most frequently detected class II ''haplotypes'' are DRB1*11-DQB1*03 (8.9%), DRB1*01-DQB1*05 (3.6%), and DRB1*04-DQB1*03 (2.7%). Compared with other populations, our result, deduced from the analysis of genetic distances and the construction of neighbor-joining (NJ) dendrogram, and principal component analysis (PCA) indicates that Syrians are related to Middle Eastern populations. Our data about the Syrian population will aid researchers in studying the relation of HLA class II with different diseases in a Syrian population and will add to the available international literature associated with these loci. PMID:26853713

  3. Association of HLA and post-schistosomal hepatic disorder: a systematic review and meta-analysis.

    PubMed

    Huy, Nguyen Tien; Hamada, Mohamed; Kikuchi, Mihoko; Lan, Nguyen Thi Phuong; Yasunami, Michio; Zamora, Javier; Hirayama, Kenji

    2011-12-01

    Several human genetic variants, HLA antigens and alleles are reportedly linked to post-schistosomal hepatic disorder (PSHD), but the results from these reports are highly inconclusive. In order to estimate overall associations between human genetic variants, HLA antigens, HLA alleles and PSHD, we systematically reviewed and performed a meta-analysis of relevant studies in both post-schistosomal hepatic disorder and post-schistosomal non-hepatic disorder patients. PubMed, Scopus, Google Scholar, The HuGE Published Literature database, Cochrane Library, and manual search of reference lists of articles published before July 2009 were used to retrieve relevant studies. Two reviewers independently selected articles and extracted data on study characteristics and data regarding the association between genetic variants, HLA antigens, HLA alleles and PSHD in the form of 2×2 tables. A meta-analysis using fixed-effects or random-effects models to pooled odds ratios (OR) with corresponding 95% confidence intervals were calculated only if more than one study had investigated particular variation. We found 17 articles that met our eligibility criteria. Schistosoma mansoni and Schistosoma japonicum were reported as the species causing PSHD. Since human genetic variants were only investigated in one study, these markers were not assessed by meta-analysis. Thus, only HLA-genes (a total of 66 HLA markers) were conducted in the meta-analysis. Our meta-analysis showed that human leucocyte antigens HLA-DQB1*0201 (OR=2.64, P=0.018), DQB1*0303 (OR=1.93, P=0.008), and DRB1*0901 (OR=2.14, P=0.002) alleles and HLA-A1 (OR=5.10, P=0.001), A2 (OR=2.17, P=0.005), B5 (OR=4.63, P=0.001), B8 (OR=2.99, P=0.02), and B12 (OR=5.49, P=0.005) serotypes enhanced susceptibility to PSHD, whereas HLA-DQA1*0501 (OR=0.29, P≤0.001) and DQB1*0301 (OR=0.58, P=0.007) were protective factors against the disease. We further suggested that the DRB1*0901-DQB1*0201, DRB1*0901-DQB1*0303 and A1-B8 haplotypes

  4. The importance of non-HLA antibodies in transplantation.

    PubMed

    Zhang, Qiuheng; Reed, Elaine F

    2016-08-01

    The development of post-transplantation antibodies against non-HLA autoantigens is associated with rejection and decreased long-term graft survival. Although our knowledge of non-HLA antibodies is incomplete, compelling experimental and clinical findings demonstrate that antibodies directed against autoantigens such as angiotensin type 1 receptor, perlecan and collagen, contribute to the process of antibody-mediated acute and chronic rejection. The mechanisms that underlie the production of autoantibodies in the setting of organ transplantation is an important area of ongoing investigation. Ischaemia-reperfusion injury, surgical trauma and/or alloimmune responses can result in the release of organ-derived autoantigens (such as soluble antigens, extracellular vesicles or apoptotic bodies) that are presented to B cells in the context of the transplant recipient's antigen presenting cells and stimulate autoantibody production. Type 17 T helper cells orchestrate autoantibody production by supporting the proliferation and maturation of autoreactive B cells within ectopic tertiary lymphoid tissue. Conversely, autoantibody-mediated graft damage can trigger alloimmunity and the development of donor-specific HLA antibodies that can act in synergy to promote allograft rejection. Identification of the immunologic phenotypes of transplant recipients at risk of non-HLA antibody-mediated rejection, and the development of targeted therapies to treat such rejection, are sorely needed to improve both graft and patient survival. PMID:27345243

  5. Dual, HLA-B27 Subtype-dependent Conformation of a Self-peptide

    PubMed Central

    Hülsmeyer, Martin; Fiorillo, Maria Teresa; Bettosini, Francesca; Sorrentino, Rosa; Saenger, Wolfram; Ziegler, Andreas; Uchanska-Ziegler, Barbara

    2004-01-01

    The products of the human leukocyte antigen subtypes HLA-B*2705 and HLA-B*2709 differ only in residue 116 (Asp vs. His) within the peptide binding groove but are differentially associated with the autoimmune disease ankylosing spondylitis (AS); HLA-B*2705 occurs in AS-patients, whereas HLA-B*2709 does not. The subtypes also generate differential T cell repertoires as exemplified by distinct T cell responses against the self-peptide pVIPR (RRKWRRWHL). The crystal structures described here show that pVIPR binds in an unprecedented dual conformation only to HLA-B*2705 molecules. In one binding mode, peptide pArg5 forms a salt bridge to Asp116, connected with drastically different interactions between peptide and heavy chain, contrasting with the second, conventional conformation, which is exclusively found in the case of B*2709. These subtype-dependent differences in pVIPR binding link the emergence of dissimilar T cell repertoires in individuals with HLA-B*2705 or HLA-B*2709 to the buried Asp116/His116 polymorphism and provide novel insights into peptide presentation by major histocompatibility antigens. PMID:14734527

  6. HLA-A11 is associated with poor prognosis in childhood acute lymphoblastic leukemia (ALL).

    PubMed

    Orgad, S; Cohen, I J; Neumann, Y; Vogel, R; Kende, G; Ramot, B; Zaizov, R; Gazit, E

    1988-12-01

    A possible association between HLA antigens, susceptibility or resistance to leukemia, and responsiveness to treatment has been studied in 144 patients with childhood acute lymphoblastic leukemia (ALL) and compared to other prognostic factors, i.e. white blood cell (WBC) counts, age at onset, sex, ethnic origin, and cell surface markers. All sequentially newly diagnosed children (97) comprised the group for the prospective study (PSG) and were followed for 6 years. The group included 37 patients classified as T-ALL, 41 as CALLA+, 27 as NULL, 12 as B and pre-B, and 27 unclassified patients, who were diagnosed before 1980. During the follow-up period, 45 patients of the PSG died. Forty-seven patients designated long-term survivors (LTS) have been followed 6-20 years after diagnosis, having completed a 3-5 year course of anti-leukemia therapy, and having remained disease free thereafter. High WBC counts at diagnosis and T-cell-surface markers were associated with poor prognosis, as were enthnic origin and specific HLA antigens. Thus, there was one (1) a significant increase in HLA-A30 and a decrease in HLA B-14 in the PSG Jewish patients; and (2) a complete absence of HLA-ALL in LTS while, in the PSG, 8 of 9 HLA-All-positive patients died during the follow-up period. This suggests that HLA-All is associated with poor prognosis in childhood ALL. PMID:3199882

  7. Clinical Relevance of HLA Gene Variants in HBV Infection

    PubMed Central

    Wang, Li; Zou, Zhi-Qiang; Wang, Kai

    2016-01-01

    Host gene variants may influence the natural history of hepatitis B virus (HBV) infection. The human leukocyte antigen (HLA) system, the major histocompatibility complex (MHC) in humans, is one of the most important host factors that are correlated with the clinical course of HBV infection. Genome-wide association studies (GWASs) have shown that single nucleotide polymorphisms (SNPs) near certain HLA gene loci are strongly associated with not only persistent HBV infection but also spontaneous HBV clearance and seroconversion, disease progression, and the development of liver cirrhosis and HBV-related hepatocellular carcinoma (HCC) in chronic hepatitis B (CHB). These variations also influence the efficacy of interferon (IFN) and nucleot(s)ide analogue (NA) treatment and response to HBV vaccines. Meanwhile, discrepant conclusions were reached with different patient cohorts. It is therefore essential to identify the associations of specific HLA allele variants with disease progression and viral clearance in chronic HBV infection among different ethnic populations. A better understanding of HLA polymorphism relevance in HBV infection outcome would enable us to elucidate the roles of HLA SNPs in the pathogenesis and clearance of HBV in different areas and ethnic groups, to improve strategies for the prevention and treatment of chronic HBV infection. PMID:27243039

  8. Emerging topics and new perspectives on HLA-G.

    PubMed

    Fainardi, Enrico; Castellazzi, Massimiliano; Stignani, Marina; Morandi, Fabio; Sana, Gwenaëlle; Gonzalez, Rafael; Pistoia, Vito; Baricordi, Olavio Roberto; Sokal, Etienne; Peña, Josè

    2011-02-01

    Following the Fifth International Conference on non-classical HLA-G antigens (HLA-G), held in Paris in July 2009, we selected some topics which focus on emerging aspects in the setting of HLA-G functions. In particular, HLA-G molecules could play a role in: (1) various inflammatory disorders, such as multiple sclerosis, intracerebral hemorrhage, gastrointestinal, skin and rheumatic diseases, and asthma, where they may act as immunoregulatory factors; (2) the mechanisms to escape immune surveillance utilized by several viruses, such as human cytomegalovirus, herpes simplex virus type 1, rabies virus, hepatitis C virus, influenza virus type A and human immunodeficiency virus 1 (HIV-1); and (3) cytokine/chemokine network and stem cell transplantation, since they seem to modulate cell migration by the downregulation of chemokine receptor expression and mesenchymal stem cell activity blocking of effector cell functions and the generation of regulatory T cells. However, the immunomodulatory circuits mediated by HLA-G proteins still remain to be clarified. PMID:21080027

