Science.gov

Sample records for multiple common hla

  1. Multiple Common Properties of Human β2-Microglobulin and the Common Portion Fragment Derived from HL-A Antigen Molecules

    PubMed Central

    Nakamuro, K.; Tanigaki, N.; Pressman, D.

    1973-01-01

    11,000-Dalton common portion fragments derived from HL-A antigen molecules were isolated and found to have a significantly high homology to β2-microglobulin in amino-acid composition. Common portion fragments are also very similar to β2-microglobulin with respect to molecular size, charge, and distribution in tissues. Moreover, both are found in the spent culture media of human cell lines and in human plasma and urine. Thus it appears that β2-microglobulin may well be the same substance as the common portion fragment of HL-A antigen molecules. PMID:4517941

  2. Common immunogenetic profile in children with multiple autoimmune diseases: the signature of HLA-DQ pleiotropic genes.

    PubMed

    Larizza, Daniela; Calcaterra, Valeria; Klersy, Catherine; Badulli, Carla; Caramagna, Claudia; Ricci, Antonio; Brambilla, Paola; Salvaneschi, Laura; Martinetti, Miryam

    2012-09-01

    Type 1 diabetes mellitus (T1DM), celiac disease (CD) and autoimmune thyroid disease (ATD) are autoimmune conditions relatively common in paediatric age and frequently occur in association in the same subject. This event is not by chance and requires an explanation. Here, we studied the distribution of HLA-DQ αβ heterodimers in 334 Italian children with T1DM, ATD and CD alone or in association and in 224 Italian healthy controls. In particular, 164 patients had T1DM (133 alone, 20+ATD, 7+CD and 4+CD+ATD), 118 had ATD (110 alone, 8+CD) and 52 had CD (40 alone, 11+ATD and 1+T1DM). 51 patients suffered from multiple autoimmune diseases. The risk for multiple autoimmune diseases was significantly associated with the increased number of HLA-DQ markers of susceptibility for both T1DM (p = 0.003) and CD (p = 0.006). The presence of one or more diabetogenic DQ molecules significantly increased the probability of developing not only T1DM (p < 0.001) but also CD (p < 0.001) and ATD (p = 0.001). Similarly, the presence of one or more celiac HLA-DQ heterodimers significantly increased the likelihood of developing not only CD (p < 0.001), but also T1DM (p < 0.001) and ATD (p < 0.001). We confirm that the sharing of the immunogenetic background is responsible for the development of multiple autoimmune diseases although with a different risk according to the number and type of susceptible HLA-DQ heterodimers as reported in the algorithm proposed here. It is likely that combinations of DQA1 and DQB1 alleles are the real culprits of the progression towards multiple autoimmune diseases and HLA-DQ genomic typing will improve the capability to predict associated autoimmune diseases in infancy.

  3. HLA antigens in multiple sclerosis of northern Spanish population.

    PubMed Central

    López-Larrea, C; Uría, D F; Coto, E

    1990-01-01

    HLA-A, -B, -C, -DR, -DQ antigens were studied in 43 multiple sclerosis (MS) patients with clinically definite remittent sclerosis from Asturias (North Spain). The prevalence of HLA-B7, B7 and B27 were significantly increased in MS. HLA-B35 was under-represented in these patients. DR2 was increased but not significantly. No association with DQw1 was discovered. The existence of several susceptibility factors in the more common B7/DR2/DQw1 haplotype is discussed. PMID:2351974

  4. 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

  5. Common and Low Frequency Variants in MERTK Are Independently Associated with Multiple Sclerosis Susceptibility with Discordant Association Dependent upon HLA-DRB1*15:01 Status

    PubMed Central

    Binder, Michele D.; Fox, Andrew D.; Merlo, Daniel; Johnson, Laura J.; Giuffrida, Lauren; Calvert, Sarah E.; Akkermann, Rainer; Ma, Gerry Z. M.; Perera, Ashwyn A.; Gresle, Melissa M.; Laverick, Louise; Foo, Grace; Fabis-Pedrini, Marzena J.; Spelman, Timothy; Jordan, Margaret A.; Baxter, Alan G.; Foote, Simon; Butzkueven, Helmut; Kilpatrick, Trevor J.; Field, Judith

    2016-01-01

    Multiple Sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system. The risk of developing MS is strongly influenced by genetic predisposition, and over 100 loci have been established as associated with susceptibility. However, the biologically relevant variants underlying disease risk have not been defined for the vast majority of these loci, limiting the power of these genetic studies to define new avenues of research for the development of MS therapeutics. It is therefore crucial that candidate MS susceptibility loci are carefully investigated to identify the biological mechanism linking genetic polymorphism at a given gene to the increased chance of developing MS. MERTK has been established as an MS susceptibility gene and is part of a family of receptor tyrosine kinases known to be involved in the pathogenesis of demyelinating disease. In this study we have refined the association of MERTK with MS risk to independent signals from both common and low frequency variants. One of the associated variants was also found to be linked with increased expression of MERTK in monocytes and higher expression of MERTK was associated with either increased or decreased risk of developing MS, dependent upon HLA-DRB1*15:01 status. This discordant association potentially extended beyond MS susceptibility to alterations in disease course in established MS. This study provides clear evidence that distinct polymorphisms within MERTK are associated with MS susceptibility, one of which has the potential to alter MERTK transcription, which in turn can alter both susceptibility and disease course in MS patients. PMID:26990204

  6. 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

  7. HLA-DR and HLA-DP genotypes and immunoglobulin E responses to common major allergens.

    PubMed

    Young, R P; Dekker, J W; Wordsworth, B P; Schou, C; Pile, K D; Matthiesen, F; Rosenberg, W M; Bell, J I; Hopkin, J M; Cookson, W O

    1994-05-01

    In order to test for human histocompatibility leucocyte antigens (HLA) class II restriction of IgE responses, 431 subjects from 83 families were genotyped at the HLA-DR and HLA-DP loci and serotyped for IgE responses to six major allergens from common aero-allergen sources. A possible excess of HLA-DR1 was found in subjects who were responsive to Fel d I compared with those who were not (Odds Ratio (OR) = 2, P = 0.002), and a possible excess of HLA-DR4 was found in subjects responsive to Alt a I (OR = 1.9, P = 0.006). Increased sharing of HLA-DR/DP haplotypes was seen in sibling pairs responding to both allergens. Der p I, Der p II, Phl p V and Can f I were not associated with any definite excess of HLA-DR alleles. No significant correlations were seen with HLA-DP genotype and reactivity to any of the allergens. The results suggest class II HLA restriction is insufficient to account for individual differences in reactivity to common allergens.

  8. Common antigenic structures of HL-A antigens

    PubMed Central

    Nakamuro, K.; Tanigaki, N.; Kreiter, V. P.; Pressman, D.

    1974-01-01

    Spent culture media of all the human cell lines tested have been found to contain the antigenic activity present on the 11,000-Dalton HL-A common portion fragment of the HL-A antigen molecule that appears to be a characteristic, invariant portion of HL-A antigen molecules. From the culture medium of one of these lines, RPMI 1788, a lymphoid cell line, the substance carrying HL-A common activity was isolated, which was shown to be identical to the HL-A common portion fragment with respect to molecular size, electrophoretic mobility, isoelectric focusing patterns, and certain antigenic characteristics. By an isolation procedure involving differential ultrafiltration, gel filtration, and column electrophoresis, 8 litres of the culture medium yielded 1.5–2.0 A280 units of the substance representing 15–20 per cent of the HL-A common antigenic activity originally present. A single protein band with a Rf of 0.47 was obtained by disc electrophoresis. The molecular size was shown to be about 11,000 Daltons by gel filtration and by sodium dodecyl sulphate—acrylamide gel electrophoresis. Upon isoelectric focusing two bands were obtained which corresponded exactly to those obtained with HL-A common portion fragment prepared from papain-solubilized HL-A antigen preparations by acid dissociation. The isoelectric point of the major band was 5.0. The reactions of this substance with rabbit antisera against human lymphoid cell membrane and against the substance were essentially identical to the reactions of HL-A common portion fragment with these same antisera. ImagesFIG. 3Fig. 4Fig. 5 PMID:4476726

  9. Common antigen structures of HL-A antigens

    PubMed Central

    Miyakawa, Y.; Tanigaki, N.; Yagi, Y.; Pressman, D.

    1973-01-01

    Antigenic determinants recognizable by rabbits were found to be present on the molecular fragments (48,000 Daltons) which were obtained by papain-solubilization of the membrane fractions of cultured human lymphoid cells and which carried the HL-A determinants. Results were obtained which suggest that these antigenic determinants are present in common on these molecular fragments carrying HL-A determinants regardless of their HL-A specificity and are restricted to the molecular fragments which carry HL-A determinants. The study was made by use of radioimmune methods involving the binding of radioiodine-labelled soluble HL-A antigen preparations by anti-HL-A alloantisera and by rabbit antisera raised against the membrane fractions of cultured human lymphoid cells. PMID:4119543

  10. Multiple HLA class I and II associations in classical Hodgkin lymphoma and EBV status defined subgroups.

    PubMed

    Huang, Xin; Kushekhar, Kushi; Nolte, Ilja; Kooistra, Wierd; Visser, Lydia; Bouwman, Ilby; Kouprie, Niels; Veenstra, Rianne; van Imhoff, Gustaaf; Olver, Bianca; Houlston, Richard S; Poppema, Sibrand; Diepstra, Arjan; Hepkema, Bouke; van den Berg, Anke

    2011-11-10

    The pathogenesis of classical Hodgkin lymphoma (cHL) involves environmental and genetic factors. To explore the role of the human leukocyte antigen (HLA) genes, we performed a case-control genotyping study in 338 Dutch cHL patients and more than 5000 controls using a PCR-based sequence-specific oligonucleotide probe hybridization approach. HLA-A68 and HLA-DR11 (5) were significantly increased in the cHL patient population compared with the controls. Three class II associations were observed in the EBV(-) cHL population with an increase of HLA-DR15 (2) and a decrease of HLA-DR4 and HLA-DR7. Allele frequencies of HLA-A1, HLA-B37, and HLA-DR10 were significantly increased in the EBV(+) cHL population; these alleles are in strong linkage disequilibrium and form a common haplotype in whites. The allele frequency of HLA-A2 was significantly decreased in the EBV(+) cHL population. Sequence-specific oligonucleotide probe analysis revealed significant differences between EBV(+) and EBV(-) cHL patients for 19 probes that discriminate between HLA-A*01 and HLA-A*02. In conclusion, the HLA-A1 and HLA-A2 antigens and not specific single nucleotide variants shared by multiple alleles are responsible for the association with EBV(+) cHL. Furthermore, several new protective and predisposing HLA class I and II associations for the EBV(+), the EBV(-), and the entire cHL population were identified.

  11. The South Amerindian allotype HLA-B*3909 has the largest known similarity in peptide specificity and common natural ligands with HLA-B27.

    PubMed

    Yagüe, J; Ramos, M; Vázquez, J; Marina, A; Albar, J P; López de Castro, J A

    1999-03-01

    HLA-B*3909 has only been found among South Amerindians, and presumably arose locally in these populations. It differs from B*3901 by a single Tyr to Ser change at position 99. To analyze the influence of this polymorphism on peptide specificity, pool sequence analysis and sequencing of multiple individual ligands from B*3901 and B*3909 were carried out. Both allotypes bind peptides with Arg2 or His2 and nonpolar C-terminal residues. However, whereas His2 is the predominant B*3901 motif, a majority of the B*3909-bound peptides have Arg2. In addition, B*3909 binds peptides with Pro2, and also shows an increased preference for Pro3. In spite of their differences, both subtypes bind overlapping peptide repertoires, as indicated by the identification of several identical ligands from their respective peptide pools. B*3909 is significantly more similar in its peptide specificity to HLA-B27 than B*3901. This is due to the increased preference of B*3909 for Arg2 and to low suitability of HLA-B27 for His2. The similarity between HLA-B27 and B*3909 was confirmed by identification of a natural ligand common to both allotypes. In addition, multiple HLA-B27 ligands bound efficiently B*3909 in vitro. The results indicate that, among the HLA class I allotypes of known peptide specificity, B*3909 is the most similar in its peptide binding properties to HLA-B27, which is absent in South Amerindians. This may have implications for the susceptibility of individuals in these populations to spondyloarthropathies.