  9. Advances in the study of HLA-restricted epitope vaccines

    PubMed Central

    Zhao, Lingxiao; Zhang, Min; Cong, Hua

    2013-01-01

    Vaccination is a proven strategy for protection from disease. An ideal vaccine would include antigens that elicit a safe and effective protective immune response. HLA-restricted epitope vaccines, which include T-lymphocyte epitopes restricted by HLA alleles, represent a new and promising immunization approach. In recent years, research in HLA-restricted epitope vaccines for the treatment of tumors and for the prevention of viral, bacterial, and parasite-induced infectious diseases have achieved substantial progress. Approaches for the improvement of the immunogenicity of epitope vaccines include (1) improving the accuracy of the methods used for the prediction of epitopes, (2) making use of additional HLA-restricted CD8+ T-cell epitopes, (3) the inclusion of specific CD4+ T-cell epitopes, (4) adding B-cell epitopes to the vaccine construction, (5) finding more effective adjuvants and delivery systems, (6) using immunogenic carrier proteins, and (7) using multiple proteins as epitopes sources. In this manuscript, we review recent research into HLA-restricted epitope vaccines. PMID:23955319

  10. Many de novo donor-specific antibodies recognize β2 -microglobulin-free, but not intact HLA heterodimers.

    PubMed

    Michel, K; Santella, R; Steers, J; Sahajpal, A; Downey, F X; Thohan, V; Oaks, M

    2016-05-01

    Solid-phase single antigen bead (SAB) assays are standard of care for detection and identification of donor-specific antibody (DSA) in patients who receive solid organ transplantation (SOT). While several studies have documented the reproducibility and sensitivity of SAB testing for DSA, there are little data available concerning its specificity. This study describes the identification of antibodies to β2 -microglobulin-free human leukocyte antigen (β2 -m-fHLA) heavy chains on SAB arrays and provides a reassessment of the clinical relevance of DSA testing by this platform. Post-transplant sera from 55 patients who were positive for de novo donor-specific antibodies on a SAB solid-phase immunoassay were tested under denaturing conditions in order to identify antibodies reactive with β2 -m-fHLA or native HLA (nHLA). Antibodies to β2 -m-fHLA were present in nearly half of patients being monitored in the post-transplant period. The frequency of antibodies to β2 -m-fHLA was similar among DSA and HLA antigens that were irrelevant to the transplant (non-DSA). Among the seven patients with clinical or pathologic antibody-mediated rejection (AMR), none had antibodies to β2 -m-fHLA exclusively; thus, the clinical relevance of β2 -m-fHLA is unclear. Our data suggests that SAB testing produces false positive reactions due to the presence of β2 -m-fHLA and these can lead to inappropriate assignment of unacceptable antigens during transplant listing and possibly inaccurate identification of DSA in the post-transplant period. PMID:27060279

  11. [Distribution and frequency of HLA alleles and haplotypes in Brazilians with type 1 diabetes mellitus].

    PubMed

    Alves, Crésio; Meyer, Isadora; Vieira, Nara; Toralles, Maria Betânia P; LeMaire, Denise

    2006-06-01

    The genetic predisposition to type 1 diabetes (DM1) is associated with genes of the human leukocyte antigen (HLA) system, specially the HLA-DR and -DQ. In Caucasians, the HLA-DR3 and -DR4 antigens are associated with susceptibility and the -DR2, with protection. In Brazil, a country with a large miscegenation of European Caucasians, Native Amerindians and African Blacks, the genetic basis of DM1 has not been adequately studied. The aim of this paper is to present a critical review of articles indexed in the MEDLINE and LILACS-BIREME data basis about the association of HLA with DM1 in Brazilians. Eight papers, all of them from the Southeast region, were found. Immunogenetic susceptibility to DM1 in Brazilians was associated with HLA-DRB1*03, -DRB*04, -DQB1*0201, -DQB1*0302 alleles, and protection against DM1 was associated with HLA-DQB1*0602, -DQB1*0301 alleles and -DR2 and -DR7 antigens. Since the Brazilian population is not racially homogeneous, it is not possible to extrapolate studies from a single region to the remainder of the country. It is necessary to study populations from different regions to identify new associations or to strengthen associations with the ones already identified. This knowledge will contribute to future prophylactic or therapeutic interventions in the group of Brazilians at risk of developing DM1. PMID:16936983

  12. Better allele-level matching improves transplant-related mortality after double cord blood transplantation

    PubMed Central

    Oran, Betül; Cao, Kai; Saliba, Rima M.; Rezvani, Katayoun; de Lima, Marcos; Ahmed, Sairah; Hosing, Chitra M.; Popat, Uday R.; Carmazzi, Yudith; Kebriaei, Partow; Nieto, Yago; Rondon, Gabriela; Willis, Dana; Shah, Nina; Parmar, Simrit; Olson, Amanda; Moore, Brandt; Marin, David; Mehta, Rohtesh; Fernández-Viña, Marcelo; Champlin, Richard E.; Shpall, Elizabeth J.

    2015-01-01

    Cord blood transplant requires less stringent human leukocyte antigen matching than unrelated donors. In 133 patients with hematologic malignancies who engrafted after double cord blood transplantation with a dominant unit, we studied the effect of high resolution testing at 4 loci (-A, -B, -C, -DRB1) for its impact on 2-year transplant-related mortality. Ten percent of the dominant cord blood units were matched at 7–8/8 alleles using HLA-A, -B, -C, and -DRB1; 25% were matched at 6/8, 40% at 5/8, and 25% at 4/8 or less allele. High resolution typing at 4 loci showed that there was no 2-year transplant-related mortality in 7–8/8 matched patients. Patients with 5–6/8 matched dominant cord blood units had 2-year transplant-related mortality of 39% while patients with 4/8 or less matched units had 60%. Multivariate regression analyses confirmed the independent effect of high resolution typing on the outcome when adjusted for age, diagnosis, CD34+ cell dose infused, graft manipulation and cord to cord matching. The worst prognostic group included patients aged over 32 years with 4/8 or less matched cord blood units compared with patients who were either younger than 32 years old independent of allele-level matching, or aged over 32 years but with 5–6/8 matched cord blood units (Hazard Ratio 2.2; 95% confidence interval: 1.3–3.7; P<0.001). Patients with 7–8/8 matched units remained the group with the best prognosis. Our data suggest that high resolution typing at 4 loci and selecting cord blood units matched at at least 5/8 alleles may reduce transplant-related mortality after double cord blood transplantation. PMID:26250579

  13. [Genetic aspects in multiple sclerosis. II: HLA system].

    PubMed

    De Rezende, P A; Arruda, W O

    1996-09-01

    Review of studies about HLA antigens and multiple sclerosis (MS). The HLA system, in special class II antigens, subregions DR and DQ, is probably involved in the immunopathogenesis of MS. Haplotype DRB1*1501.DQA1*0102.DQB1*0602, corresponding to phenotype DR2.Dw2.DQ6, is positively associated with MS in several caucasoid populations. Clinical heterogeneity of MS, as well as different diagnostic criteria adopted by investigators are potential sources of confusion and may lead to discrepant results. A better standardization of clinical and laboratorial methodology, appropriate subdivision of patients with different clinical forms of MS, may allow a more accurate evaluation of the role of genetic factors in the pathogenesis of MS. PMID:9109989

  14. A strong association between thyrotropin receptor-blocking antibody-positive atrophic autoimmune thyroiditis and HLA-DR8 and HLA-DQB1 0302 in Koreans

    SciTech Connect

    Cho, Bo Youn; Chung, Jae Hoon; Lee, Hong Kyu; Koh, Chang-Soon; Lee, Jung-Bin ); Shong, Young Kee ); Han, Hoon ); Chang, Youn Bok )

    1993-09-01

    The authors investigated whether the associations between HLA alleles of patients with autoimmune hypothyroidism varied according to the presence or absence of TSH receptor-blocking antibody (TRBab). They analyzed the HLA-A, -B, -C, and -DR antigens by serotyping and the DQA1 and DQB1 genes using both enzymatic DNA amplification and sequence-specific oligonucleotide hybridizations. The patient population consisted of 47 Korean patients with atrophic autoimmune thyroiditis and 62 patients with goitrous autoimmune thyroiditis. The antigen frequency of HLA-DR8 was significantly increased in 23 atrophic autoimmune thyroiditis patients that were positive for TSH binding inhibitor immunoglobulin (TBII) compared to 136 controls [52% vs. 16%; x[sup 2] = 13.1; Pc (corrected P value) = 0.003]. This relative risk was 5.7; the etiological fraction was 0.43. HLA-DQB1*0302 was also increased in patients with TBII-positive atrophic autoimmune thyroiditis (24% vs. 7%; x[sup 2] = 11.2; Pc = 0.012; relative risk = 4.4; etiological fraction = 0.19). No specific DR antigens or DQB1 alleles were increased in either TBII-negative atrophic autoimmune thyroidities or goitrous autoimmune thyroiditis. A significant decrease in the frequency of HLA-DR6 antigen was observed in both TBII-positive atrophic antoimmune thyroiditis (0% vs. 32%; x[sup 2] = 8.4; Pc = 0.03) and goitrous autoimmune thyroiditis (0% vs. 32%; x[sup 2] = 23.2; Pc < 0.001) patients. The frequency of the HLC-Cwl antigen was significantly increased in all patient groups. The authors conclude that TRBab-positive atrophic autoimmune thyroiditis is immunogenetically different from both goitrous autoimmune thyroiditis and TRBab-negative atrophic autoimmune thyroiditis. It is possible that HLA-DR8 and/or DQB1*0302 may be related to the susceptibility genes involved in the production of TRBab in Koreans. 32 refs., 5 tabs.

  15. Characterization of a new HLA-B allele (B{sup *}3702) generated by an intronic recombination event

    SciTech Connect

    Santos, S.; Vicario, J.L.; Merino, J.L.; Balas, A.

    1996-12-31

    Routine serological HLA typing of s Syrian family revealed a Bw4-associated HLA-B blank antigen showing Mendelian segregation together with the haplotype A1, Cw2, DR11, DQ7 (a father and one of his children, cells NO. 5958641 and No. 1958125). A more extensive serological analysis was done by using additional polyclonal and monoclonal antibodies (mAb; One-Lambda BL-60 and LM172 plates) as well as the 12th International Workshop class I mAb plate. Both cells showed no conclusive typing reactions with sera towards HLA-B27 and HLA-B37 antigens. Two mAb, PAMELA (27,44,38) and FAY (13,27,37,47), were able to recognize this antigen. The great majority of polyclonal reagents against B37 showed negative reactions, while weak results were frequently observed with anti-B27 allosera. 8 refs., 1 fig., 1 tab.

  16. Methylation of CIITA promoter IV causes loss of HLA-II inducibility by IFN-γ in promyelocytic cells

    PubMed Central

    De Ambrosis, Alessandro; Banelli, Barbara; Pira, Giuseppina Li; Aresu, Ottavia; Romani, Massimo; Ferrini, Silvano; Accolla, Roberto S.

    2008-01-01

    The human promyelocytic cell line THP-1 expresses high level of HLA class II (HLA-II) molecules after IFN-γ treatment. Here, we report a variant of THP-1 that does not express HLA-II after IFN-γ. The variant's HLA-II phenotype is constant over time in culture and it is not related to a defective IFN-γ-signalling pathway. Transfection of CIITA, the HLA-II transcriptional activator, under the control of a cytomegalovirus promoter rescues high level of HLA-DR surface expression in the variant indicating that the biosynthetic block resides in the expression of CIITA and not in the CIITA-dependent transactivation of the HLA-II promoters. Treatment of the variant with 5-azacytidine (5-aza), which inhibits CpG methylation, restores inducibility of HLA-II by IFN-γ both at transcriptional and phenotypic level and antigen presenting and processing function of the variant. DNA studies demonstrate that the molecular defect of the THP-1 variant originates from the methylation of the CIITA promoter IV. Furthermore, treatment with 5-aza produces a substantial demethylation of CIITA promoter IV and a significant increase of IFN-γ-dependent HLA-II expression in another myelomonocytic cell line, U937. Therefore hyper-methylation of CIITA promoter IV may be a relevant mechanism of epigenetic control preventing HLA-II IFN-γ inducibility in the myelomonocytic cell lineage. PMID:18829986

  17. Differential expression of HLA-G and ILT-2 receptor in human tuberculosis: Localized versus disseminated disease.

    PubMed

    Saurabh, Abhinav; Thakral, Deepshi; Mourya, Manish K; Singh, Amar; Mohan, Anant; Bhatnagar, Anuj K; Mitra, Dipendra K; Kanga, Uma

    2016-09-01

    Human leukocyte antigen-G (HLA-G) is an anti-inflammatory and immunosuppressive molecule that can modulate immune cell activation. The role of HLA-G in tuberculosis, an immune-mediated and chronic bacterial disease remains to be elucidated. We investigated the expression profile of soluble and membrane bound HLA-G in pulmonary TB (PTB), TB pleural effusion (TB-PE, localized disease) and Miliary TB (disseminated form). The expression of HLA-G receptor, ILT-2 was also determined on the immune cells. We observed that the plasma sHLA-G levels were significantly increased in Miliary TB than in TB-PE patients. In contrast, immunophenotyping revealed that the percent frequency of CD3(+) T cells expressing HLA-G was significantly reduced in Miliary TB as compared to TB-PE, whereas frequency of CD14(+) monocytes expressing HLA-G was significantly higher in TB-PE patients. Strikingly in the TB-PE cases, comparison of disease site, i.e. pleural effusion with peripheral blood showed increased expression of both soluble and surface HLA-G, whereas ILT-2 expressing cells were reduced at the local disease site. Furthermore, we demonstrated that in TB-PE cases, HLA-G expression on CD3(+) T cells was influenced by broad spectrum MMP inhibitor. Thus, differential expression of HLA-G could potentially be a useful biomarker to distinguish different states of TB disease. PMID:26776460

  18. Regulatory T cells modulate granulomatous inflammation in an HLA-DP2 transgenic murine model of beryllium-induced disease.

    PubMed

    Mack, Douglas G; Falta, Michael T; McKee, Amy S; Martin, Allison K; Simonian, Philip L; Crawford, Frances; Gordon, Terry; Mercer, Robert R; Hoover, Mark D; Marrack, Philippa; Kappler, John W; Tuder, Rubin M; Fontenot, Andrew P

    2014-06-10

    Susceptibility to chronic beryllium disease (CBD) is linked to certain HLA-DP molecules, including HLA-DP2. To elucidate the molecular basis of this association, we exposed mice transgenic (Tg) for HLA-DP2 to beryllium oxide (BeO) via oropharyngeal aspiration. As opposed to WT mice, BeO-exposed HLA-DP2 Tg mice developed mononuclear infiltrates in a peribronchovascular distribution that were composed of CD4(+) T cells and included regulatory T (Treg) cells. Beryllium-responsive, HLA-DP2-restricted CD4(+) T cells expressing IFN-γ and IL-2 were present in BeO-exposed HLA-DP2 Tg mice and not in WT mice. Using Be-loaded HLA-DP2-peptide tetramers, we identified Be-specific CD4(+) T cells in the mouse lung that recognize identical ligands as CD4(+) T cells derived from the human lung. Importantly, a subset of HLA-DP2 tetramer-binding CD4(+) T cells expressed forkhead box P3, consistent with the expansion of antigen-specific Treg cells. Depletion of Treg cells in BeO-exposed HLA-DP2 Tg mice exacerbated lung inflammation and enhanced granuloma formation. These findings document, for the first time to our knowledge, the development of a Be-specific adaptive immune response in mice expressing HLA-DP2 and the ability of Treg cells to modulate the beryllium-induced granulomatous immune response. PMID:24912188

  19. An Anti-C1s Monoclonal, TNT003, Inhibits Complement Activation Induced by Antibodies Against HLA.

    PubMed

    Thomas, K A; Valenzuela, N M; Gjertson, D; Mulder, A; Fishbein, M C; Parry, G C; Panicker, S; Reed, E F

    2015-08-01

    Antibody-mediated rejection (AMR) of solid organ transplants (SOT) is characterized by damage triggered by donor-specific antibodies (DSA) binding donor Class I and II HLA (HLA-I and HLA-II) expressed on endothelial cells. While F(ab')2 portions of DSA cause cellular activation and proliferation, Fc regions activate the classical complement cascade, resulting in complement deposition and leukocyte recruitment, both hallmark features of AMR. We characterized the ability of an anti-C1s monoclonal antibody, TNT003, to inhibit HLA antibody (HLA-Ab)-induced complement activation. Complement deposition induced by HLA-Ab was evaluated using novel cell- and bead-based assays. Human aortic endothelial cells (HAEC) were cultured with HLA-Ab and human complement; production of activated complement proteins was measured by flow cytometry. Additionally, C3d deposition was measured on single antigen beads (SAB) mixed with HLA-Ab and human complement. TNT003 inhibited HLA-Ab mediated complement deposition on HAEC in a concentration-dependent manner; C3a, C4a and C5a anaphylatoxin production was also diminished by TNT003. Finally, TNT003 blocked C3d deposition induced by Class I (HLAI-Ab)- and Class II (HLAII-Ab)-specific antibodies on SAB. These data suggest TNT003 may be useful for modulating the effects of DSA, as TNT003 inhibits complement deposition and split product formation generated by HLA-I/II-Ab in vitro. PMID:25904443

  20. Primary sclerosing cholangitis in genetically diverse populations listed for liver transplantation: Unique clinical and HLA associations

    PubMed Central

    Bowlus, Christopher L.; Li, Chin-Shang; Karlsen, Tom H.; Lie, Benedicte A.; Selmi, Carlo