  12. HLA polymorphism of the Zhuang population reflects the common HLA characteristics among Zhuang-Dong language-speaking populations*

    PubMed Central

    Shi, Li; Huang, Xiao-qin; Shi, Lei; Tao, Yu-fen; Yao, Yu-feng; Yu, Liang; Lin, Ke-qin; Yi, Wen; Sun, Hao; Tokunaga, Katsushi; Chu, Jia-you

    2011-01-01

    A study of the human leukocyte antigen (HLA) genetic characteristics in the Zhuang, the largest ethnic population in China, would provide insight into Zhuang history and give a useful tool for disease associations, transplantation, and anthropology. In the present study, we report the comprehensive HLA-A, HLA-B, HLA-C, and HLA-DRB1 alleles and haplotypes in the Zhuang population of southern China for the first time. A total of 13 HLA-A, 24 HLA-B, 22 HLA-C, and 18 HLA-DRB1 were identified in 104 Zhuang individuals. The frequencies of HLA-A*11:01, A*02:07, A*24:02, A*02:03, and A*33:03 on A loci, B*15:02, B*58:01, B*46:01, and B*13:01 on B loci, C*03:04, C*08:01, C*01:02, C*03:02, and C*07:02 on C loci, and DRB1*15:01, DRB1*16:02, DRB1*14:01, DRB1*15:02, and DRB1*03:01 on the DRB1 loci were >10%. The A*33:03-C*03:02-B*58:01-DRB1*03:01 and A*02:07-C*01:02-B*46:01-DRB1*14:01 haplotypes were predominant in the Zhuang. The phylogenetic tree, as well as the analysis of haplotypes, suggested that the Zhuang are genetically similar to southern Chinese populations, especially the Zhuang-Dong language-speaking populations, such as the Bouyei, Dai, and Maonan. Even though the Zhuang and southern Chinese populations shared common alleles and haplotypes, the Zhuang has maintained its unique genetic characteristics. PMID:21634035

  13. Modification of Multiple Sclerosis Phenotypes by African Ancestry at HLA

    PubMed Central

    Cree, Bruce A. C.; Reich, David E.; Khan, Omar; De Jager, Philip L.; Nakashima, Ichiro; Takahashi, Toshiyuki; Bar-Or, Amit; Tong, Christine; Hauser, Stephen L.; Oksenberg, Jorge R.

    2015-01-01

    Background In those with multiple sclerosis (MS), African American individuals have a more severe disease course, an older age at onset, and more often have clinical manifestations restricted to the optic nerves and spinal cord (opticospinal MS) than white persons. Objective To determine whether genetic variation influences clinical MS patterns. Design Retrospective multicenter cohort study. Participants Six hundred seventy-three African American and 717 white patients with MS. Main Outcome Measures Patients with MS were geno-typed for HLA-DRB1 and HLA-DQB1 alleles. The proportion of European ancestry at HLA was estimated by genotyping single-nucleotide polymorphisms with known significant frequency differences in West African and European populations. These genotypes were correlated with the opticospinal disease phenotype, disability measures, and age at onset. Results Subjects with DRB1*15 alleles were twice as likely to have typical MS rather than opticospinal MS (P = .001). Of the subjects with opticospinal MS or a history of recurrent transverse myelitis who were seropositive for anti–aquaporin 4 antibodies (approximately 5%), none carried DRB1*15 alleles (P = .008). Independently of DRB1* 15, African ancestry at HLA correlated with disability as measured by the Multiple Sclerosis Severity Score (P < .001) andriskof cane dependency (hazard ratio, 1.36; P < .001); DRB1*15 alleles were associated with a 2.1-year earlier age at onset (P < .001). Conclusions These data indicate that the role of HLA in MS is not limited to disease susceptibility but that genes embedded in this locus also influence clinical outcomes. PMID:19204159

  14. Modification of Multiple Sclerosis Phenotypes by African Ancestry at HLA.

    PubMed

    Cree, Bruce A C; Reich, David E; Khan, Omar; De Jager, Philip L; Nakashima, Ichiro; Takahashi, Toshiyuki; Bar-Or, Amit; Tong, Christine; Hauser, Stephen L; Oksenberg, Jorge R

    2009-02-01

    In those with multiple sclerosis (MS), African American individuals have a more severe disease course, an older age at onset, and more often have clinical manifestations restricted to the optic nerves and spinal cord (opticospinal MS) than white persons. To determine whether genetic variation influences clinical MS patterns. Retrospective multicenter cohort study. Six hundred seventy-three African American and 717 white patients with MS. Patients with MS were genotyped for HLA-DRB1 and HLA-DQB1 alleles. The proportion of European ancestry at HLA was estimated by genotyping single-nucleotide polymorphisms with known significant frequency differences in West African and European populations. These genotypes were correlated with the opticospinal disease phenotype, disability measures, and age at onset. Subjects with DRB1*15 alleles were twice as likely to have typical MS rather than opticospinal MS (P = .001). Of the subjects with opticospinal MS or a history of recurrent transverse myelitis who were seropositive for anti-aquaporin 4 antibodies (approximately 5%), none carried DRB1*15 alleles (P = .008). Independently of DRB1*15, African ancestry at HLA correlated with disability as measured by the Multiple Sclerosis Severity Score (P < .001) and risk of cane dependency (hazard ratio, 1.36; P < .001); DRB1*15 alleles were associated with a 2.1-year earlier age at onset (P < .001). These data indicate that the role of HLA in MS is not limited to disease susceptibility but that genes embedded in this locus also influence clinical outcomes.

  15. Is there a relationship between narcolepsy, multiple sclerosis and HLA-DQB1*06:02?

    PubMed

    Lorenzoni, Paulo José; Werneck, Lineu Cesar; Crippa, Ana Christina de Souza; Zanatta, Alessandra; Kay, Cláudia S Kamoi; Silvado, Carlos Eduardo S; Scola, Rosana Herminia

    2017-06-01

    We studied multiple sclerosis (MS) patients with the HLA-DQB1*06:02 allele and compared them with MS patients who did not carry the HLA-DQB1*06:02 allele. We analyzed clinical and neurophysiological criteria for narcolepsy in six MS patients with HLA-DQB1*06:02, compared with 12 MS patients who were HLA-DQB1*06:02 non-carriers. Only two patients with HLA-DQB1*06:02 allele scored higher than 10 on the Epworth Sleepiness Scale. Polysomnography recording parameters and the multiple sleep latency test showed an absence of narcolepsy in the study group. Our study suggested no significant correlation between narcolepsy, MS and HLA-DQB1*06:02. The HLA-DQB1*06:02 allele alone was not sufficient to cause MS patients to develop narcolepsy.

  16. Is there a common pathogenesis in aggressive periodontitis & ankylosing spondylitis in HLA-B27 patient?

    PubMed

    Agrawal, Neeraj; Agarwal, Kavita; Varshney, Atul; Agrawal, Navneet; Dubey, Ashutosh

    2016-05-01

    HLA-B27 is having strong association to ankylosing spondylitis (AS) and other inflammatory diseases collectively known as seronegative spondyloarthropathy. In literature, although the evidence for association between AS and periodontitis as well as AS and HLA-B27 are there but the association of aggressive periodontitis in HLA-B27 positive patient with AS are not there. We hypothesize that there may be a common pathogenesis in aggressive periodontitis and ankylosing spondylitis in HLA-B27 patient. A 27-years-old female presented with the features of generalized aggressive periodontitis and difficulty in walking. On complete medical examination, ankylosing spondylitis was diagnosed with further positive HLA-B27 phenotype and negative rheumatic factor. This report may open up a new link to explore in the pathogenesis of aggressive periodontitis. Copyright © 2016 Elsevier Ltd. All rights reserved.

  17. Role of HLA class II genes in susceptibility and resistance to multiple sclerosis: studies using HLA transgenic mice

    PubMed Central

    Luckey, David; Bastakoty, Dikshya; Mangalam, Ashutosh K.

    2011-01-01

    Multiple sclerosis (MS), an inflammatory and demyelinating autoimmune disease of CNS has both, a genetic and an environmental predisposition. Among all the genetic factors associated with MS susceptibility, HLA-class II haplotypes such as DR2/DQ6, DR3/DQ2, and DR4/DQ8 show the strongest association. Although a direct role of HLA-DR alleles in MS have been confirmed, it has been difficult to understand the contribution of HLA-DQ alleles in disease pathogenesis, due to strong linkage disequilibrium. Population studies have indicated that DQ alleles may play a modulatory role in the progression of MS. To better understand the mechanism by which HLA-DR and -DQ genes contribute to susceptibility and resistance to MS, we utilized single and double transgenic mice expressing HLA class II gene(s) lacking endogenous mouse class II genes. HLA class II transgenic mice have helped us in identifying immunodominant epitopes of PLP in context of various HLA-DR and -DQ molecules. We have shown that HLA-DR3 transgenic mice were susceptible to PLP91-110 induced experimental autoimmune encephalomyelitis (EAE), while DQ6 (DQB1*0601) and DQ8 (DQB1*0302) transgenic mice were resistant. Surprisingly DQ6/DR3 double transgenic mice were resistant while DQ8/DR3 mice showed higher disease incidence and severity than DR3 mice. The protective effect of DQ6 in DQ6/DR3 mice was mediated by IFNγ, while the disease exacerbating effect of DQ8 molecule was mediated by IL17. Further, we have observed that myelin-specific antibodies play an important role in PLP91-110 induced EAE in HLA-DR3DQ8 transgenic mice. Based on these observations, we hypothesize that epistatic interaction between HLA-DR and -DQ genes play an important role in predisposition to MS and our HLA transgenic mouse model provides a novel tool to study the effect of linkage disequilibrium in MS. PMID:21632210

  18. Intrathecal soluble HLA-E correlates with disease activity in patients with multiple sclerosis and may cooperate with soluble HLA-G in the resolution of neuroinflammation.

    PubMed

    Morandi, Fabio; Venturi, Consuelo; Rizzo, Roberta; Castellazzi, Massimiliano; Baldi, Eleonora; Caniatti, Maria Luisa; Tola, Maria Rosaria; Granieri, Enrico; Fainardi, Enrico; Uccelli, Antonio; Pistoia, Vito

    2013-09-01

    Expression and function of the immunoregulatory molecule HLA-E was investigated in patients with relapsing-remitting (RR) multiple sclerosis (MS). Serum and cerebrospinal fluid (CSF) soluble (s)HLA-E and -G levels were measured by ELISA in 80 RRMS patients. Controls were patients with other inflammatory neurological disorders (OIND, n = 81) and noninflammatory neurological disorders (NIND, n = 86). Serum sHLA-E concentrations were higher in RRMS than in NIND patients only. CSF sHLA-E concentrations were higher in RRMS than controls. Increased CSF sHLA-E levels were detected in MRI inactive and clinically stable RRMS patients. sHLA-E intrathecal synthesis (ITS) was higher in RRMS than controls, and the number of patients with sHLA-E ITS above cut-off was higher i) in MS than controls, and ii) in clinically stable than clinically active MS patients. sHLA-E CSF levels and ITS correlated with i) the same sHLA-G parameters, and ii) disease duration. HLA-E expression and co-expression with CD markers were investigated in MS plaques from three different cases by immunohistochemistry and confocal microscopy, respectively. Infiltrating T lymphocytes and macrophages, as well as resident microglial cells and astrocytes expressed HLA-E. CSF samples from MS patients were finally tested for inhibitory activity of in vitro CTL and NK cell mediated cytotoxicity. sHLA-E⁺ were more effective than sHLA-E⁻ CSF samples in such inhibition. Maximum inhibition was achieved with sHLA-E⁺/sHLA-G⁺ CSF samples In conclusion, increased sHLA-E CSF levels may play an immunomodulatory role in MS, contributing to the inhibition of intrathecal inflammatory response. The potential of sHLA-E as biomarker of MS activity warrants further investigation.

  19. Common and Well-Documented HLA Alleles: 2012 Update to the CWD Catalogue

    PubMed Central

    Mack, Steven J.; Cano, Pedro; Hollenbach, Jill A.; He, Jun; Hurley, Carolyn Katovich; Middleton, Derek; Moraes, Maria Elisa; Pereira, Shalini E.; Kempenich, Jane H.; Reed, Elaine F.; Setterholm, Michelle; Smith, AnaJane G.; Tilanus, Marcel G.; Torres, Margareth; Varney, Michael D.; Voorter, Christien E. M.; Fischer, Gottfried F.; Fleischhauer, Katharina; Goodridge, Damian; Klitz, William; Little, Ann-Margaret; Maiers, Martin; Marsh, Steven G. E.; Müller, Carlheinz R.; Noreen, Harriet; Rozemuller, Erik H.; Sanchez-Mazas, Alicia; Senitzer, David; Trachtenberg, Elizabeth; Fernandez-Vina, Marcelo

    2013-01-01

    We have updated the catalogue of common and well-documented (CWD) HLA alleles to reflect current understanding of the prevalence of specific allele sequences. The original CWD catalogue designated 721 alleles at the HLA-A, -B, -C, -DRB1, -DRB3/4/5, -DQA1, -DQB1, and –DPB1 loci in IMGT/HLA Database release 2.15.0 as being CWD. The updated CWD catalogue designates 1122 alleles at the HLA-A, -B, -C, -DRB1, -DRB3/4/5, -DQA1, -DQB1, -DPA1 and –DPB1 loci as being CWD, and represents 14.3% of the HLA alleles in IMGT/HLA Database release 3.9.0. In particular, we identified 415 of these alleles as being “common” (having known frequencies) and 707 as being “well-documented” on the basis of ~140,000 sequence-based typing observations and available HLA haplotype data. Using these allele prevalence data, we have also assigned CWD status to specific G and P designations. We identified 147/151 G groups and 290/415 P groups as being CWD. The CWD catalogue will be updated on a regular basis moving forward, and will incorporate changes to the IMGT/HLA Database as well as empirical data from the histocompatibility and immunogenetics community. This version 2.0.0 of the CWD catalogue is available online at cwd.immunogenomics.org, and will be integrated into the Allele Frequencies Net Database, the IMGT/HLA Database and National Marrow Donor Program’s bioinformatics web pages. PMID:23510415

  20. Association of HLA Genetic Risk Burden With Disease Phenotypes in Multiple Sclerosis

    PubMed Central

    Isobe, Noriko; Keshavan, Anisha; Gourraud, Pierre-Antoine; Zhu, Alyssa H.; Datta, Esha; Schlaeger, Regina; Caillier, Stacy J.; Santaniello, Adam; Lizée, Antoine; Himmelstein, Daniel S.; Baranzini, Sergio E.; Hollenbach, Jill; Cree, Bruce A. C.; Hauser, Stephen L.; Oksenberg, Jorge R.; Henry, Roland G.

    2016-01-01

    IMPORTANCE Although multiple HLA alleles associated with multiple sclerosis (MS) risk have been identified, genotype-phenotype studies in the HLA region remain scarce and inconclusive. OBJECTIVES To investigate whether MS risk-associated HLA alleles also affect disease phenotypes. DESIGN, SETTING, AND PARTICIPANTS A cross-sectional, case-control study comprising 652 patients with MS who had comprehensive phenotypic information and 455 individuals of European origin serving as controls was conducted at a single academic research site. Patients evaluated at the Multiple Sclerosis Center at University of California, San Francisco between July 2004 and September 2005 were invited to participate. Spinal cord imaging in the data set was acquired between July 2013 and March 2014; analysis was performed between December 2014 and December 2015. MAIN OUTCOMES AND MEASURES Cumulative HLA genetic burden (HLAGB) calculated using the most updated MS-associated HLA alleles vs clinical and magnetic resonance imaging outcomes, including age at onset, disease severity, conversion time from clinically isolated syndrome to clinically definite MS, fractions of cortical and subcortical gray matter and cerebral white matter, brain lesion volume, spinal cord gray and white matter areas, upper cervical cord area, and the ratio of gray matter to the upper cervical cord area. Multivariate modeling was applied separately for each sex data set. RESULTS Of the 652 patients with MS, 586 had no missing genetic data and were included in the HLAGB analysis. In these 586 patients (404 women [68.9%]; mean [SD] age at disease onset, 33.6 [9.4] years), HLAGB was higher than in controls (median [IQR], 0.7 [0–1.4] and 0 [−0.3 to 0.5], respectively; P = 1.8 × 10−27). A total of 619 (95.8%) had relapsing-onset MS and 27 (4.2%) had progressive-onset MS. No significant difference was observed between relapsing-onset MS and primary progressive MS. A higher HLAGB was associated with younger age at onset

  1. Common Genetic Variants Found in HLA and KIR Immune Genes in Autism Spectrum Disorder

    PubMed Central

    Torres, Anthony R.; Sweeten, Thayne L.; Johnson, Randall C.; Odell, Dennis; Westover, Jonna B.; Bray-Ward, Patricia; Ward, David C.; Davies, Christopher J.; Thomas, Aaron J.; Croen, Lisa A.; Benson, Michael

    2016-01-01

    The “common variant—common disease” hypothesis was proposed to explain diseases with strong inheritance. This model suggests that a genetic disease is the result of the combination of several common genetic variants. Common genetic variants are described as a 5% frequency differential between diseased vs. matched control populations. This theory was recently supported by an epidemiology paper stating that about 50% of genetic risk for autism resides in common variants. However, rare variants, rather than common variants, have been found in numerous genome wide genetic studies and many have concluded that the “common variant—common disease” hypothesis is incorrect. One interpretation is that rare variants are major contributors to genetic diseases and autism involves the interaction of many rare variants, especially in the brain. It is obvious there is much yet to be learned about autism genetics. Evidence has been mounting over the years indicating immune involvement in autism, particularly the HLA genes on chromosome 6 and KIR genes on chromosome 19. These two large multigene complexes have important immune functions and have been shown to interact to eliminate unwanted virally infected and malignant cells. HLA proteins have important functions in antigen presentation in adaptive immunity and specific epitopes on HLA class I proteins act as cognate ligands for KIR receptors in innate immunity. Data suggests that HLA alleles and KIR activating genes/haplotypes are common variants in different autism populations. For example, class I allele (HLA-A2 and HLA-G 14 bp-indel) frequencies are significantly increased by more than 5% over control populations (Table 2). The HLA-DR4 Class II and shared epitope frequencies are significantly above the control populations (Table 2). Three activating KIR genes: 3DS1, 2DS1, and 2DS2 have increased frequencies of 15, 22, and 14% in autism populations, respectively. There is a 6% increase in total activating KIR genes in

  2. Common Genetic Variants Found in HLA and KIR Immune Genes in Autism Spectrum Disorder.

    PubMed

    Torres, Anthony R; Sweeten, Thayne L; Johnson, Randall C; Odell, Dennis; Westover, Jonna B; Bray-Ward, Patricia; Ward, David C; Davies, Christopher J; Thomas, Aaron J; Croen, Lisa A; Benson, Michael

    2016-01-01

    The "common variant-common disease" hypothesis was proposed to explain diseases with strong inheritance. This model suggests that a genetic disease is the result of the combination of several common genetic variants. Common genetic variants are described as a 5% frequency differential between diseased vs. matched control populations. This theory was recently supported by an epidemiology paper stating that about 50% of genetic risk for autism resides in common variants. However, rare variants, rather than common variants, have been found in numerous genome wide genetic studies and many have concluded that the "common variant-common disease" hypothesis is incorrect. One interpretation is that rare variants are major contributors to genetic diseases and autism involves the interaction of many rare variants, especially in the brain. It is obvious there is much yet to be learned about autism genetics. Evidence has been mounting over the years indicating immune involvement in autism, particularly the HLA genes on chromosome 6 and KIR genes on chromosome 19. These two large multigene complexes have important immune functions and have been shown to interact to eliminate unwanted virally infected and malignant cells. HLA proteins have important functions in antigen presentation in adaptive immunity and specific epitopes on HLA class I proteins act as cognate ligands for KIR receptors in innate immunity. Data suggests that HLA alleles and KIR activating genes/haplotypes are common variants in different autism populations. For example, class I allele (HLA-A2 and HLA-G 14 bp-indel) frequencies are significantly increased by more than 5% over control populations (Table 2). The HLA-DR4 Class II and shared epitope frequencies are significantly above the control populations (Table 2). Three activating KIR genes: 3DS1, 2DS1, and 2DS2 have increased frequencies of 15, 22, and 14% in autism populations, respectively. There is a 6% increase in total activating KIR genes in autism over

  3. Promiscuous CTL recognition of viral epitopes on multiple human leukocyte antigens: biological validation of the proposed HLA A24 supertype.

    PubMed

    Burrows, Scott R; Elkington, Rebecca A; Miles, John J; Green, Katherine J; Walker, Susan; Haryana, Sofia M; Moss, Denis J; Dunckley, Heather; Burrows, Jacqueline M; Khanna, Rajiv

    2003-08-01

    Multiple HLA class I alleles can bind peptides with common sequence motifs due to structural similarities in the peptide binding cleft, and these groups of alleles have been classified into supertypes. Nine major HLA supertypes have been proposed, including an A24 supertype that includes A*2301, A*2402, and A*3001. Evidence for this A24 supertype is limited to HLA sequence homology and/or similarity in peptide binding motifs for the alleles. To investigate the immunological relevance of this proposed supertype, we have examined two viral epitopes (from EBV and CMV) initially defined as HLA-A*2301-binding peptides. The data clearly demonstrate that each peptide could be recognized by CTL clones in the context of A*2301 or A*2402; thus validating the inclusion of these three alleles within an A24 supertype. Furthermore, CTL responses to the EBV epitope were detectable in both A*2301(+) and A*2402(+) individuals who had been previously exposed to this virus. These data substantiate the biological relevance of the A24 supertype, and the identification of viral epitopes with the capacity to bind promiscuously across this supertype could aid efforts to develop CTL-based vaccines or immunotherapy. The degeneracy in HLA restriction displayed by some T cells in this study also suggests that the dogma of self-MHC restriction needs some refinement to accommodate foreign peptide recognition in the context of multiple supertype alleles.

  4. Variability in the CIITA gene interacts with HLA in multiple sclerosis.

    PubMed

    Gyllenberg, A; Piehl, F; Alfredsson, L; Hillert, J; Bomfim, I L; Padyukov, L; Orho-Melander, M; Lindholm, E; Landin-Olsson, M; Lernmark, Å; Olsson, T; Kockum, I

    2014-01-01

    The human leukocyte antigen (HLA) is the main genetic determinant of multiple sclerosis (MS) risk. Within the HLA, the class II HLA-DRB1*15:01 allele exerts a disease-promoting effect, whereas the class I HLA-A*02 allele is protective. The CIITA gene is crucial for expression of class II HLA molecules and has previously been found to associate with several autoimmune diseases, including MS and type 1 diabetes. We here performed association analyses with CIITA in 2000 MS cases and up to 6900 controls as well as interaction analysis with HLA. We find that the previously investigated single-nucleotide polymorphism rs4774 is associated with MS risk in cases carrying the HLA-DRB1*15 allele (P=0.01, odds ratio (OR): 1.21, 95% confidence interval (CI): 1.04-1.40) or the HLA-A*02 allele (P=0.01, OR: 1.33, 95% CI: 1.07-1.64) and that these associations are independent of the adjacent confirmed MS susceptibility gene CLEC16A. We also confirm interaction between rs4774 and HLA-DRB1*15:01 such that individuals carrying the risk allele for rs4774 and HLA-DRB1*15:01 have a higher than expected risk for MS. In conclusion, our findings support previous data that variability in the CIITA gene affects MS risk, but also that the effect is modulated by MS-associated HLA haplotypes. These findings further underscore the biological importance of HLA for MS risk.

  5. Multiple order common path spectrometer

    NASA Technical Reports Server (NTRS)

    Newbury, Amy B. (Inventor)

    2010-01-01

    The present invention relates to a dispersive spectrometer. The spectrometer allows detection of multiple orders of light on a single focal plane array by splitting the orders spatially using a dichroic assembly. A conventional dispersion mechanism such as a defraction grating disperses the light spectrally. As a result, multiple wavelength orders can be imaged on a single focal plane array of limited spectral extent, doubling (or more) the number of spectral channels as compared to a conventional spectrometer. In addition, this is achieved in a common path device.

  6. Human leucocyte antigen (HLA) class I and II typing in Belgian multiple sclerosis patients.

    PubMed

    Lysandropoulos, Andreas P; Racapé, Judith; Holovska, Vanda; Toungouz, Michel

    2017-03-01

    This is one of the first studies to compare the frequencies of different human leucocyte antigen (HLA) class I and II alleles and haplotype HLA-DRB1*15-DQB1*06 in a cohort of 119 patients with multiple sclerosis (MS) and a cohort of 124 healthy controls in Belgium. An association with MS was found for the HLA-DRB1*15 (odds ratio [OR] 2.60 [95% confidence interval (CI) 1.51-4.50]) and HLA-DQB1*06 (OR 1.97 [95% CI 1.18-3.29]) alleles, and for haplotype DRB1*15-DQB1*06 (OR 2.63 [95% CI 1.52-4.56]). The HLA-B*07 allele also tended to be more frequent in MS patients (OR 1.46 [95% CI 0.80-2.65]) and more frequent among MS patients with than in those without the HLA-DRB1*15 allele (26/54 [48.1%] versus 6/65 [9.2%]; p value <0.0001). Other alleles were underrepresented in MS patients, such as the HLA-DRB1*07 (OR 0.39 [95% CI 0.21-0.73]) and HLA-A*02 (OR 0.56 [95% CI 0.34-0.94]), showing a protective role against the disease. The HLA-B*44 (OR 0.58 [95% CI 0.31-1.09]) and HLA-DRB1*04 (OR 0.75 [95% CI 0.42-1.34]) alleles tended to be less frequent in MS patients. Altogether, the significant results observed in this population are in line with those from other countries and confirm that propensity to MS can be due to a complex presence of various HLA class I and class II alleles.