    2010-01-01

    Primary sclerosing cholangitis (PSC) is well characterized in European populations. We aimed to characterize clinical characteristics and human leukocyte antigen (HLA) associations in a population of European American, Hispanic and African-American PSC patients listed for liver transplantation. Demographic, clinical, and HLA data stratified by population from 6,767 liver transplant (LT) registrants of the United Network for Organ Sharing (UNOS) with a diagnosis of PSC (4.7% of registrants) were compared to registrants with other diagnoses. Compared to European Americans and Hispanics, African American cases were significantly younger (46.6 ± 13.7, 42.3 ± 15.9, and 39.7 ± 13.1, respectively; p = 0.002), listed with a higher Model of End Stage Liver Disease (MELD) score (15.2 ± 7.5, 14.9 ± 7.6, and 18.1 ± 9.3, respectively; p = 0.001), and less frequently noted to have inflammatory bowel disease (71.4% versus 60.5%, p < 0.01) compared to European Americans. In multivariate analysis, African origin was a significant factor associated with listing for LT with PSC (OR relative to European Americans 1.33, 95% C.I. 1.27 – 1.41). HLA associations in European Americans, Hispanics and African Americans with PSC compared to alcoholic liver disease were detected for HLA-B8, HLA-DR13 and the protective HLA-DR4. However, HLA-DR3, which is in linkage disequilibrium with HLA-B8, only showed associations in European Americans and Hispanics. African Americans with PSC listed for LT differ clinically from European Americans and Hispanics. The association with HLA-B8 but not HLA-DR3 in African Americans should make possible the refinement of the HLA associations in PSC. PMID:21031548

  1. Role of Chlamydia trachomatis and HLA-B27 in sexually acquired reactive arthritis.

    PubMed Central

    Keat, A C; Maini, R N; Nkwazi, G C; Pegrum, G D; Ridgway, G L; Scott, J T

    1978-01-01

    Inflammatory arthritis, tendinitis, and fasciitis after non-specific urethritis ("sexually acquired reactive arthritis" (SARA)) was studied prospectively in 531 men with non-specific urethritis, with particular reference to the frequency of isolation of Chlamydia trachomatis and the presence of HLA-B27. Satisfactory cultures were obtained from the urethral swabs from 384 patients; and HLA typing was performed on 482, of whom 30 (6%) were HLA-B27-positive. Arthritis developed in 16 patients, and five of the 14 (36%) with satisfactory cultures were positive for C trachomatis; 135 of the patients without arthritis were also positive for C trachomatis, an identical proportion. Seven of the 15 patients (40%) with arthritis who were HLA-typed were HLA-B27-positive. Six of the 30 patients with HLA-B27 developed peripheral arthritis in contrast to only nine of the 452 patients lacking the antigen, suggesting a tenfold increase susceptibility. C trachomatis, however, was no more prevalent in cultures from HLA-B27-positive men than from the others. Thus carriage of C trachomatis is unlikely to be influenced by HLA-B27. C trachomatis may be an important pathogen in some cases of SARA but does not appear to be an exclusive trigger factor for this condition. PMID:630254

  2. Distribution of HLA haplotypes across Japanese Archipelago: similarity, difference and admixture.

    PubMed

    Nakaoka, Hirofumi; Inoue, Ituro

    2015-11-01

    The human leukocyte antigen (HLA) region is the most polymorphic region in the human genome. The polymorphic nature of the HLA region is thought to have been shaped from balancing selection. The complex migration events during the Out-of-Africa expansion have influenced geographic patterns of HLA allele frequencies and diversities across present-day human populations. Differences in the HLA allele frequency may contribute geographic differences in the susceptibility to many diseases, such as infectious, autoimmune and metabolic diseases. Here we briefly reviewed characteristics of frequency distribution of HLA alleles and haplotypes in Japanese population. A large part of HLA alleles and haplotypes that are common in Japanese are shared with neighboring Asian populations. The differentiations in HLA alleles and haplotypes across Japanese regional populations may provide clues to model for peopling of Japanese Archipelago and for design of genetic association studies. Finally, we introduce recent topics that new HLA alleles derived from ancient admixtures with Neanderthals and Denisovans are thought to have played an important role in the adaptation of modern humans to local pathogens during Out-of-Africa expansion. PMID:26202576

  3. Role of microRNAs on HLA-G expression in human tumors.

    PubMed

    Seliger, Barbara

    2016-09-01

    The non-classical human leukocyte antigen G (HLA-G) known to protect the embryo from immune cell destruction leading to fetal maternal tolerance is often overexpressed in human tumors of distinct origin thereby leading to an escape from T and NK cell-mediated immune response. The molecular mechanisms controlling HLA-G expression are complex and involve deregulation at the transcriptional, epigenetic and posttranscriptional level. Using bioinformatics and high through put analyses a number of microRNAs (miRs) have been identified, which were able to bind to the 3' UTR of HLA-G with distinct efficacy. This caused by a downregulation of HLA-G surface expression, which was associated with an increased immune response thereby overcoming the HLA-G-mediated immune tolerance. Reduced expression of HLA-G-specific miRs was associated with tumor progression and metastases and appear to affect directly or indirectly tumor characteristics, such as cell proliferation, apoptosis and resistance to chemotherapy. Recently, an interaction between long non-coding RNAs, such as HOTAIR, and HLA-G-specific miRs has also been demonstrated. This review summarizes the control of HLA-G expression and function by microRNAs as well as its clinical significance. PMID:27142884

  4. Associations of HLA-A, -B and -DRB1 Types with Oral Diseases in Swiss Adults

    PubMed Central

    Mauramo, Matti; Ramseier, Adrian Markus; Buser, Andreas; Tiercy, Jean-Marie; Weiger, Roland; Waltimo, Tuomas

    2014-01-01

    Human leukocyte antigens (HLA) are crucial components of host defense against microbial challenge but the associations of HLA types with oral infectious diseases have not been studied in detail. This prospective cross-sectional study examined associations of HLA-A, -B and -DRB1 types with common oral diseases in a healthy Swiss adult population. 257 subjects (107 m, 150 f, mean age: 43.5 yr; range: 21–58 yr) with known HLA-A, -B and -DRB1 profiles and comprehensive medical records were included. A thorough anamnesis was followed by oral examinations including saliva flow measurements, the DMFT score for cariological status, complete periodontal status with plaque and bleeding indexes as well as assessment of mucosal alterations and temporomandibular dysfunction (TMD). Student’s t-test and Pearson chi-square test were utilized to compare the oral diseases between HLA positive and negative subjects. Bonferroni correction for multiple comparisons was used and PBonf<0.05 was considered statistically significant. HLA types -B15 (PBonf = 0.002), -B51 (PBonf = 0.02) and -DRB1*12 (PBonf = 0.02) were associated with less periodontal disease manifestations. HLA-A32 had a positive association with TMD dysfunction (PBonf = 0.012). No other statistically significant associations were observed. In conclusion, HLA types may contribute to the development of oral diseases in generally healthy Caucasian adults. PMID:25072155

  5. HLA genetic diversity in Hungarians and Hungarian Gypsies: complementary differentiation patterns and demographic signals revealed by HLA-A, -B and -DRB1 in Central Europe.

    PubMed

    Inotai, D; Szilvasi, A; Benko, S; Boros-Major, A; Illes, Z; Bors, A; Kiss, K P; Rajczy, K; Gelle-Hossó, A; Buhler, S; Nunes, J M; Sanchez-Mazas, A; Tordai, A

    2015-08-01

    Systematic analyses of human leukocyte antigen (HLA) profiles in different populations may increase the efficiency of bone marrow donor selection and help reconstructing human peopling history. We typed HLA-A, -B, and -DRB1 allele groups in two bone marrow donor cohorts of 2402 Hungarians and 186 Hungarian Gypsies and compared them with several Central-European, Spanish Gypsy, and Indian populations. Our results indicate that different European Gypsy populations share a common origin but diverged genetically as a consequence of founder effect and rapid genetic drift, whereas other European populations are related genetically in relation to geography. This study also suggests that while HLA-A accurately depicts the effects of genetic drift, HLA-B, and -DRB1 conserve more signatures of ancient population relationships, as a result of balancing selection. PMID:26149581

  6. The prognostic impact of soluble and vesicular HLA-G and its relationship to circulating tumor cells in neoadjuvant treated breast cancer patients.

    PubMed

    König, Lisa; Kasimir-Bauer, Sabine; Hoffmann, Oliver; Bittner, Ann-Kathrin; Wagner, Bettina; Manvailer, Luis Felipe Santos; Schramm, Sabine; Bankfalvi, Agnes; Giebel, Bernd; Kimmig, Rainer; Horn, Peter A; Rebmann, Vera

    2016-09-01

    The non-classical human leukocyte antigen G (HLA-G) molecule and its soluble forms exert multiple immune suppressive regulatory functions in malignancy and in stem cells contributing to immune escape mechanisms. HLA-G can be secreted as free soluble HLA-G molecules or via extracellular vesicles (EVs). Here we evaluated these soluble HLA-G forms as prognostic marker for prediction of the clinical outcome of neoadjuvant chemotherapy (NACT) treated breast cancer (BC) patients. Plasma samples of BC patients procured before (n=142) and after (n=154) NACT were quantified for total soluble HLA-G (sHLA-Gtot) and HLA-G levels in ExoQuick™ derived EV fractions (sHLA-GEV) by ELISA. The corresponding increments were specified as free sHLA-G (sHLA-Gfree). Total and free sHLA-G were significantly increased in NACT treated BC patients compared to healthy controls (n=16). High sHLA-Gfree levels were exclusively associated to estrogen receptor expression before NACT. Importantly, high sHLA-GEV levels before NACT were related to disease progression and the detection of stem cell-like circulating tumor cells, but high sHLA-Gfree levels indicated an improved clinical outcome. Thus, this study demonstrates for the first time that the different sHLA-G subcomponents represent dissimilar qualitative prognostic impacts on the clinical outcome of NACT treated BC patients, whereas the total sHLA-G levels without separating into subcomponents are not related to clinical outcome. PMID:26796737

  7. MHC class II super-enhancer increases surface expression of HLA-DR and HLA-DQ and affects cytokine production in autoimmune vitiligo

    PubMed Central

    Cavalli, Giulio; Hayashi, Masahiro; Jin, Ying; Yorgov, Daniel; Santorico, Stephanie A.; Holcomb, Cherie; Rastrou, Melinda; Erlich, Henry; Tengesdal, Isak W.; Dagna, Lorenzo; Neff, C. Preston; Palmer, Brent E.; Spritz, Richard A.; Dinarello, Charles A.