  7. Common variants in the HLA-DRB1-HLA-DQA1 Class II region are associated with susceptibility to visceral leishmaniasis

    PubMed Central

    Fakiola, Michaela; Strange, Amy; Cordell, Heather J.; Miller, E. Nancy; Pirinen, Matti; Su, Zhan; Mishra, Anshuman; Mehrotra, Sanjana; Monteiro, Gloria R.; Band, Gavin; Bellenguez, Céline; Dronov, Serge; Edkins, Sarah; Freeman, Colin; Giannoulatou, Eleni; Gray, Emma; Hunt, Sarah E.; Lacerda, Henio G.; Langford, Cordelia; Pearson, Richard; Pontes, Núbia N.; Rai, Madhukar; Singh, S.P.; Smith, Linda; Sousa, Olivia; Vukcevic, Damjan; Bramon, Elvira; Brown, Matthew A.; Casas, Juan P.; Corvin, Aiden; Duncanson, Audrey; Jankowski, Janusz; Markus, Hugh S.; Mathew, Christopher G.; Palmer, Colin N.A.; Plomin, Robert; Rautanen, Anna; Sawcer, Stephen J.; Trembath, Richard C.; Viswanathan, Ananth C.; Wood, Nicholas W.; Wilson, Mary E.; Deloukas, Panos; Peltonen, Leena; Christiansen, Frank; Witt, Campbell; Jeronimo, Selma M.B.; Sundar, Shyam; Spencer, Chris C.A.; Blackwell, Jenefer M.; Donnelly, Peter

    2013-01-01

    To identify susceptibility loci for visceral leishmaniasis we undertook genome-wide association studies in two populations; 989 cases and 1089 controls from India, and 357 cases in 308 Brazilian families (1970 individuals). The HLA-DRB1-HLA-DQA1 locus was the only region to show strong evidence of association in both populations. Replication at this region was undertaken in a second Indian population comprising 941 cases and 990 controls, resulting in Pcombined=2.76×10−17 and OR(95%CI)=1.41(1.30-1.52) across the three cohorts at rs9271858. A conditional analysis provided evidence for multiple associations within the HLA-DRB1-HLA-DQA1 region, and a model in which risk differed between three groups of haplotypes better explained the signal and was significant in the Indian discovery and replication cohorts. In conclusion the HLA-DRB1-HLA-DQA1 HLA class II region contributes to visceral leishmaniasis susceptibility in India and Brazil, suggesting shared genetic risk factors for visceral leishmaniasis that cross the epidemiological divides of geography and parasite species. PMID:23291585

  8. Five HLA-DP Molecules Frequently Expressed in the Worldwide Human Population Share a Common HLA Supertypic Binding Specificity

    PubMed Central

    Sidney, John; Steen, Amiyah; Moore, Carrie; Ngo, Sandy; Chung, Jolan; Peters, Bjoern; Sette, Alessandro

    2010-01-01

    Compared with DR and DQ, knowledge of the binding repertoires and specificities of HLA-DP alleles is somewhat limited. However, a growing body of literature has indicated the importance of DP-restricted responses in the context of cancer, allergy, and infectious disease. In the current study, we developed high-throughput binding assays for the five most common HLA-DPB1 alleles in the general worldwide population. Using these assays on a comprehensive panel of single-substitution analogs and large peptide libraries, we derived novel detailed binding motifs for DPB1*0101 and DPB1*0501. We also derived more detailed quantitative motifs for DPB1*0201, DPB1*0401, and DPB1*0402, which were previously characterized on the basis of sets of eluted ligands and/or limited sets of substituted peptides. Unexpectedly, all five DP molecules, originally selected only on the basis of their frequency in human populations, were found to share largely overlapping peptide motifs. Testing panels of known DP epitopes and a panel of peptides spanning a set of Phleum pratense Ags revealed that these molecules also share largely overlapping peptide-binding repertoires. This demonstrates that a previously hypothesized DP supertype extends far beyond what was originally envisioned and includes at least three additional very common DP specificities. Taken together, these DP supertype molecules are found in >90% of the human population. Thus, these findings have important implications for epitope-identification studies and monitoring of human class II-restricted immune responses. PMID:20139279

  9. Influence of HLA-C Expression Level on HIV Control

    PubMed Central

    Apps, Richard; Qi, Ying; Carlson, Jonathan M.; Chen, Haoyan; Gao, Xiaojiang; Thomas, Rasmi; Yuki, Yuko; Del Prete, Greg Q.; Goulder, Philip; Brumme, Zabrina L.; Brumme, Chanson J.; John, Mina; Mallal, Simon; Nelson, George; Bosch, Ronald; Heckerman, David; Stein, Judy L.; Soderberg, Kelly A.; Moody, M. Anthony; Denny, Thomas N.; Zeng, Xue; Fang, Jingyuan; Moffett, Ashley; Lifson, Jeffrey D.; Goedert, James J.; Buchbinder, Susan; Kirk, Gregory D.; Fellay, Jacques; McLaren, Paul; Deeks, Steven G.; Pereyra, Florencia; Walker, Bruce; Michael, Nelson L.; Weintrob, Amy; Wolinsky, Steven; Liao, Wilson; Carrington, Mary

    2013-01-01

    A variant upstream of human leukocyte antigen C (HLA-C) shows the most significant genome-wide effect on HIV control in European Americans and is also associated with the level of HLA-C expression. We characterized the differential cell surface expression levels of all common HLA-C allotypes and tested directly for effects of HLA-C expression on outcomes of HIV infection in 5243 individuals. Increasing HLA-C expression was associated with protection against multiple outcomes independently of individual HLA allelic effects in both African and European Americans, regardless of their distinct HLA-C frequencies and linkage relationships with HLA-B and HLA-A. Higher HLA-C expression was correlated with increased likelihood of cytotoxic T lymphocyte responses and frequency of viral escape mutation. In contrast, high HLA-C expression had a deleterious effect in Crohn’s disease, suggesting a broader influence of HLA expression levels in human disease. PMID:23559252

  10. 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

  11. 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.

  12. HLA-DR2 dose effect on susceptibility to multiple sclerosis and influence on disease course.

    PubMed

    Barcellos, L F; Oksenberg, J R; Begovich, A B; Martin, E R; Schmidt, S; Vittinghoff, E; Goodin, D S; Pelletier, D; Lincoln, R R; Bucher, P; Swerdlin, A; Pericak-Vance, M A; Haines, J L; Hauser, S L

    2003-03-01

    Models of disease susceptibility in multiple sclerosis (MS) often assume a dominant action for the HLA-DRB1*1501 allele and its associated haplotype (DRB1*1501-DQB1*0602 or DR2). A robust and phenotypically well-characterized MS data set was used to explore this model in more detail. A dose effect of HLA-DR2 haplotypes on MS susceptibility was revealed. This observation suggests that, in addition to the role of HLA-DR2 in MS, two copies of a susceptibility haplotype further increase disease risk. Second, we report that DR2 haplotypes modify disease expression. There is a paucity of benign MS and an increase of severe MS in individuals homozygous for DR2. Concepts of the molecular mechanisms that underlie linkage and association of the human leukocyte antigen (HLA) region to MS need to be revised to accommodate these data.

  13. HLA-DR2 Dose Effect on Susceptibility to Multiple Sclerosis and Influence on Disease Course

    PubMed Central

    Barcellos, L. F.; Oksenberg, J. R.; Begovich, A. B.; Martin, E. R.; Schmidt, S.; Vittinghoff, E.; Goodin, D. S.; Pelletier, D.; Lincoln, R. R.; Bucher, P.; Swerdlin, A.; Pericak-Vance, M. A.; Haines, J. L.; Hauser, S. L.

    2003-01-01

    Models of disease susceptibility in multiple sclerosis (MS) often assume a dominant action for the HLA-DRB1*1501 allele and its associated haplotype (DRB1*1501-DQB1*0602 or DR2). A robust and phenotypically well-characterized MS data set was used to explore this model in more detail. A dose effect of HLA-DR2 haplotypes on MS susceptibility was revealed. This observation suggests that, in addition to the role of HLA-DR2 in MS, two copies of a susceptibility haplotype further increase disease risk. Second, we report that DR2 haplotypes modify disease expression. There is a paucity of benign MS and an increase of severe MS in individuals homozygous for DR2. Concepts of the molecular mechanisms that underlie linkage and association of the human leukocyte antigen (HLA) region to MS need to be revised to accommodate these data. PMID:12557126

  14. Unraveling Multiple MHC Gene Associations with Systemic Lupus Erythematosus: Model Choice Indicates a Role for HLA Alleles and Non-HLA Genes in Europeans

    PubMed Central

    Morris, David L.; Taylor, Kimberly E.; Fernando, Michelle M.A.; Nititham, Joanne; Alarcón-Riquelme, Marta E.; Barcellos, Lisa F.; Behrens, Timothy W.; Cotsapas, Chris; Gaffney, Patrick M.; Graham, Robert R.; Pons-Estel, Bernardo A.; Gregersen, Peter K.; Harley, John B.; Hauser, Stephen L.; Hom, Geoffrey; Langefeld, Carl D.; Noble, Janelle A.; Rioux, John D.; Seldin, Michael F.; Criswell, Lindsey A.; Vyse, Timothy J.

    2012-01-01

    We have performed a meta-analysis of the major-histocompatibility-complex (MHC) region in systemic lupus erythematosus (SLE) to determine the association with both SNPs and classical human-leukocyte-antigen (HLA) alleles. More specifically, we combined results from six studies and well-known out-of-study control data sets, providing us with 3,701 independent SLE cases and 12,110 independent controls of European ancestry. This study used genotypes for 7,199 SNPs within the MHC region and for classical HLA alleles (typed and imputed). Our results from conditional analysis and model choice with the use of the Bayesian information criterion show that the best model for SLE association includes both classical loci (HLA-DRB1∗03:01, HLA-DRB1∗08:01, and HLA-DQA1∗01:02) and two SNPs, rs8192591 (in class III and upstream of NOTCH4) and rs2246618 (MICB in class I). Our approach was to perform a stepwise search from multiple baseline models deduced from a priori evidence on HLA-DRB1 lupus-associated alleles, a stepwise regression on SNPs alone, and a stepwise regression on HLA alleles. With this approach, we were able to identify a model that was an overwhelmingly better fit to the data than one identified by simple stepwise regression either on SNPs alone (Bayes factor [BF] > 50) or on classical HLA alleles alone (BF > 1,000). PMID:23084292

  15. Unraveling multiple MHC gene associations with systemic lupus erythematosus: model choice indicates a role for HLA alleles and non-HLA genes in Europeans.

    PubMed

    Morris, David L; Taylor, Kimberly E; Fernando, Michelle M A; Nititham, Joanne; Alarcón-Riquelme, Marta E; Barcellos, Lisa F; Behrens, Timothy W; Cotsapas, Chris; Gaffney, Patrick M; Graham, Robert R; Pons-Estel, Bernardo A; Gregersen, Peter K; Harley, John B; Hauser, Stephen L; Hom, Geoffrey; Langefeld, Carl D; Noble, Janelle A; Rioux, John D; Seldin, Michael F; Criswell, Lindsey A; Vyse, Timothy J

    2012-11-02

    We have performed a meta-analysis of the major-histocompatibility-complex (MHC) region in systemic lupus erythematosus (SLE) to determine the association with both SNPs and classical human-leukocyte-antigen (HLA) alleles. More specifically, we combined results from six studies and well-known out-of-study control data sets, providing us with 3,701 independent SLE cases and 12,110 independent controls of European ancestry. This study used genotypes for 7,199 SNPs within the MHC region and for classical HLA alleles (typed and imputed). Our results from conditional analysis and model choice with the use of the Bayesian information criterion show that the best model for SLE association includes both classical loci (HLA-DRB1(∗)03:01, HLA-DRB1(∗)08:01, and HLA-DQA1(∗)01:02) and two SNPs, rs8192591 (in class III and upstream of NOTCH4) and rs2246618 (MICB in class I). Our approach was to perform a stepwise search from multiple baseline models deduced from a priori evidence on HLA-DRB1 lupus-associated alleles, a stepwise regression on SNPs alone, and a stepwise regression on HLA alleles. With this approach, we were able to identify a model that was an overwhelmingly better fit to the data than one identified by simple stepwise regression either on SNPs alone (Bayes factor [BF] > 50) or on classical HLA alleles alone (BF > 1,000).

  16. Redundancy in Antigen-Presenting Function of the HLA-DR and -DQ Molecules in the Multiple Sclerosis-Associated HLA-DR2 Haplotype1

    PubMed Central

    Sospedra, Mireia; Muraro, Paolo A.; Stefanová, Irena; Zhao, Yingdong; Chung, Katherine; Li, Yili; Giulianotti, Marc; Simon, Richard; Mariuzza, Roy; Pinilla, Clemencia; Martin, Roland

    2009-01-01

    The three HLA class II alleles of the DR2 haplotype, DRB1*1501, DRB5*0101, and DQB1*0602, are in strong linkage disequilibrium and confer most of the genetic risk to multiple sclerosis. Functional redundancy in Ag presentation by these class II molecules would allow recognition by a single TCR of identical peptides with the different restriction elements, facilitating T cell activation and providing one explanation how a disease-associated HLA haplotype could be linked to a CD4+ T cell-mediated autoimmune disease. Using combinatorial peptide libraries and B cell lines expressing single HLA-DR/DQ molecules, we show that two of five in vivo-expanded and likely disease-relevant, cross-reactive cerebrospinal fluid-infiltrating T cell clones use multiple disease-associated HLA class II molecules as restriction elements. One of these T cell clones recognizes >30 identical foreign and human peptides using all DR and DQ molecules of the multiple sclerosis-associated DR2 haplotype. A T cell signaling machinery tuned for efficient responses to weak ligands together with structural features of the TCR-HLA/peptide complex result in this promiscuous HLA class II restriction. PMID:16424227

  17. Examination of four HLA class I pseudogenes: Common events in the evolution of HLA genes and pseudogenes

    SciTech Connect

    Geraghty, D.E.; Pei, J. ); Koller, B.H. ); Hansen, J.A. )

    1992-09-15

    The HLA class I gene family in lymphoblastoid cell line 721 has been studied in detail and a number of sequences in addition to the classical genes have been identified. The cloning, characterization, and nucleotide sequences of four sequences, all full length HLA class I pseudogenes, are described in this report. These pseudogenes, contained within 5.4-, 5.9-, 7.0-, and 9.2-kb HindIII fragments, each have the class I exon-intron structure as well as class I homology in their 5[prime] and 3[prime] flanking regions. However, all four sequences have one or more substitutions that perturb the coding region, leaving little doubt that they are in fact pseudogenes. Comparisons among these sequences and the HLA class I genes revealed that their homology with the class I genes is patchwork. Thus, although some regions have diverged, other contiguous intron-exon sequences are highly conserved. Comparisons in the 5[prime] regions indicate that the pseudogene promoters more closely resemble the classical HLA promoters than the nonclassical promoters as none of the unique structural features found in the HLA-E, -F, or -G regulatory regions are present in any of the pseudogene promoters. Further comparisons revealed that at least two putative gene conversion events, similar to those hypothesized to have occurred in the evolution of some HLA genes, may have occurred in the evolution of some of the pseudogenes. These and other hypothetical events in the evolution of the class I gene family are discussed. 47 refs., 6 figs., 2 tabs.