    2016-01-01

    Genetic risk for autoimmunity in HLA genes is most often attributed to structural specificity resulting in presentation of self-antigens. Autoimmune vitiligo is strongly associated with the MHC class II region. Here, we fine-map vitiligo MHC class II genetic risk to three SNPs only 47 bp apart, located within a predicted super-enhancer in an intergenic region between HLA-DRB1 and HLA-DQA1, localized by a genome-wide association study of 2,853 Caucasian vitiligo patients. The super-enhancer corresponds to an expression quantitative trait locus for expression of HLA-DR and HLA-DQ RNA; we observed elevated surface expression of HLA-DR (P = 0.008) and HLA-DQ (P = 0.02) on monocytes from healthy subjects homozygous for the high-risk SNP haplotype. Unexpectedly, pathogen-stimulated peripheral blood mononuclear cells from subjects homozygous for the high-risk super-enhancer haplotype exhibited greater increase in production of IFN-γ and IL-1β than cells from subjects homozygous for the low-risk haplotype. Specifically, production of IFN-γ on stimulation of dectin-1, mannose, and Toll-like receptors with Candida albicans and Staphylococcus epidermidis was 2.5- and 2.9-fold higher in high-risk subjects than in low-risk subjects, respectively (P = 0.007 and P = 0.01). Similarly, production of IL-1β was fivefold higher in high-risk subjects than in low-risk subjects (P = 0.02). Increased production of immunostimulatory cytokines in subjects carrying the high-risk haplotype may act as an “adjuvant” during the presentation of autoantigens, tying together genetic variation in the MHC with the development of autoimmunity. This study demonstrates that for risk of autoimmune vitiligo, expression level of HLA class II molecules is as or more important than antigen specificity. PMID:26787888

  8. Mechanism of a lymphocyte abnormality associated with HLA-B8/DR3 in clinically healthy individuals.

    PubMed Central

    Hashimoto, S; McCombs, C C; Michalski, J P

    1989-01-01

    An important unanswered question in clinical immunology is why the histocompatibility antigens HLA-B8/DR3 should be associated with at least nine quite different immune-mediated diseases. The purpose of this study was to examine the mechanism of an immunologic abnormality, commonly found in healthy individuals with HLA-DR3, that may reflect an immune defect predisposing to autoimmunity. Fourteen healthy subjects with HLA-DR3 had a proliferative response to a suboptimal concentration of PHA nearly eight-fold lower than that observed in 10 individuals without this HLA antigen. Impaired responsiveness to PHA was more strongly associated with HLA-DR3 than with HLA-B8. The IL-2 concentration in mitogen-stimulated cultures was similarly decreased in subjects with HLA-DR3 and was highly predictive of the proliferative response 24 h later (r = 0.82, P less than 0.0001). Inhibition of IL-2 utilization by anti-IL-2 receptor antibody indicated that the reduced IL-2 concentration reflects impaired lymphokine production rather than increased utilization. Expression of IL-2 receptors is decreased in these subjects, although the magnitude of their proliferative response is appropriate for the available lymphokine. These results indicate that impaired lymphocyte activation associated with HLA-DR3 reflects impaired IL-2 production and an abnormality of activation events preceding the production of this lymphokine. PMID:2787712

  9. Mapping the HLA diversity of the Iberian Peninsula.

    PubMed

    Romòn, Iñigo; Montes, Carmen; Ligeiro, Dario; Trindade, Hélder; Sanchez-Mazas, Alicia; Nunes, José Manuel; Buhler, Stéphane

    2016-10-01

    The polymorphism of HLA genes can be used to reconstruct human peopling history. However, this huge diversity impairs successful matching in stem cell transplantation, a situation which has led to the recruitment of millions of donors worldwide. In parallel to the increase of recruitment, registries are progressively relying on information from population genetics to optimize their donor pools in terms of HLA variability. In this study, the HLA data of 65,000 Spanish bone marrow donors were analyzed together with 60,000 Portuguese individuals to provide a comprehensive HLA genetic map of the Iberian Peninsula. The frequencies of many alleles were shown to vary continuously across the Peninsula, either increasing or decreasing from the Mediterranean coast to the Atlantic domain or from the Strait of Gibraltar to the Pyrenees and Bay of Biscay. Similar patterns were observed for several haplotypes. In addition, within some regions neighboring provinces share a close genetic similarity. These results outline the genetic landscape of the Iberian Peninsula, and confirm that the analysis of the HLA polymorphism may reveal relevant signatures of past demographic events even when data from donor registries are used. This conclusion stimulates future developments of the Spanish registry, presented here for the first time. PMID:27377016

  10. Cell surface antigens and function of monocytes and a monocyte-like cell line before and after infection with HIV.

    PubMed

    Mann, D L; Gartner, S; LeSane, F; Blattner, W A; Popovic, M

    1990-02-01

    The human immunodeficiency virus (HIV-1) preferentially infects cells that express the CD4 molecule, including monocytes and cells of the monocyte lineage. The monocyte-like cell line U937 and monocytes isolated from peripheral blood lymphocytes (PBL) were infected with HIV-1. Cell surface antigen expression was determined in infected and noninfected cells as was the ability to stimulate in mixed lymphocyte reaction. The CD4 antigen decreased in infected cells U937 and PBL monocytes. MHC class II antigens HLA-DR, HLA-DQ, and HLA-DP increased in HIV-1 infected U937 cells. In infected PBL-derived monocytes, HLA-DR increased, HLA-DQ decreased, and HLA-DP was unchanged. Infected U937 and PBL monocytes were capable of stimulating allogeneic lymphocytes, thus demonstrating retention of the alloantigen presentation function of HIV-1-infected monocytes. PMID:1967231

  11. Associations of HLA-A, HLA-B and HLA-C alleles frequency with prevalence of herpes simplex virus infections and diseases across global populations: implication for the development of an universal CD8+ T-cell epitope-based vaccine.

    PubMed

    Samandary, Sarah; Kridane-Miledi, Hédia; Sandoval, Jacqueline S; Choudhury, Zareen; Langa-Vives, Francina; Spencer, Doran; Chentoufi, Aziz A; Lemonnier, François A; BenMohamed, Lbachir

    2014-08-01

    A significant portion of the world's population is infected with herpes simplex virus type 1 and/or type 2 (HSV-1 and/or HSV-2), that cause a wide range of diseases including genital herpes, oro-facial herpes, and the potentially blinding ocular herpes. While the global prevalence and distribution of HSV-1 and HSV-2 infections cannot be exactly established, the general trends indicate that: (i) HSV-1 infections are much more prevalent globally than HSV-2; (ii) over a half billion people worldwide are infected with HSV-2; (iii) the sub-Saharan African populations account for a disproportionate burden of genital herpes infections and diseases; (iv) the dramatic differences in the prevalence of herpes infections between regions of the world appear to be associated with differences in the frequencies of human leukocyte antigen (HLA) alleles. The present report: (i) analyzes the prevalence of HSV-1 and HSV-2 infections across various regions of the world; (ii) analyzes potential associations of common HLA-A, HLA-B and HLA-C alleles with the prevalence of HSV-1 and HSV-2 infections in the Caucasoid, Oriental, Hispanic and Black major populations; and (iii) discusses how our recently developed HLA-A, HLA-B, and HLA-C transgenic/H-2 class I null mice will help validate HLA/herpes prevalence associations. Overall, high prevalence of herpes infection and disease appears to be associated with high frequency of HLA-A(∗)24, HLA-B(∗)27, HLA-B(∗)53 and HLA-B(∗)58 alleles. In contrast, low prevalence of herpes infection and disease appears to be associated with high frequency of HLA-B(∗)44 allele. The finding will aid in developing a T-cell epitope-based universal herpes vaccine and immunotherapy. PMID:24798939

  12. Associations of HLA-A, HLA-B and HLA-C Alleles Frequency with Prevalence of Herpes Simplex Virus Infections and Diseases Across Global Populations: Implication for the Development of an Universal CD8+ T-Cell Epitope-Based Vaccine

    PubMed Central

    Samandary, Sarah; Kridane-Miledi, Hédia; Sandoval, Jacqueline S.; Choudhury, Zareen; Langa-Vives, Francina; Spencer, Doran; Chentoufi, Aziz A.; Lemonnier, François A.; BenMohamed, Lbachir

    2014-01-01

    A significant portion of the world’s population is infected with herpes simplex virus type 1 and/or type 2 (HSV-1 and/or HSV-2), that cause a wide range of diseases including genital herpes, oro-facial herpes, and the potentially blinding ocular herpes. While the global prevalence and distribution of HSV-1 and HSV-2 infections cannot be exactly established, the general trends indicate that: (i) HSV-1 infections are much more prevalent globally than HSV-2; (ii) Over half billion people worldwide are infected with HSV-2; (iii) the sub-Saharan African populations account for a disproportionate burden of genital herpes infections and diseases; (iv) the dramatic differences in the prevalence of herpes infections between regions of the world appear to be associated with differences in the frequencies of human leukocyte antigen (HLA) alleles. The present report: (i) analyzes the prevalence of HSV-1 and HSV-2 infections across various regions of the world; (ii) analyzes potential associations of common HLA-A, HLA-B and HLA-C alleles with the prevalence of HSV-1 and HSV-2 infections in the Caucasoid, Oriental, Hispanic and Black major populations; and (iii) discusses how our recently developed HLA-A, HLA-B, and HLA-C transgenic/H-2 class I null mice will help validate HLA/herpes prevalence associations. Overall, high prevalence of herpes infection and disease appears to be associated with high frequency of HLA-A*24, HLA-B*27, HLA-B*53 and HLA-B*58 alleles. In contrast, low prevalence of herpes infection and disease appears to be associated with high frequency of HLA-B*44 allele. The finding will aid in developing a T-cell epitope-based universal herpes vaccine and immunotherapy. PMID:24798939

  13. Analysis of HLA class I-II haplotype frequency and segregation in a cohort of patients with advanced stage ovarian cancer.