  18. Mapping Multiple Sclerosis Susceptibility to the HLA-DR Locus in African Americans

    PubMed Central

    Oksenberg, Jorge R.; Barcellos, Lisa F.; Cree, Bruce A. C.; Baranzini, Sergio E.; Bugawan, Teodorica L.; Khan, Omar; Lincoln, Robin R.; Swerdlin, Amy; Mignot, Emmanuel; Lin, Ling; Goodin, Douglas; Erlich, Henry A.; Schmidt, Silke; Thomson, Glenys; Reich, David E.; Pericak-Vance, Margaret A.; Haines, Jonathan L.; Hauser, Stephen L.

    2004-01-01

    An underlying complex genetic susceptibility exists in multiple sclerosis (MS), and an association with the HLA-DRB1*1501-DQB1*0602 haplotype has been repeatedly demonstrated in high-risk (northern European) populations. It is unknown whether the effect is explained by the HLA-DRB1 or the HLA-DQB1 gene within the susceptibility haplotype, which are in strong linkage disequilibrium (LD). African populations are characterized by greater haplotypic diversity and distinct patterns of LD compared with northern Europeans. To better localize the HLA gene responsible for MS susceptibility, case-control and family-based association studies were performed for DRB1 and DQB1 loci in a large and well-characterized African American data set. A selective association with HLA-DRB1*15 was revealed, indicating a primary role for the DRB1 locus in MS independent of DQB1*0602. This finding is unlikely to be solely explained by admixture, since a substantial proportion of the susceptibility chromosomes from African American patients with MS displayed haplotypes consistent with an African origin. PMID:14669136

  19. High-Density SNP Mapping of the HLA Region Identifies Multiple Independent Susceptibility Loci Associated with Selective IgA Deficiency

    PubMed Central

    Ferreira, Ricardo C.; Pan-Hammarström, Qiang; Graham, Robert R.; Fontán, Gumersindo; Lee, Annette T.; Ortmann, Ward; Wang, Ning; Urcelay, Elena; Fernández-Arquero, Miguel; Núñez, Concepción; Jorgensen, Gudmundur; Ludviksson, Björn R.; Koskinen, Sinikka; Haimila, Katri; Padyukov, Leonid; Gregersen, Peter K.

    2012-01-01

    Selective IgA deficiency (IgAD; serum IgA<0.07 g/l) is the most common form of human primary immune deficiency, affecting approximately 1∶600 individuals in populations of Northern European ancestry. The polygenic nature of IgAD is underscored by the recent identification of several new risk genes in a genome-wide association study. Among the characterized susceptibility loci, the association with specific HLA haplotypes represents the major genetic risk factor for IgAD. Despite the robust association, the nature and location of the causal variants in the HLA region remains unknown. To better characterize the association signal in this region, we performed a high-density SNP mapping of the HLA locus and imputed the genotypes of common HLA-B, -DRB1, and -DQB1 alleles in a combined sample of 772 IgAD patients and 1,976 matched controls from 3 independent European populations. We confirmed the complex nature of the association with the HLA locus, which is the result of multiple effects spanning the entire HLA region. The primary association signal mapped to the HLA-DQB1*02 allele in the HLA Class II region (combined P = 7.69×10−57; OR = 2.80) resulting from the combined independent effects of the HLA-B*0801-DRB1*0301-DQB1*02 and -DRB1*0701-DQB1*02 haplotypes, while additional secondary signals were associated with the DRB1*0102 (combined P = 5.86×10−17; OR = 4.28) and the DRB1*1501 (combined P = 2.24×10−35; OR = 0.13) alleles. Despite the strong population-specific frequencies of HLA alleles, we found a remarkable conservation of these effects regardless of the ethnic background, which supports the use of large multi-ethnic populations to characterize shared genetic association signals in the HLA region. We also provide evidence for the location of association signals within the specific extended haplotypes, which will guide future sequencing studies aimed at characterizing the precise functional variants contributing to disease

  20. Structure of HLA-A*0301 in complex with a peptide of proteolipid protein: insights into the role of HLA-A alleles in susceptibility to multiple sclerosis

    SciTech Connect

    McMahon, Róisín M.; Friis, Lone; Siebold, Christian; Friese, Manuel A.; Fugger, Lars; Jones, E. Yvonne

    2011-05-01

    The structure of the human major histocompatability (MHC) class I molecule HLA-A*0301 (HLA-A3) in complex with a nonameric peptide (KLIETYFSK) has been determined by X-ray crystallography to 2.7 Å resolution. The structure of the human major histocompatability (MHC) class I molecule HLA-A*0301 (HLA-A3) in complex with a nonameric peptide (KLIETYFSK) has been determined by X-ray crystallography to 2.7 Å resolution. HLA-A3 is a predisposing allele for multiple sclerosis (MS), an autoimmune disease of the central nervous system. The KLIETYFSK peptide is a naturally processed epitope of proteolipid protein, a myelin protein and candidate target for immune-mediated myelin destruction in MS. Comparison of the structure of HLA-A3 with that of HLA-A2, an MHC class I molecule which is protective against MS, indicates that both MHC class I molecules present very similar faces for T-cell receptor recognition whilst differing in the specificity of their peptide-binding grooves. These characteristics may underlie the opposing (predisposing versus protective) associations that they exhibit both in humans and in mouse models of MS-like disease. Furthermore, subtle alterations within the peptide-binding groove of HLA-A3 and other A3-like MHC class I molecules, members of the so-called A3 superfamily, may be sufficient to alter their presentation of autoantigen peptides such as KLIETYFSK. This in turn may modulate their contribution to the associated risk of autoimmune disease.

  1. Genetic factors and multiple sclerosis in the Moroccan population: a role for HLA class II.

    PubMed

    Ouadghiri, S; El Alaoui Toussi, K; Brick, C; Ait Benhaddou, E H; Benseffaj, N; Benomar, A; El Yahyaoui, M; Essakalli, M

    2013-12-01

    Multiple sclerosis (MS) is an autoimmune inflammatory demyelinating disease of the central nervous system that mainly affects young adults. The association between susceptibility to MS and HLA class II genes, in particular the DRB1*15 allele, has been reported in diverse ethnic groups. The aim of our study was to investigate the distribution of HLA-DRB1* and -DQB1* alleles in Moroccan population and their implication in the susceptibility to the disease. Fifty-seven MS patients were compared to 172 healthy controls unrelated to one another and matched by age, sex and ethnic origin. HLA class II (DRB1* and DQB1*) typing was performed by PCR-SSP and/or Luminex (PCR-SSO). Allelic and haplotypic frequencies, P-values, odds ratio (OR) and 95% confidence interval (CI) were calculated using the software SPSS. A significant increase of DRB1*15 allele frequency (17.6% vs 8.4%, OR=2.67, 95% CI=1.36-5.23, P=0.004) and HLA-DRB1*15-DQB1*06 haplotype (8.8% vs 4.08%, OR=2.78, 95% CI=1.41-5.48, P=0.002) were observed in Moroccan MS patients. No association of the DR15 allele with sex or age at onset was appreciated. Concerning HLA-DQB1* alleles, no significant difference between patients and controls was found. Our results reveal a role for HLA-DRB1*15 allele molecules in the predisposition of Moroccan patients to MS. Although this study should be confirmed on a larger sample size, it analyzes for the first time the possible role of a genetic marker for susceptibility to MS in Moroccan population. Copyright © 2013 Elsevier Masson SAS. All rights reserved.

  2. Common phenotype and different non-HLA genes in Graves' disease and alopecia areata.

    PubMed

    Taketomo, Yasunori; Noso, Shinsuke; Babaya, Naru; Hiromine, Yoshihisa; Ito, Hiroyuki; Kanto, Kousei; Niwano, Fumimaru; Oiso, Naoki; Kawada, Akira; Kawabata, Yumiko; Ikegami, Hiroshi

    2017-02-01

    Our previous observations clarified that Graves' disease (GD) is the most frequent autoimmune disease in patients with alopecia areata (AA), and 42.7% of patients with AA were positive for thyrotropin receptor antibody (TRAb). A class II HLA haplotype DRB1(∗)15:01-DQB1(∗)06:02 was suggested to contribute to autoimmunity against the thyroid gland in AA. To further clarify the genetic factors contributing to organ specificity in autoimmune diseases, we studied the contribution of non-HLA genes to organ specificity in GD and AA. A high frequency of AA (13.4%) was observed in patients with GD, indicating strong phenotypic association between GD and AA. CTLA4 and TSHR were significantly associated with GD (Pc=0.007 and Pc<0.002, respectively), but not with AA, even in TRAb-positive patients. The difference in the association between GD and AA suggests that the CTLA4 and TSHR are not main factors contributing to determining common genetic basis among GD and AA.

  3. 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.

  4. HLA-class I markers and multiple sclerosis susceptibility in the Italian population

    PubMed Central

    Bergamaschi, L; Leone, M A; Fasano, M E; Guerini, F R; Ferrante, D; Bolognesi, E; Barizzone, N; Corrado, L; Naldi, P; Agliardi, C; Dametto, E; Salvetti, M; Visconti, A; Galimberti, D; Scarpini, E; Vercellino, M; Bergamaschi, R; Monaco, F; Caputo, D; Momigliano-Richiardi, P; D'Alfonso, S

    2009-01-01

    Previous studies reported an association with multiple sclerosis (MS) of distinct HLA-class I markers, namely HLA-A*02, HLA-Cw*05 and MOG-142L. In this work, we tested the association with MS of A*02 and Cw*05 in 1273 Italian MS patients and 1075 matched controls, which were previously analyzed for MOG-142, and explored the relationship among these three markers in modulating MS risk. HLA-A*02 conferred a statistically robust MS protection (odds ratio, OR=0.61; 95% confidence intervals, CI=0.51–0.72, P<10−9), which was independent of DRB1*15 and of any other DRB1* allele and remained similar after accounting for the other two analyzed class I markers. Conversely, the protective effect we previously observed for MOG-142L was secondary to its linkage disequilibrium with A*02. Cw*05 was not associated considering the whole sample, but its presence significantly enhanced the protection in the HLA-A*02-positive group, independently of DRB1: the OR conferred by A*02 in Cw*05-positive individuals (0.22, 95% CI=0.13–0.38) was significantly lower than in Cw*05-negative individuals (0.69, 95% CI=0.58–0.83) with a significant (P=4.94 × 10−5) multiplicative interaction between the two markers. In the absence of A*02, Cw*05 behaved as a risk factor, particularly in combination with DRB1*03 (OR=3.89, P=0.0006), indicating that Cw*05 might be a marker of protective or risk haplotypes, respectively. PMID:19907433

  5. The Association of HLA Class 1 and Class 2 Antigens with Multiple Myeloma in Iranian Patients.

    PubMed

    Sayad, Arezou; Akbari, Mohammad Taghi; Mehdizadeh, Mahshid; Roshandel, Elham; Abedinpour, Soheila; Hajifathali, Abbas

    2014-12-05

    Amaç: Multiple myeloma (MM), malign plazma hürelerinin klonal çoğalması ile karakterize bir B hücre neoplazisidir. Çeşitli çalışmaların sonuçlarına göre, bazı sınıf 1 ve 2 HLA genlerinin hastalığa yatkınlık sağladığına dair görüşler ortaya atılmıştır. Farklı popülasyonlarda yapılan çalışmalarda, farklı HLA sınıf 1 ve 2 allellerinin MM üzerine etkisi olduğu bildirilmiştir. Bu çalışmada, İranlı MM hastalarında HLA sınıf 1 ve sınıf 2 antijenlerinin birlikteliğini değerlendirdik. Gereç ve Yöntemler: HLA-Ready Gene ABDR kitleriyle tekli spesifik primer polimeraz zincir reaksiyonu yönteminin kullanıldığı bu olgu-kontrol genetiplendirme çalışmasında, hasta grubuna Taleghani Hastanesi kemik iliği nakli bölümünden seçilen 105 İranlı MM hastası ve 150 de kontrol olgusu dahil edilmiştir.Bulgular: Çalışma sonucunda, HLA-A*03 hasta grubunda %21 ve kontrol grubunda %12 bulunurken, HLA-B*18 ise hasta grubunda %11 ve kontrol grubunda %3 olarak saptanmıştır. MM hastalarının HLA-A*03 ve HLA-B*18 allele sahip olma oranı kontrol olgularıyla karşılaştırıldığında istatistiki olarak anlamlı olacak şekilde yüksek bulunmuştur (p=0,039, OR=2,057 ve p=0,013, OR=3,567, sırasıyla). Sonuç: Bizim bulgularımız, İran toplumunda HLA-A*03 ve HLA-B*18 allel varlığının istatistiki olarak anlamlı olacak şekilde MM’ye yatkınlık yarattığını ortaya koymaktadır. Bununla birlikte, diğer toplumlara bakıldığında adı geçen allellerin aynı sonucu doğurmadıkları görülmektedir. Farklı etnik gruplar arasındaki bu birlikteliği değerlendiren fazla sayıda çalışma olmadığı için, gelecek dönemlerde MM’li hastalarda HLA genlerinin birlikteliğinin sonuçlarını izah edebilecek daha ayrıntılı çalışmalara gereksinim vardır.

  6. HLA-DRB*1501 associations with magnetic resonance imaging measures of grey matter pathology in multiple sclerosis.

    PubMed

    Yaldizli, Özgür; Sethi, Varun; Pardini, Matteo; Tur, Carmen; Mok, Kin Y; Muhlert, Nils; Liu, Zheng; Samson, Rebecca S; Wheeler-Kingshott, Claudia A M; Yousry, Tarek A; Houlden, Henry; Hardy, John; Miller, David H; Chard, Declan T

    2016-05-01

    The HLA-DRB*1501 haplotype influences the risk of developing multiple sclerosis (MS), but it is not known how it affects grey matter pathology. To assess HLA-DRB(*)1501 effects on magnetic resonance imaging (MRI) cortical grey matter pathology. Whole and lesional cortical grey matter volumes, lesional and normal-appearing grey matter magnetization transfer ratio were measured in 85 people with MS and 36 healthy control subjects. HLA-DRB(*)1501 haplotype was determined by genotyping (rs3135388). No significant differences were observed in MRI measures between the HLA-DRB(*)1501 subgroups. The HLA-DRB(*)1501 haplotype is not strongly associated with MRI-visible grey matter pathology. Copyright © 2016 Elsevier B.V. All rights reserved.

  7. HLA-DR-dependent variation of intrathecal IgG1 (Gm) allotype synthesis in multiple sclerosis.

    PubMed

    Salier, J P; Martin-Mondiere, C; Sesboüé, R; Daveau, M; Goust, J M; Govaerts, A; Schuller, E; Degos, J D

    1985-03-01

    Genetic susceptibility to multiple sclerosis (MS) in Caucasians was previously shown to be correlated to the presence of given alleles at the HLA-DR and Gm loci. We now demonstrate that the humoral immune response in MS central nervous system (CNS) is modulated by both loci: the levels of IgG1 subclass and IgG1 allotypes in cerebrospinal fluid of MS patients depend on both their Gm genotype and their HLA-DR2 or HLA-DR7 phenotype. That HLA-DR molecules may either participate in a preferential recruitment of IgG1 allotype-producing B cells in MS CNS or act after such a selective homing is discussed. These results demonstrate that both HLA and Gm loci are synergistically involved in the modulation of the humoral immune response.

  8. HLA-B35, a common genetic trait, in a familial case of Henoch-Schoenlein purpura and Berger's disease.

    PubMed

    Pellegrin, M C; Matarazzo, L; Neri, E; Pennesi, M; Crovella, S

    2014-04-08

    Nephritis characterized by IgA mesangial depositions has been described both in Henoch-Schoenlein purpura (HSP) and in Berger's disease (BD), but common genetic traits are still uncertain. We report here the case of two brothers, the first affected by HSP with persistent nephritis and the second by BD, accidentally discovered as silent microhematuria 1 year after HSP onset in the first brother. HLA genotyping demonstrated the presence of HLA-B35 in both patients. Our findings reinforce the need to screen for urinary abnormalities in family members of patients affected by HSP nephritis to identify a silent IgA nephropathy.

  9. Filling the gaps - the generation of full genomic sequences for 15 common and well-documented HLA class I alleles using next-generation sequencing technology.

    PubMed

    Lind, C; Ferriola, D; Mackiewicz, K; Papazoglou, A; Sasson, A; Monos, D

    2013-03-01

    Many common and well-documented (CWD) HLA alleles have only been partially characterized. The DNA sequence of these incomplete alleles, as published in the IMGT/HLA database, is most often limited to exons that code for the extracellular domains of the mature protein. Here we describe the application of next-generation sequencing technology to obtain full length genomic sequence from a single long-range PCR amplicon for 15 common and well-documented HLA Class I alleles. This technology is well suited to fill in the gaps of the current HLA allele sequence database which is largely incomplete. A more comprehensive catalog of HLA allele sequences would be beneficial in the evaluation of mismatches in transplantation, studies of population genetics, the evolution of HLAs, regulatory mechanisms and HLA expression, and issues related to the genomic organization of the MHC. Copyright © 2012. Published by Elsevier Inc.

  10. HLA-DRB1*14 is a protective allele for multiple sclerosis in an admixed Colombian population.

    PubMed

    Toro, Jaime; Cuellar-Giraldo, David; Díaz-Cruz, Camilo; Burbano, Lisseth-Estefania; Guío, Claudia-Marcela; Reyes, Saúl; Cortes, Fabián; Cárdenas-Robledo, Simón; Narváez, Diana M; Cárdenas, Wilmer; Porras, Alexandra; Lattig, María-Claudia; Groot de Restrepo, Helena

    2016-02-01

    The aim of this study was to determine ancestry informative markers, mitochondrial DNA haplogroups, and the association between HLA-DRB1 alleles and multiple sclerosis (MS) in a group of patients from Bogotá, Colombia. In this case-control study, genomic DNA was isolated and purified from blood samples. HLA-DRB1 allele genotyping was done using PCR. Mitochondrial hypervariable region 1 was amplified and haplogroups were determined using HaploGrep software. Genomic ancestry was estimated by genotyping a panel of ancestry informative markers. To test the association of HLA polymorphisms and MS, we ran separate multivariate logistic regression models. Bonferroni correction was used to account for multiple regression tests. A total of 100 patients with MS (mean age 40.4 ± 12 years; 70% females) and 200 healthy controls (mean age 37.6 ± 11 years; 83.5% females) were included in the analysis. Ancestry proportions and haplogroup frequencies did not differ between patients and controls. HLA-DRB1*15 was present in 31% of cases and 13.5% of controls, whereas HLA-DRB1*14 was present in 5% of cases and 15.5% of controls. In the multivariate model, HLA-DRB1*15 was significantly associated with MS (odds ratio [OR] = 3.05, p < 0.001), whereas HLA-DRB1*14 was confirmed as a protective factor in our population (OR = 0.16, p = 0.001). This study provides evidence indicating that HLA-DRB1*15 allele confers susceptibility to MS and HLA-DRB1*14 allele exerts resistance to MS in a highly admixed population. This latter finding could partially explain the low prevalence of MS in Bogotá, Colombia.

  11. HLA-DRB1*14 is a protective allele for multiple sclerosis in an admixed Colombian population

    PubMed Central

    Cuellar-Giraldo, David; Díaz-Cruz, Camilo; Burbano, Lisseth-Estefania; Guío, Claudia-Marcela; Reyes, Saúl; Cortes, Fabián; Cárdenas-Robledo, Simón; Narváez, Diana M.; Cárdenas, Wilmer; Porras, Alexandra; Lattig, María-Claudia; Groot de Restrepo, Helena

    2015-01-01

    Objective: The aim of this study was to determine ancestry informative markers, mitochondrial DNA haplogroups, and the association between HLA-DRB1 alleles and multiple sclerosis (MS) in a group of patients from Bogotá, Colombia. Methods: In this case-control study, genomic DNA was isolated and purified from blood samples. HLA-DRB1 allele genotyping was done using PCR. Mitochondrial hypervariable region 1 was amplified and haplogroups were determined using HaploGrep software. Genomic ancestry was estimated by genotyping a panel of ancestry informative markers. To test the association of HLA polymorphisms and MS, we ran separate multivariate logistic regression models. Bonferroni correction was used to account for multiple regression tests. Results: A total of 100 patients with MS (mean age 40.4 ± 12 years; 70% females) and 200 healthy controls (mean age 37.6 ± 11 years; 83.5% females) were included in the analysis. Ancestry proportions and haplogroup frequencies did not differ between patients and controls. HLA-DRB1*15 was present in 31% of cases and 13.5% of controls, whereas HLA-DRB1*14 was present in 5% of cases and 15.5% of controls. In the multivariate model, HLA-DRB1*15 was significantly associated with MS (odds ratio [OR] = 3.05, p < 0.001), whereas HLA-DRB1*14 was confirmed as a protective factor in our population (OR = 0.16, p = 0.001). Conclusions: This study provides evidence indicating that HLA-DRB1*15 allele confers susceptibility to MS and HLA-DRB1*14 allele exerts resistance to MS in a highly admixed population. This latter finding could partially explain the low prevalence of MS in Bogotá, Colombia. PMID:26740965

  12. Multiple sclerosis in Gypsies from southern Spain: prevalence, mitochondrial DNA haplogroups and HLA class II association.

    PubMed

    Fernández, O; Fernández, V; Martinez-Cabrera, V; Mayorga, C; Alonso, A; León, A; Arnal, C; Hens, M; Luque, G; de Ramón, E; Caballero, A; Leyva, L

    2008-05-01

    Occasional reports have mentioned the prevalence of multiple sclerosis (MS) among Gypsies, and no studies have examined to date the prevalence of MS or human leukocyte antigen (HLA) genetics associations in the Spanish Gypsy population. We decided to study the prevalence, mitochondrial DNA (mtDNA) haplogroups and HLA class II distribution among gypsies with MS in southern Spain. We searched for Gypsy MS patients and studied HLA class II alleles by polymerase chain reaction with sequence-specific oligonucleotide (PCR/SSO) probe hybridization or sequence-specific primers amplification. An additional study of the mtDNA haplogroups by sequencing of the hypervariable segments of the control region was also performed to provide details of their ethnic origin. Estimated prevalence of MS in the Gypsy population in Malaga was 52/100,000. No significant differences were found in mtDNA between Gypsy MS patients and Gypsy controls. DRB1*1501, DQB1*0602 and DQB1*0608 alleles were the only positive HLA association with MS. The Gypsies in our series have the same anthropological origin as other European gypsy groups, as shown by mtDNA haplogroups. Although interpreted with great caution because of the small sample size, we found that the prevalence of MS in Gypsies in Malaga is not as low as that in Central Europe, although it is significantly less than that found in Caucasians from Spain (75-79/100,000). DQB1*0602 was the strongest positive association found with Gypsy MS patients, and DRB1*1501-DQB1*0602 was the most frequent haplotype in this group.

  13. HLA Polymorphism in Algerian Children With Lymphomas.

    PubMed

    Galleze, Assia; Raache, Rachida; Amroun, Habiba; Cherif, Nacera; Fadli, Mohamed; Meçabih, Fethi; Mecheti, Bachira; Belhani, Meriem; Bensenouci, Abdelatif; Abbadi, Mohamed C; Attal, Nabila

    2015-11-01

    Non-Hodgkin lymphoma (NHL) and Hodgkin lymphoma (HL) are the 2 types of lymphoma that represent the third most common childhood malignancy. Multiple etiological factors are involved in lymphoma pathogenesis, including viral infection, immune deficiencies, environmental agents, and genetic factors. Strong arguments supporting a genetic linkage between the susceptibility to lymphomas and human leukocyte antigens (HLA) are reported and give an idea about susceptibility or protection from the disease. Seventy-one cases were included in this study: 36 cases of non-Hodgkin lymphoma and 35 patients with Hodgkin lymphoma. Their ages ranged from 4 to 18 years. The control group consisted of 70 unrelated healthy individuals, with a mean age of 5 to 17 years. The genotype of HLA-A, HLA-B, HLA-DR, and HLA-DQ alleles was typed by means of PCR sequence-specific priming. HLA-B*18, HLA-DRB1*03, *07, and HLA-DQB1*02 were significantly increased in patients with lymphomas when compared with controls, whereas HLA-DRB1*13 and DQB1*03 were significantly decreased when compared with controls. These results indicate that HLA-B*18, DRB1*03, *07, and DQB1*02 may contribute to lymphoma susceptibility, whereas HLA-DRB1*13 and DQB1*03 may confer protection to lymphoma in the Algerian population.

  14. HLA Epitopes: The Targets of Monoclonal and Alloantibodies Defined

    PubMed Central

    Nguyen, Anh

    2017-01-01

    Sensitization to human leukocyte antigens (HLA) in organ transplant patients causes graft rejection, according to the humoral theory of transplantation. Sensitization is almost ubiquitous as anti-HLA antibodies are found in almost all sera of transplant recipients. Advances in testing assays and amino acid sequencing of HLA along with computer software contributed further to the understanding of antibody-antigen reactivity. It is commonly understood that antibodies bind to HLA antigens. With current knowledge of epitopes, it is more accurate to describe that antibodies bind to their target epitopes on the surface of HLA molecular chains. Epitopes are present on a single HLA (private epitope) or shared by multiple antigens (public epitope). The phenomenon of cross-reactivity in HLA testing, often explained as cross-reactive groups (CREGs) of antigens with antibody, can be clearly explained now by public epitopes. Since 2006, we defined and reported 194 HLA class I unique epitopes, including 56 cryptic epitopes on dissociated HLA class I heavy chains, 83 HLA class II epitopes, 60 epitopes on HLA-DRB1, 15 epitopes on HLA-DQB1, 3 epitopes on HLA-DQA1, 5 epitopes on HLA-DPB1, and 7 MICA epitopes. In this paper, we provide a summary of our findings. PMID:28626773

  15. Prevalence of HLA-B27 in Moroccan healthy subjects and patients with ankylosing spondylitis and mapping construction of several factors influencing AS diagnosis by using multiple correspondence analysis.