    PubMed

    Gamzatova, Z; Villabona, L; van der Zanden, H; Haasnoot, G W; Andersson, E; Kiessling, R; Seliger, B; Kanter, L; Dalianis, T; Bergfeldt, K; Masucci, G V

    2007-09-01

    In solid tumors, human leucocyte antigen (HLA)-A2 has been suggested to be a risk factor and a negative prognostic factor. The HLA-A2 allele in Scandinavia has a high prevalence; it decreases with latitude and also with ovarian cancer mortality in Europe. Furthermore, an association of the HLA-A2 allele with severe prognosis in serous adenocarcinoma of the ovary in stages III-IV was found. Thirty-two unrelated Swedish women with relapsing or progressive ovarian cancer were analysed for the genotypes at the HLA-A, HLA-B, HLA-Cw, and HLA-DRB1 loci by the polymerase chain reaction/sequence-specific primer method. The frequencies of HLA alleles of healthy Swedish bone marrow donors provided by the coordinating centre of the Bone Marrow Donors Worldwide Registries, Leiden, the Netherlands were used as controls. When this cohort of epithelial ovarian cancer patients was compared with healthy Swedish donors, the frequency of HLA-A1 and HLA-A2 gene/phenotype appears, although not statistically significant, to be increased in patients with ovarian carcinoma, while HLA-A3 was decreased. HLA-A2 homozygotes were twofold higher in patients. The A2-B8 haplotype was significantly increased (corrected P value). A2-B5, A2-B15, A2-DRB1*03, A2-DRB1*04, A2-B15-Cw3, and A2-B8-DRB1*03 had odds ratio as well as the level of the lower confidence interval above 1 and significant P value only when considered as single, non-corrected analysis. HLA-B15 and HLA-Cw3 were only present in HLA-A2-positive patients showing that the HLA-A2-HLA-Cw3 and HLA-B15 haplotypes were segregated. In this selected cohort with advanced disease, there are indications of an unusual overrepresentation of HLA class I and II genes/haplotypes as well as segregation for the HLA-A2-HLA-Cw3 and HLA-B15 haplotypes. These findings are presented as a descriptive analysis and need further investigations on a larger series of ovarian cancer patients to establish prognostic associations. PMID:17661908

  14. NRAMP1, VDR, HLA-DRB1, and HLA-DQB1 Gene Polymorphisms in Susceptibility to Tuberculosis among the Chinese Kazakh Population: A Case-Control Study

    PubMed Central

    Wu, Fang; Zhang, Wanjiang; Zhang, Le; Wu, Jiangdong; Li, Chunzhu; Meng, Xianjie; Wang, Xi; He, Peng; Zhang, Jie

    2013-01-01

    Background. To explore the potential role of natural-resistance-associated macrophage protein 1 (NRAMP1) gene, vitamin D receptor (VDR) gene, (human leukocyte antigen, (HLA-DRB1) HLA) -DRB1 gene, and HLA-DQB1 gene polymorphisms in susceptibility to tuberculosis (TB) in the Chinese Kazakh population. Methods. A case-control study was performed on the Chinese Kazak population. Genetic polymorphisms of NRAMP1 gene (3′UTR) and VDR gene (TaqI and FokI) were analysed using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and sequencing analysis in TB patients and healthy controls. Genetic polymorphisms of HLA-DRB1 gene and HLA-DQB1 gene in the two groups were detected with polymerase chain reaction-sequence-specific primers (PCR-SSPs) technique and sequencing analysis. Results. There was statistically significant difference in the 3′UTR polymorphism between the TB patients and healthy controls in the Chinese Kazak population (P = 0.002; OR = 1.859; 95% CI = 1.182–2.926). Significant difference was observed in the FokI polymorphism between the TB patients and healthy controls (P = 0.001; OR = 1.530; 95% CI = 1.007–2.325). It does not disclose any significant association between the disease and TaqI (P > 0.05). Alleles HLA-DRB1∗04 and HLA-DQB1∗0201 occurred more frequently in patients than in controls (P = 0.011 and 0.002; OR = 1.889 and 1.802; 95% CI = 1.153–3.095 and 1.230–2.639, resp.). Conclusions. Polymorphisms in the NRAMP1 gene, VDR gene, HLA-DRB1 gene, and HLA-DQB1 gene are statistically associated with susceptibility to TB in the Chinese Kazakh population. PMID:24024195

  15. Association of HLA-DR4/HLA-DRB1*04 with Vogt-Koyanagi-Harada disease: A Systematic Review and Meta-analysis

    PubMed Central

    Shi, Tingkun; Lv, Wenjuan; Zhang, Li; Chen, Jianhuan; Chen, Haoyu

    2014-01-01

    Human leukocyte antigen (HLA)-DR4/HLA-DRB1*04 has been reported to be a risk factor for Vogt-Koyanagi-Harada disease (VKH) with various strength of association. Its sub-alleles were also found to be associated with VKH. However the results were inconsistent. In this study, we systematically searched the related literature, pooled the odds ratios (ORs) and 95% confidence interval (CI) of association of HLA-DR4/HLA-DRB1*04 or its sub-alleles with VKH from individual studies, and explored the potential source of heterogeneity. A total of 1853 VKH patients and 4164 controls from 21 articles were included in this meta-analysis. The pooled OR of association of HLA-DR4/HLA-DRB1*04 and VKH was 8.42 (95% CI: 5.69–12.45). There were significant heterogeneity (I2 = 71%). Subgroup analysis indicated that ethnicity was the source of heterogeneity (all I2 = 0, ORs ranged from 2.09–13.69 in subgroups). The sub-alleles, HLA-DRB1*0404 (OR = 2.57), 0405 (OR = 10.31) and 0410 (OR = 6.52) increased the risk of VKH; 0401 (OR = 0.21) protected VKH; while other sub-alleles were not associated with VKH. Our meta-analysis confirmed the association between VKH and HLA-DR4/DRB1*04, found the strength of association is different in different ethnic groups, and identified HLA-DRB1*0404, 0405 and 0410 as risk sub-alleles while 0401 as protective sub-allele. PMID:25382027

  16. Melanocyte antigen triggers autoimmunity in human psoriasis.

    PubMed

    Arakawa, Akiko; Siewert, Katherina; Stöhr, Julia; Besgen, Petra; Kim, Song-Min; Rühl, Geraldine; Nickel, Jens; Vollmer, Sigrid; Thomas, Peter; Krebs, Stefan; Pinkert, Stefan; Spannagl, Michael; Held, Kathrin; Kammerbauer, Claudia; Besch, Robert; Dornmair, Klaus; Prinz, Jörg C

    2015-12-14

    Psoriasis vulgaris is a common T cell-mediated inflammatory skin disease with a suspected autoimmune pathogenesis. The human leukocyte antigen (HLA) class I allele, HLA-C*06:02, is the main psoriasis risk gene. Epidermal CD8(+) T cells are essential for psoriasis development. Functional implications of HLA-C*06:02 and mechanisms of lesional T cell activation in psoriasis, however, remained elusive. Here we identify melanocytes as skin-specific target cells of an HLA-C*06:02-restricted psoriatic T cell response. We found that a Vα3S1/Vβ13S1 T cell receptor (TCR), which we had reconstituted from an epidermal CD8(+) T cell clone of an HLA-C*06:02-positive psoriasis patient specifically recognizes HLA-C*06:02-positive melanocytes. Through peptide library screening, we identified ADAMTS-like protein 5 (ADAMTSL5) as an HLA-C*06:02-presented melanocytic autoantigen of the Vα3S1/Vβ13S1 TCR. Consistent with the Vα3S1/Vβ13S1-TCR reactivity, we observed numerous CD8(+) T cells in psoriasis lesions attacking melanocytes, the only epidermal cells expressing ADAMTSL5. Furthermore, ADAMTSL5 stimulation induced the psoriasis signature cytokine, IL-17A, in CD8(+) T cells from psoriasis patients only, supporting a role as psoriatic autoantigen. This unbiased analysis of a TCR obtained directly from tissue-infiltrating CD8(+) T cells reveals that in psoriasis HLA-C*06:02 directs an autoimmune response against melanocytes through autoantigen presentation. We propose that HLA-C*06:02 may predispose to psoriasis via this newly identified autoimmune pathway. PMID:26621454

  17. Melanocyte antigen triggers autoimmunity in human psoriasis

    PubMed Central

    Arakawa, Akiko; Siewert, Katherina; Stöhr, Julia; Besgen, Petra; Kim, Song-Min; Rühl, Geraldine; Nickel, Jens; Vollmer, Sigrid; Thomas, Peter; Krebs, Stefan; Pinkert, Stefan; Spannagl, Michael; Held, Kathrin; Kammerbauer, Claudia; Besch, Robert; Dornmair, Klaus

    2015-01-01

    Psoriasis vulgaris is a common T cell–mediated inflammatory skin disease with a suspected autoimmune pathogenesis. The human leukocyte antigen (HLA) class I allele, HLA-C*06:02, is the main psoriasis risk gene. Epidermal CD8+ T cells are essential for psoriasis development. Functional implications of HLA-C*06:02 and mechanisms of lesional T cell activation in psoriasis, however, remained elusive. Here we identify melanocytes as skin-specific target cells of an HLA-C*06:02–restricted psoriatic T cell response. We found that a Vα3S1/Vβ13S1 T cell receptor (TCR), which we had reconstituted from an epidermal CD8+ T cell clone of an HLA-C*06:02–positive psoriasis patient specifically recognizes HLA-C*06:02–positive melanocytes. Through peptide library screening, we identified ADAMTS-like protein 5 (ADAMTSL5) as an HLA-C*06:02–presented melanocytic autoantigen of the Vα3S1/Vβ13S1 TCR. Consistent with the Vα3S1/Vβ13S1-TCR reactivity, we observed numerous CD8+ T cells in psoriasis lesions attacking melanocytes, the only epidermal cells expressing ADAMTSL5. Furthermore, ADAMTSL5 stimulation induced the psoriasis signature cytokine, IL-17A, in CD8+ T cells from psoriasis patients only, supporting a role as psoriatic autoantigen. This unbiased analysis of a TCR obtained directly from tissue-infiltrating CD8+ T cells reveals that in psoriasis HLA-C*06:02 directs an autoimmune response against melanocytes through autoantigen presentation. We propose that HLA-C*06:02 may predispose to psoriasis via this newly identified autoimmune pathway. PMID:26621454

  18. Heme Oxygenase-1 Inhibits HLA Class I Antibody-Dependent Endothelial Cell Activation

    PubMed Central

    Vijayan, Vijith; Hiller, Oliver; Figueiredo, Constanca; Aljabri, Abid; Blasczyk, Rainer; Theilmeier, Gregor; Becker, Jan Ulrich; Larmann, Jan; Immenschuh, Stephan

    2015-01-01

    Antibody-mediated rejection (AMR) is a key limiting factor for long-term graft survival in solid organ transplantation. Human leukocyte antigen (HLA) class I (HLA I) antibodies (Abs) play a major role in the pathogenesis of AMR via their interactions with HLA molecules on vascular endothelial cells (ECs). The antioxidant enzyme heme oxygenase (HO)-1 has anti-inflammatory functions in the endothelium. As complement-independent effects of HLA I Abs can activate ECs, it was the goal of the current study to investigate the role of HO-1 on activation of human ECs by HLA I Abs. In cell cultures of various primary human macro- and microvascular ECs treatment with monoclonal pan- and allele-specific HLA I Abs up-regulated the expression of inducible proinflammatory adhesion molecules and chemokines (vascular cell adhesion molecule-1 [VCAM-1], intercellular cell adhesion molecule-1 [ICAM-1], interleukin-8 [IL-8] and monocyte chemotactic protein 1 [MCP-1]). Pharmacological induction of HO-1 with cobalt-protoporphyrin IX reduced, whereas inhibition of HO-1 with either zinc-protoporphyrin IX or siRNA-mediated knockdown increased HLA I Ab-dependent up-regulation of VCAM-1. Treatment with two carbon monoxide (CO)-releasing molecules, which liberate the gaseous HO product CO, blocked HLA I Ab-dependent EC activation. Finally, in an in vitro adhesion assay exposure of ECs to HLA I Abs led to increased monocyte binding, which was counteracted by up-regulation of HO-1. In conclusion, HLA I Ab-dependent EC activation is modulated by endothelial HO-1 and targeted induction of this enzyme may be a novel therapeutic approach for the treatment of AMR in solid organ transplantation. PMID:26690352

  19. Distribution of HLA class II alleles among Spanish patients with pemphigus vulgaris.

    PubMed

    González-Escribano, M F; Jiménez, G; Walter, K; Montes, M; Perez-Bernal, A M; Rodríguez, M R; Conejo-Mir, J S; Núñez-Roldán, A

    1998-09-01

    Twenty-six unrelated Spanish Caucasian individuals affected by pemphigus vulgaris (PV) were HLA typed and frequencies compared with those of 200 ethnically matched healthy controls. Twenty-three out of 26 patients were HLA-DR4. The frequency of HLA-DR14 was also increased (31%; controls: 4%). Of the 23 patients positive for HLA-DR4, 21 carried the DRB1*0402 allele. Therefore, the frequency of HLA-DRB1*0402 among patients was 81% (4% in controls; P=4.7x10(-27), OR=100.8). Interestingly, HLA-DR13, a frequent HLA-DR specificity in the Spanish general population (27%), was absent among the PV patients (P=0.009; Pc=0.1; OR=0.05). Taking together these data, we can conclude that, in the Spanish population, PV is preferentially and strongly associated with HLA-DRB1*0402, whereas DRB1*13 seems to confer a protective effect in our population. PMID:9802608

  20. An investigation into the association between HLA-G 14 bp insertion/deletion polymorphism and multiple sclerosis susceptibility.

    PubMed

    Mohammadi, Nabiallah; Adib, Minoo; Alsahebfosoul, Fereshteh; Kazemi, Mohammad; Etemadifar, Masoud

    2016-01-15

    Human Leukocyte Antigen G (HLA-G) gene polymorphism and expression rate have recently been suggested to have a potential role in susceptibility to Multiple Sclerosis (MS), a chronic inflammatory demyelinating and neurodegenerative disease of the central nervous system with unknown etiology. The aim of this study was to investigate the association of the frequency of HLA-G gene 14 bp insertion/deletion polymorphism and its plasma level with MS susceptibility. In this study, the HLA-G gene from 212 patients and 210 healthy individuals was amplified using real time PCR and screened for the 14 bp insertion/deletion polymorphism. In addition, HLA-G plasma levels of the patients were measured and compared to normal controls by ELISA method. Our results revealed that 14 bp insertion in HLA-G could result in lower plasma HLA-G level of the subjects, regardless of their health status and vice versa. Additionally, significant correlation of HLA-G genotype and its plasma level with MS susceptibility was observed. In conclusion, not only HLA-G 14 bp insertion/deletion polymorphism could be associated with expression rate of the HLA-G gene and its plasma level, but also could be considered as a risk factor for susceptibility to MS in our study population. PMID:26711580

  1. Prevalence of HLA-B*5701 and Its Relationship with Abacavir Hypersensitivity Reaction in Iranian HIV-Infected Patients

    PubMed Central

    Baniasadi, Shadi; Shokouhi, Shokoufeh Baradaran; Tabarsi, Payam; Alehashem, Maryam; Khalili, Hossein; Fahimi, Fanak

    2016-01-01

    Background: Hypersensitivity reaction (HSR) is a major adverse effect of abacavir (ABC), which occurs in 5–8% of Caucasians. The relationship between Human Leukocyte Antigen (HLA) and ABC HSR has been reported in various populations. It has been proposed to administer ABC only to HLA-B*5701 negative patients to avoid this reaction. The purpose of this study was to assess the prevalence of HLA-B*5701 in Iranian HIV positive patients. We also sought to find the relationship between this allele with ABC HSR in patients who received the medication. Materials and Methods: We screened patients for HLA-B*5701 allele using SybrGreen real time PCR-melting method on blood samples from HIV positive patients who were referred to our hospital. The quality of the extracted genome was evaluated by B-globin housekeeping gene as internal control prior to HLA-B*5701 allele screening. Results: Of 198 HIV-infected patients, 6 (3.0%) had the HLA-B*5701 allele (95% CI, 1%–5%). Among the 28 patients who were given ABC, one individual had the HLA-B*5701 allele and experienced ABC HSR. Conclusion: Prevalence of HLA-B*5701 in Iranian patients was lower than that in Caucasians but was comparable with that of other Middle Eastern populations. Screening for HLA-B*5701 before ABC administration as part of antiretroviral therapy may reduce the risk of HSR.