    PubMed

    Akassou, Amal; Yacoubi, Hanae; Jamil, Afaf; Dakka, Nadia; Amzazi, Saaïd; Sadki, Khalid; Niamane, Redouane; Elhassani, Selma; Bakri, Youssef

    2015-11-01

    The aim of the present study was to determine the prevalence of human leukocyte antigen HLA-B27 in Moroccan healthy controls and in patients with ankylosing spondylitis (AS), and to analyze the correlation between HLA-B27 and AS in Moroccan patients. The prevalence of HLA-B27 was determined by evaluating the number of HLA-B27-positive samples in 128 healthy subjects and in 53 patients diagnosed with AS according to the ESSG and AMOR criteria. HLA-B27 was determined by the polymerase chain reaction using sequence-specific primers. Multivariate analysis of our data (HLA-B27, age, sex, and family history) for AS and healthy controls was performed by multiple correspondence analysis (MCA). The frequency of HLA-B27 was significantly greater in AS patients (45.3 %) than in healthy controls (4.7 %) [p < 0.0001, OR 16.8, and CI 95 % (5.83-51.03)]. In addition, HLA-B27 was more common in male patients than in female ones (p < 0.05). 100 % of the AS patients reported a family history of AS, whereas only 20 % of the healthy controls reported a family history of AS. The graphical interpretation of MCA showed a significant relation between the presence of HLA-B27 and AS. This study strengthens the link between HLA-B27 and AS and represents a very valuable informative diagnostic tool, especially in regard to male patients who have a family history of AS.

  16. Month of birth, HLA-DRB1*15 locus and risk of multiple sclerosis in offspring.

    PubMed

    Guijarro-Castro, C; Sanchez-Zapardiel, E; Munoz, D; Fernandez, O; Leyva, L; Castro-Panete, M J; Picon-Munoz, C; Talise, M; Martinez-Feito, A; Paz-Artal, E

    2016-09-01

    Introduccion. El haplotipo HLA-DRB1*1501 es el marcador genetico que se ha asociado con un riesgo tres veces mayor de padecer esclerosis multiple (EM) en caucasicos occidentales. Recientemente se ha sabido que hay una asociacion entre el mes de nacimiento en abril, el genotipo HLA-DRB1 y el riesgo de EM en paises del norte de Europa y Canada. Esto apoya la teoria de que debe haber una interaccion entre un factor de riesgo estacional con un locus cercano al HLA-DRB1*15 durante la gestacion o cerca del posparto. Sujetos y metodos. Se realizo el genotipado de la presencia y subtipo de HLA-DRB1*1501 en 326 pacientes de dos centros espa˜oles y en 226 controles sin patologia neurologica. Se compararon los meses de nacimiento de la muestra de pacientes con los nacimientos mensuales locales en los mismos periodos. Resultados. Comparados los pacientes con EM que eran portadores del alelo HLA-DRB1*15 (10,3%) frente a los pacientes no portadores (3,8%), significativamente mas pacientes nacian en diciembre (p = 0,0185). Tambien se confirmaba el mismo mes de nacimiento de diciembre entre sanos portadores frente a no portadores de HLA-DRB1*15 y entre pacientes portadores de HLA-DRB1*15 frente a sanos. Conclusiones. El mes de nacimiento, el genotipo HLA-DRB1*15 y el riesgo de presentar EM estan asociados. A diferencia de los resultados obtenidos en paises del norte de Europa, donde esta asociacion se ha encontrado en el mes de abril, en Espa˜a es en diciembre. Se demuestra la interaccion de un factor de riesgo estacional en invierno en el locus HLA-DRB1*15 o cercano a este durante la gestacion o tras el nacimiento.

  17. Binding motifs of copolymer 1 to multiple sclerosis- and rheumatoid arthritis-associated HLA-DR molecules.

    PubMed

    Fridkis-Hareli, M; Neveu, J M; Robinson, R A; Lane, W S; Gauthier, L; Wucherpfennig, K W; Sela, M; Strominger, J L

    1999-04-15

    Copolymer 1 (Cop 1, poly (Y, E, A, K)) is a random synthetic amino acid copolymer effective in the treatment of relapsing forms of multiple sclerosis (MS). Cop 1 binds promiscuously, with high affinity and in a peptide-specific manner to purified MS-associated HLA-DR2 (DRB1*1501) and rheumatoid arthritis-associated HLA-DR1 (DRB1*0101) or HLA-DR4 (DRB1*0401) molecules. In the present work at least 95% of added Cop 1 could be bound to recombinant "empty" HLA-DR1 and -DR4, and 80% could be bound to HLA-DR2 proteins. Amino acid composition, HPLC profiles, and sequencing patterns of Cop 1 eluted by acid extraction from HLA-DR molecules were similar to those of the unseparated Cop 1. Protruding N-terminal ends of Cop 1 bound to HLA-DR1, -DR2, or -DR4 molecules were then treated with aminopeptidase I, followed by elution, HPLC, and pool sequencing. In contrast to untreated or unbound Cop 1, this material exhibited distinct motifs at some positions with increases in levels of E at the first and second cycles, of K at the second and third cycles, and of Y (presumably at P1 of the bound peptide) at the third to fifth cycles, regardless of the HLA-DR molecule employed. No preference was seen at the following cycles that were mainly A. These first pooled HLA-DR binding epitopes provide clues to the components of Cop 1 that are biologically active in suppressing MS and possibly rheumatoid arthritis.

  18. The co-inheritance of type 1 diabetes and multiple sclerosis in Sardinia cannot be explained by genotype variation in the HLA region alone.

    PubMed

    Marrosu, Maria Giovanna; Motzo, Costantino; Murru, Raffaele; Lampis, Rosanna; Costa, Gianna; Zavattari, Patrizia; Contu, Daniela; Fadda, Elisabetta; Cocco, Eleonora; Cucca, Francesco

    2004-12-01

    Type 1 diabetes (T1D) and multiple sclerosis (MS) are two autoimmune diseases which exhibit a considerably higher incidence in Sardinia compared with the surrounding southern European populations. Surprisingly, a 5-fold increased prevalence of T1D has also been observed in Sardinian MS patients. Susceptibility to both disorders is associated with common variants of the HLA-DRB1 and -DQB1 loci. In this study, we determined the relative contribution of genotype variation of these loci to the co-occurrence of the two disorders in Sardinia. We genotyped 1052 T1D patients and 1049 MS patients (31 of whom also had T1D) together with 1917 ethnically matched controls. On the basis of the absolute risks for T1D of the HLA-DRB1-DQB1 genotypes, we established that these loci would only contribute to a 2-fold increase in T1D prevalence in MS patients. From this evidence, we conclude that shared disease associations due to the HLA-DRB1-DQB1 loci provide only a partial explanation for the observed increased prevalence of T1D in Sardinian MS patients. The data suggest that variation at other non-HLA class II loci, and/or unknown environmental factors contribute significantly to the co-occurrence of these two traits.

  19. Sex and age at diagnosis are correlated with the HLA-DR2, DQ6 haplotype in multiple sclerosis.

    PubMed

    Celius, E G; Harbo, H F; Egeland, T; Vartdal, F; Vandvik, B; Spurkiand, A

    2000-09-15

    The HLA-DR2, DQ6 (i.e., HLA-DRB1*1501, DQA1*0102, DQB1*0602) haplotype contributes to the risk of developing multiple sclerosis (MS) in Caucasoids of Northern European heritage. A correlation between the clinical expression of MS and the presence of HLA-DR2, DQ6 has, however, not convincingly been shown. In this study conventional bivariate analysis and logistic regression analysis were used to study the relationship between HLA-DR2, DQ6 and four disease variables in a cohort of 286 Norwegian MS patients from the Oslo area. Logistic regression analysis showed that HLA-DR2, DQ6 was significantly more frequent among female than male patients (P=0. 0251), and was negatively correlated with age at diagnosis regardless of sex (P=0.0254). No significant correlation was observed between HLA-DR2, DQ6 and type of disease (relapsing-remitting versus primary chronic progressive MS) or presence/absence of oligoclonal bands in the cerebrospinal fluid.

  20. Dissection of the HLA association with multiple sclerosis in the founder isolated population of Sardinia.

    PubMed

    Marrosu, M G; Murru, R; Murru, M R; Costa, G; Zavattari, P; Whalen, M; Cocco, E; Mancosu, C; Schirru, L; Solla, E; Fadda, E; Melis, C; Porru, I; Rolesu, M; Cucca, F

    2001-12-01

    Several studies have indicated that multiple sclerosis (MS) is associated and linked to the major histocompatibility complex (MHC)/human leukocyte antigen (HLA) region of chromosome 6p21.3, but the exact location and nature of the primarily associated locus within the HLA complex is still controversial and largely presumptive. By linkage disequilibrium mapping, we have systematically investigated this chromosome region in the founder population of Sardinia to determine the relative associations of the various loci with MS. An overall 11.4 Mb region, which encompasses the whole HLA complex, was scanned with 19 microsatellite markers and with single nucleotide polymorphisms within 12 functional candidate genes and assessed for MS association using the extended transmission disequilibrium test (ETDT). A peak of association represented by the three adjacent DRB1, -DQA1 and -DQB1 loci was detected in the class II region. Two additional less significant areas of association were detected, respectively, in the centromeric side of the class II region at the DPB1 locus and, telomeric of the classically defined class I loci, at the D6S1683 microsatellite. Conditional ETDT analysis indicated that these regions of association could be independent of each other. Within the main peak of association, DRB1 and DQB1 contribute to the disease association independently of each other whereas DQA1 had no detectable primary genetic effects. We evaluated the haplotype distribution at the region showing the strongest association and found five DQB1-DRB1 haplotypes positively associated with MS in Sardinia. These consistently included all the haplotypes previously found associated with MS in the various human populations, thus supporting a primary effect of the products of these loci in MS. Overall these results are consistent with a multilocus model of the MHC encoded susceptibility to MS.

  1. Chronic Cerebrospinal Vascular Insufficiency Is Not Associated with HLA DRB1*1501 Status in Multiple Sclerosis Patients

    PubMed Central

    Weinstock-Guttman, Bianca; Zivadinov, Robert; Cutter, Gary; Tamaño-Blanco, Miriam; Marr, Karen; Badgett, Darlene; Carl, Ellen; Elfadil, Makki; Kennedy, Cheryl; Benedict, Ralph H. B.; Ramanathan, Murali

    2011-01-01

    Background Chronic cerebrospinal venous insufficiency (CCSVI) was described as a vascular condition characterized by anomalies of veins outside the skull was reported to be associated with multiple sclerosis (MS). The objective was to assess the associations between HLA DRB1*1501 status and the occurrence of CCSVI in MS patients. Methodology/Principal Findings This study included 423 of 499 subjects enrolled in the Combined Transcranial and Extracranial Venous Doppler Evaluation (CTEVD) study. The HLA DRB1*1501 status was obtained in 268 MS patients and 155 controls by genotyping rs3135005, a SNP associated with DRB1*1501 status. All subjects underwent a clinical examination and Doppler scan of the head and neck. The frequency of CCSVI was higher (OR = 4.52, p<0.001) in the MS group 56.0% vs. 21.9% in the controls group and also higher in the progressive MS group 69.8% vs. 49.5% in the non-progressive MS group. The 51.9% frequency of HLA DRB1*1501 positivity (HLA+) in MS was higher compared (OR = 2.33, p<0.001) to 31.6% to controls. The HLA+ frequency in the non-progressive (51.6%) and progressive MS groups (52.3%) was similar. The frequency of HLA+ CCSVI+ was 40.7% in progressive MS, 27.5% in non-progressive MS and 8.4% in controls. The presence of CCSVI was independent of HLA DRB1*1501 status in MS patients. Conclusions/Significance The lack of strong associations of CCSVI with HLA DRB1*1501 suggests that the role of the underlying associations of CCSVI in MS should be interpreted with caution. Further longitudinal studies should determine whether interactions between these factors can contribute to disease progression in MS. PMID:21340025

  2. Common Cold - Multiple Languages: MedlinePlus

    MedlinePlus

    ... List of All Topics All Common Cold - Multiple Languages To use the sharing features on this page, please enable JavaScript. Chinese - Simplified (简体中文) Chinese - Traditional (繁體中文) French (français) Hmong (Hmoob) Khmer (Khmer) Portuguese (português) Spanish (español) Tagalog (Tagalog) Vietnamese (Tiếng Việt) ...

  3. Bias in parental transmission of the HLA-DR3 allele in Sardinian multiple sclerosis.

    PubMed

    Marrosu, M G; Sardu, C; Cocco, E; Costa, G; Murru, M R; Mancosu, C; Murru, R; Lai, M; Contu, P

    2004-09-28

    The authors analyzed the female: male (F:M) ratio according to the HLA-DRB1-DQB1 genotype in a cohort of multiple sclerosis (MS) patients from Sardinia, where the disease is associated with DR3 and DR4. In the whole cohort of 1,097 patients, F:M ratio was 2.24; however, it was 2.88 in DR3/DR3 and 2.52 in DR3/DRX (X#DR3 and DR4) individuals. Parental transmission of DR3 and DR4, assessed in a set of 565 case-parent triads, showed evidence of paternal inheritance of DR3 in affected women, thus explaining the excess of females in the DR3 category.