  2. Association of HLA-A, B, DRB1* and DQB1* alleles and haplotypes in south Indian T2DM patients.

    PubMed

    Chinniah, Rathika; Vijayan, Murali; Sivanadham, Ramgopal; Ravi, Padma Malini; Panneerselvam, Dharmarajan; Karuppiah, Balakrishnan

    2016-10-30

    The genes of Human Leukocyte Antigen (HLA) system are implicated in the susceptibility of several diseases including Type 2 diabetes (T2DM). Therefore, we aimed to investigate the association of HLA alleles with T2DM in south India. A total of 344 patients (195 males; 149 females) and 309 controls (186 males; 123 females) were genotyped for HLA-DR/-DQ alleles. Based on predominant DR/DQ haplotypes, 222 patients and 222 age/sex matched controls were HLA-A/-B genotyped. HLA alleles were typed by PCR-SSP methods. Susceptible association was observed for the alleles A*33 (OR=13.8), A*01 (OR=3.69), A*02 (OR=2.91), B*07 (OR=4.12), DRB1*11 (OR=2.23), DRB1*04 (OR=1.51), DRB1*03 (OR=1.90) and DQB1*02 (OR=1.49). Protective association was observed for the alleles A*11 (OR=0.59), A*68 (OR=0.68), B*40 (OR=0.50), B*54 (OR=0.42), B*57 (OR=0.31), B*51 (OR=0.29) and DRB1*10 (OR=0.45). Gender stratified analysis too confirmed many of these associations. Predominant susceptible haplotypes were A*33-B*40 (OR=10.27), A*01-B*07 (OR=4.97), A*02-B*07 (OR=6.50), DRB1*03-DQB1*05 (OR=1.88), DRB1*03-DQB1*06 (OR=3.01), DRB1*04-DQB1*05 (2.63), A*01-B*07-DRB1*10 (OR=8.26) and A*11-B*35-DRB1*07 (OR=9.338). Haplotypes A*03-B*07 (OR=0.57; p<0.034) and DRB1*10-DQB1*05 (OR=0.57; p<0.033) were protectively associated. Further, a very strong susceptible association was documented for four-locus haplotypes such as A*11-B*40-DRB1*15-DQB1*06 (n=15; OR=16.01; p<0.001); A*01-B*07-DRB1*10-DQB1*05 (n=8; OR=8.26; p<0.043) and A*11-B*07-DRB1*07-DQB1*05 (n=8; OR=8.26; p<0.043). Thus, a number of HLA alleles and haplotypes showed susceptible and protective association(s) in T2DM patients from south India. PMID:27496342

  3. Significant Association of HLA-B Alleles and Genotypes in Thai Children with Autism Spectrum Disorders: A Case-Control Study

    PubMed Central

    Puangpetch, Apichaya; Suwannarat, Pongwut; Chamnanphol, Montri; Koomdee, Napatrupron; Ngamsamut, Nattawat; Limsila, Penkhae; Sukasem, Chonlaphat

    2015-01-01

    Autism is a severe neurodevelopmental disorder. Many susceptible causative genes have been identified. Most of the previous reports showed the relationship between the Human Leukocyte Antigen (HLA) gene and etiology of autism. In order to identify HLA-B alleles associated with autism in Thai population, we compared the frequency of HLA-B allele in 364 autistic subjects with 952 normal subjects by using a two-stage sequence-specific oligonucleotide probe system (PCR-SSOP) method based on flow-cytometry technology. HLA-B⁎13:02 (P = 0.019, OR = 2.229), HLA-B⁎38:02 (P = 0.049, OR = 1.628), HLA-B⁎44:03 (P = 0.016, OR = 1.645), and HLA-B⁎56:01 (P = 1.78 × 10−4, OR = 4.927) alleles were significantly increased in autistic subjects compared with normal subjects. Moreover, we found that the HLA-B⁎18:02 (P = 0.016, OR = 0.375) and HLA-B⁎46:12 (P = 0.008, OR = 0.147) alleles were negatively associated with autism when compared to normal controls. Both alleles might have a protective role in disease development. In addition, four HLA-B genotypes of autistic patients had statistically significant relationship with control groups, consisting of HLA-B⁎3905/⁎5801 (P = 0.032, OR = 24.697), HLA-B⁎2704/⁎5801 (P = 0.022, OR = 6.872), HLA-B⁎3501/⁎4403 (P = 0.021, OR = 30.269), and HLA-B⁎1801/⁎4402 (P = 0.017, OR = 13.757). This is the first report on HLA-B associated with Thai autism and may serve as a marker for genetic susceptibility to autism in Thai population. PMID:26819491

  4. HLA class I variation in Iranian Lur and Kurd populations: high haplotype and allotype diversity with an abundance of KIR ligands.

    PubMed

    Ashouri, E; Norman, P J; Guethlein, L A; Han, A S; Nemat-Gorgani, N; Norberg, S J; Ghaderi, A; Parham, P

    2016-09-01

    HLA-A, -B and -C alleles of 285 individuals, representing three Iranian Lur populations and one Iranian Kurd population were sequenced completely, yielding human leukocyte antigen (HLA) class I genotypes at high resolution and filling four fields of the official HLA nomenclature. Each population has 87-99 alleles, evenly distributed between the three HLA class I genes, 145 alleles being identified in total. These alleles were already known, named and deposited in the HLA database. The alleles form 316 different HLA A-B-C haplotypes, with each population having between 80 and 112 haplotypes. The four Iranian populations form a related group that is distinguished from other populations, including other Iranians. All four KIR ligands - the A3/11, Bw4, C1 and C2 epitopes - are well represented, particularly Bw4, which is carried by three high-frequency allotypes: HLA-A*24:02, HLA-A*32:01 and HLA-B*51:01. In the Lur and Kurd populations, between 82% and 94% of individuals have the Bw4 epitope, the ligand for KIR3DL1. HLA-B*51:01 is likely of Neandertal origin and associated with Behcet's disease, also known as the Silk Road disease. The Lordegan Lur have the highest frequency of HLA-B*51:01 in the world. This allele is present on 46 Lur and Kurd haplotypes. Present at lower frequency is HLA-B*51:08, which is also associated with Behcet's disease. In the four Iranian populations, 31 haplotypes encode both Bw4(+) HLA-A and Bw4(+) HLA-B, a dual combination of Bw4 epitopes that is relatively rare in other populations, worldwide. This study both demonstrates and emphasizes the value of studying HLA class I polymorphism at highest resolution in anthropologically well-defined populations. PMID:27558013

  5. Analysis of endogenous peptides bound by soluble MHC class I molecules: a novel approach for identifying tumor-specific antigens.

    PubMed

    Barnea, Eilon; Beer, Ilan; Patoka, Renana; Ziv, Tamar; Kessler, Ofra; Tzehoval, Esther; Eisenbach, Lea; Zavazava, Nicholas; Admon, Arie

    2002-01-01

    The Human MHC Project aims at comprehensive cataloging of peptides presented within the context of different human leukocyte antigens (HLA) expressed by cells of various tissue origins, both in health and in disease. Of major interest are peptides presented on cancer cells, which include peptides derived from tumor antigens that are of interest for immunotherapy. Here, HLA-restricted tumor-specific antigens were identified by transfecting human breast, ovarian and prostate tumor cell lines with truncated genes of HLA-A2 and HLA-B7. Soluble HLA secreted by these cell lines were purified by affinity chromatography and analyzed by nano-capillary electrospray ionization-tandem mass spectrometry. Typically, a large peptide pool was recovered and sequenced including peptides derived from MAGE-B2 and mucin and other new tumor-derived antigens that may serve as potential candidates for immunotherapy. PMID:11782012

  6. MICA, MICB Polymorphisms and Linkage Disequilibrium with HLA-B in a Chinese Mongolian Population.

    PubMed

    Wang, W Y; Tian, W; Zhu, F M; Liu, X X; Li, L X; Wang, F

    2016-06-01

    In this study, polymorphisms of major histocompatibility complex class I chain-related genes A and B (MICA and MICB) and human leucocyte antigen (HLA)-B gene were investigated for 158 unrelated Chinese Mongolian subjects recruited from central Inner Mongolia Autonomous Region, northern China, by polymerase chain reaction-sequence-based typing (PCR-SBT) and cloning. Collectively, 79 alleles, including 20 MICA, 12 MICB and 47 HLA-B alleles, were identified. MICA*008:01 (21.2%), MICB*005:02 (48.1%) and HLA-B*51:01 (7.91%) were the most common alleles. Significant global linkage disequilibrium (LD) was detected between HLA-B and MICA, HLA-B and MICB, and MICA and MICB loci (all P < 0.000001). The most frequent haplotypes were HLA-B*51:01-MICA*009:01 (7.28%), HLA-B*58:01-MICB*008 (6.96%), MICA*010-MICB*005:02 (13.92%) and HLA-B*58:01-MICA*002:01-MICB*008 (6.96%). HLA-B-MICA haplotypes such as HLA-B*50:01-MICA*009:02 were associated with single MICB allele. Some HLA-B-MICA haplotypes were associated with multiple MICB alleles, including HLA-B*51:01-MICA*009:01. One novel MICB allele, MICB*031, was identified, which has possibly arisen from MICB*002:01 through single mutation event. We also confirmed the existence of a recently recognized MICA allele, MICA*073, whose ethnic origin has not been previously described. Genotype distributions at MICA, MICB and HLA-B were consistent with a neutrality model. Our results provide new insight into MIC genetic polymorphisms in Chinese ethnic groups. Findings shown here are important from an anthropologic perspective and will inform future studies of the potential role of MIC genes in allogeneic organ transplantation and HLA-linked disease association in populations of related ancestry. PMID:27028549

  7. Characterization of BAX inhibitor-1 as a novel leukemia-associated antigen.

    PubMed

    Schmidt, S M; König, T; Bringmann, A; Held, S; von Schwarzenberg, K; Heine, A; Holderried, T A W; Stevanovic, S; Grünebach, F; Brossart, P

    2009-10-01

    Using dendritic cells (DCs) electroporated with whole RNA isolated from blasts of a patient with acute myeloid leukemia (AML), we were able to generate leukemia-specific cytotoxic T lymphocytes (CTLs) capable of recognizing the leucemic cells. To identify T-cell epitopes mediating lysis of malignant cells, peptides were eluted from the patient's blasts and analyzed by mass spectrometry (LC/MS)-based peptide sequencing. Using this approach, an HLA-A24-binding peptide derived from Bax inhibitor-1 (BI-1), a regulator of apoptosis pathways, was identified as an epitope recognized by the generated CTLs. To further characterize this novel antigenic peptide, CTLs were induced using DCs electroporated with