  4. Amino Acid Variation in HLA Class II Proteins Is a Major Determinant of Humoral Response to Common Viruses

    PubMed Central

    Hammer, Christian; Begemann, Martin; McLaren, Paul J.; Bartha, István; Michel, Angelika; Klose, Beate; Schmitt, Corinna; Waterboer, Tim; Pawlita, Michael; Schulz, Thomas F.; Ehrenreich, Hannelore; Fellay, Jacques

    2015-01-01

    The magnitude of the human antibody response to viral antigens is highly variable. To explore the human genetic contribution to this variability, we performed genome-wide association studies of the immunoglobulin G response to 14 pathogenic viruses in 2,363 immunocompetent adults. Significant associations were observed in the major histocompatibility complex region on chromosome 6 for influenza A virus, Epstein-Barr virus, JC polyomavirus, and Merkel cell polyomavirus. Using local imputation and fine mapping, we identified specific amino acid residues in human leucocyte antigen (HLA) class II proteins as the most probable causal variants underlying these association signals. Common HLA-DRβ1 haplotypes showed virus-specific patterns of humoral-response regulation. We observed an overlap between variants affecting the humoral response to influenza A and EBV and variants previously associated with autoimmune diseases related to these viruses. The results of this study emphasize the central and pathogen-specific role of HLA class II variation in the modulation of humoral immune response to viral antigens in humans. PMID:26456283

  5. HLA class II, MICA and PRL gene polymorphisms: the common contribution to the systemic lupus erythematosus development in Czech population.

    PubMed

    Fojtíková, Markéta; Novota, Peter; Cejková, Pavlína; Pešičková, Satu; Tegzová, Dana; Cerná, Marie

    2011-09-01

    The genetic components contribute to the systemic lupus erythematosus development. This study for the first time determined the distribution of the polymorphisms and linkage disequilibrium in HLA class II, MICA and PRL gene among patients suffering from SLE and healthy Czech individuals. DNA was obtained from the peripheral blood cells of 123 SLE patients and 96 healthy people. Allele variants of the HLA class II, MICA transmembrane polymorphism and PRL extrapituitary promoter -1149G/T SNP were detected using the sequence-specific primers analysis, PCR-fragment analysis and PCR-RFLP, respectively. In Czech population, only DRB1*03-DQB1*0201 haplotype is significantly associated with increased risk for SLE development: the frequency in SLE group was 44.7% in comparison with 15.2% in controls, P (c) < 0.0001; OR 4.54 CI 95% (2.36-9.09). The MICA-A5.1 allele is present significantly more often in SLE (55.7%) than controls (39.9%), P (c) = 0.005; OR 1.88 CI 95% (1.29-2.77), and the combination of HLA DRB1 *03 together with MICA-A5.1 is strongly associated with SLE [P (c) < 0.000001; OR 9.71 CI 95% (3.4-27.7)]. On the other hand, the MICA-A6 allele is less frequent in SLE patients compared to controls, 10.6% and 19.7%, respectively [P (c) = 0.035; OR 0.48 CI 95% (0.28-0.82)], and the combination of absence both alleles MICA-A6 and HLA DRB*11 seems to be risk for SLE development compared to controls, 84.6 and 70.2%, respectively, [P (c) = 0.0003 OR 2.32 CI 95% (1.47-3.70)]. We found that only G allele of the -1149 G/T SNP is associated with specific clinical manifestation of SLE, arthritis [P (c) = 0.022; OR 2.63, CI 95% (1.45-4.81)]. HLA class II-MICA combinations may increase/decrease a risk for SLE development. Multiple studies focusing on the ethnical differences as well as genetic-epigenetic relationships are necessary for better understanding SLE pathogenesis.

  6. The importance of HLA DRB1 gene allele to clinical features and disability in patients with multiple sclerosis in Lithuania

    PubMed Central

    2013-01-01

    Background The association of HLA DRB1 alleles with susceptibility to multiple sclerosis (MS) has been consistently reported although its effect on the clinical features and disability is still unclear probably due to diversity in ethnicity and geographic location of the studied populations. The aim of the present study was to investigate the influence of HLA DRB1 alleles on the clinical features and disability of the patients with MS in Lithuania. Methods This was a prospective study of 120 patients with MS. HLA DRB1 alleles were genotyped using the polymerase chain reaction. Results The first symptoms of MS in patients with HLA DRB1*15 allele manifested at younger age than in those without this allele (28.32 +/− 5.49 yrs vs. 30.94 +/− 8.43 yrs, respectively, p = 0.043). HLA DRB1*08 allele was more prevalent among relapsing-remitting (RR) MS patients than among patients with progressive course of MS (25.0% vs. 8.3%, respectively, chi^2 = 6.000, p = 0.05). MS patients with this allele had lower relapse rate than those without this allele (1.00 +/− 0.97 and 1.44 +/− 0.85, respectively, p = 0.043). Degree of disability during the last visit was lower among the patients with HLA DRB1*08 allele (EDSS score 3.15 +/− 1.95 vs. 4.49 +/− 1.96, p = 0.006), and higher among those with HLA DRB1*15 allele (EDSS score 4.60 +/− 2.10 vs.4.05 +/− 1.94, p = 0.047) compared to patients without these alleles but there were no significant associations between these alleles and the duration of the disease to disability. HLA DRB1*08 allele (OR = 0.18, 95% CI 0,039-0,8, p = 0.029) was demonstradet to be independent factor to take a longer time to reach an EDSS of 6, while HLA DRB1*01 allele (OR = 5.92, 95% CI 1,30-26,8, p = 0.021) was related in a shorter time to reach and EDSS of 6. Patients with HLA DRB1*08 allele had lower IgG index compared to patients without this allele (0.58 +/− 0.17 and 0.73 +/− 0.31, respectively, p

  7. HLAProfiler utilizes k-mer profiles to improve HLA calling accuracy for rare and common alleles in RNA-seq data.

    PubMed

    Buchkovich, Martin L; Brown, Chad C; Robasky, Kimberly; Chai, Shengjie; Westfall, Sharon; Vincent, Benjamin G; Weimer, Eric T; Powers, Jason G

    2017-09-27

    The human leukocyte antigen (HLA) system is a genomic region involved in regulating the human immune system by encoding cell membrane major histocompatibility complex (MHC) proteins that are responsible for self-recognition. Understanding the variation in this region provides important insights into autoimmune disorders, disease susceptibility, oncological immunotherapy, regenerative medicine, transplant rejection, and toxicogenomics. Traditional approaches to HLA typing are low throughput, target only a few genes, are labor intensive and costly, or require specialized protocols. RNA sequencing promises a relatively inexpensive, high-throughput solution for HLA calling across all genes, with the bonus of complete transcriptome information and widespread availability of historical data. Existing tools have been limited in their ability to accurately and comprehensively call HLA genes from RNA-seq data. We created HLAProfiler ( https://github.com/ExpressionAnalysis/HLAProfiler ), a k-mer profile-based method for HLA calling in RNA-seq data which can identify rare and common HLA alleles with > 99% accuracy at two-field precision in both biological and simulated data. For 68% of novel alleles not present in the reference database, HLAProfiler can correctly identify the two-field precision or exact coding sequence, a significant advance over existing algorithms. HLAProfiler allows for accurate HLA calls in RNA-seq data, reliably expanding the utility of these data in HLA-related research and enabling advances across a broad range of disciplines. Additionally, by using the observed data to identify potential novel alleles and update partial alleles, HLAProfiler will facilitate further improvements to the existing database of reference HLA alleles. HLAProfiler is available at https://expressionanalysis.github.io/HLAProfiler/ .

  8. 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

  9. Complex relation of HLA-DRB1*1501, age at menarche, and age at multiple sclerosis onset

    PubMed Central

    Chua, Alicia S.; Xia, Zongqi; Chibnik, Lori; De Jager, Philip L.; Chitnis, Tanuja

    2016-01-01

    Objective: To examine the relationship between 2 markers of early multiple sclerosis (MS) onset, 1 genetic (HLA-DRB1*1501) and 1 experiential (early menarche), in 2 cohorts. Methods: We included 540 white women with MS or clinically isolated syndrome (N = 156 with genetic data available) and 1,390 white women without MS but with a first-degree relative with MS (Genes and Environment in Multiple Sclerosis [GEMS]). Age at menarche, HLA-DRB1*1501 status, and age at MS onset were analyzed. Results: In both cohorts, participants with at least 1 HLA-DRB1*1501 allele had a later age at menarche than did participants with no risk alleles (MS: mean difference = 0.49, 95% confidence interval [CI] = [0.03–0.95], p = 0.036; GEMS: mean difference = 0.159, 95% CI = [0.012–0.305], p = 0.034). This association remained after we adjusted for body mass index at age 18 (available in GEMS) and for other MS risk alleles, as well as a single nucleotide polymorphism near the HLA-A region previously associated with age of menarche (available in MS cohort). Confirming previously reported associations, in our MS cohort, every year decrease in age at menarche was associated with a 0.65-year earlier MS onset (95% CI = [0.07–1.22], p = 0.027, N = 540). Earlier MS onset was also found in individuals with at least 1 HLA-DRB1*1501 risk allele (mean difference = −3.40 years, 95% CI = [−6.42 to −0.37], p = 0.028, N = 156). Conclusions: In 2 cohorts, a genetic marker for earlier MS onset (HLA-DRB1*1501) was inversely related to earlier menarche, an experiential marker for earlier symptom onset. This finding warrants broader investigations into the association between the HLA region and hormonal regulation in determining the onset of autoimmune disease. PMID:27504495

  10. Interaction between HLA-DRB1-DQB1 Haplotypes in Sardinian Multiple Sclerosis Population

    PubMed Central

    Cocco, Eleonora; Murru, Raffaele; Costa, Gianna; Kumar, Amit; Pieroni, Enrico; Melis, Cristina; Barberini, Luigi; Sardu, Claudia; Lorefice, Lorena; Fenu, Giuseppe; Frau, Jessica; Coghe, Giancarlo; Carboni, Nicola; Marrosu, Maria Giovanna

    2013-01-01

    We performed a case-control study in 2,555 multiple sclerosis (MS) Sardinian patients and 1,365 healthy ethnically matched controls, analyzing the interactions between HLA-DRB1-DQB1 haplotypes and defining a rank of genotypes conferring a variable degree of risk to the disease. Four haplotypes were found to confer susceptibility (*13∶03-*03∶01 OR = 3.3, Pc 5.1×10−5, *04∶05-*03∶01 OR = 2.1, Pc 9.7×10−8, *15∶01-*06∶02 OR = 2.0, Pc = 9.1×10−3, *03∶01-*02∶01 OR = 1.7 Pc = 7.9×10−22) and protection (*11, OR = 0.8, Pc = 2.7×10−2, *16∶01-*05∶02 OR = 0.6, Pc = 4.8×10−16, *14∶01-4-*05∶031 = OR = 0.5, Pc = 9.8×10−4 and *15∶02-*06∶01 OR = 0.4, Pc = 5.1×10−4). The relative predispositional effect method confirms all the positively associated haplotypes and showed that also *08 and *04 haplotypes confers susceptibility, while the *11 was excluded as protective haplotype. Genotypic ORs highlighted two typologies of interaction between haplotypes: i) a neutral interaction, in which the global risk is coherent with the sum of the single haplotype risks; ii) a negative interaction, in which the genotypic OR observed is lower than the sum of the OR of the two haplotypes. The phylogenic tree of the MS-associated DRB1 alleles found in Sardinian patients revealed a cluster represented by *14∶01, *04∶05, *13∶03, *08∶01 and *03∶01 alleles. Sequence alignment analysis showed that amino acids near pocket P4 and pocket P9 differentiated protective from predisposing alleles under investigation. Furthermore, molecular dynamics simulation performed on alleles revealed that position 70 is crucial in binding of MBP 85–99 peptide. All together, these data suggest that propensity to MS observed in Sardinian population carried by the various HLA-DRB1-DQB1 molecules can be due to functional peculiarity in the antigen presentation mechanisms. PMID:23593151

  11. Familial Crohn's disease in multiple siblings: no linkage to the HLA system.

    PubMed

    Colombel, J F; Guillemot, F; Van Gossum, A; Dufossé, F; Cortot, A; Dupont, E; Paris, J C

    1989-01-01

    We report five families with 3 or more children having Crohn's disease. In one family, 6 out of 11 siblings were affected. HLA haplotype study in affected children showed that the probability of random segregation was only 38 percent, making improbable a linkage between the histocompatibility locus and the development of Crohn's disease. However similar clinical patterns in siblings could suggest a genetic factor not linked to the HLA system.

  12. Identification of conserved subdominant HIV Type 1 CD8(+) T Cell epitopes restricted within common HLA Supertypes for therapeutic HIV Type 1 vaccines.

    PubMed

    Karlsson, Ingrid; Kløverpris, Henrik; Jensen, Kristoffer Jarlov; Stryhn, Anette; Buus, Søren; Karlsson, Annika; Vinner, Lasse; Goulder, Philip; Fomsgaard, Anders

    2012-11-01

    The high HIV-1 prevalence, up to 4.6% in Guinea-Bissau, West Africa, makes it a relevant location for testing of therapeutic vaccines. With the aim of performing a clinical study in Guinea-Bissau, after first testing the vaccine for safety in Denmark, Europe, we here describe the design of a universal epitope peptide-based T cell vaccine with relevance for any geographic locations. The two major obstacles when designing such a vaccine are the high diversities of the HIV-1 genome and of the human major histocompatibility complex (MHC) class I. We selected 15 CD8-restricted epitopes predicted from conserved regions of HIV-1 that were subdominant (i.e., infrequently targeted) within natural infections. Moreover, the epitopes were predicted to be restricted to at least one of the five common HLA supertypes (HLA-A01, A02, A03, B07, and B44). Here, we validated the resulting peptide-specific, HLA-restricted T cell specificities using peptide-MHC class I tetramer labeling of CD8(+) T cells from HIV-1-infected individuals. The selected vaccine epitopes are infrequently targeted in HIV-1-infected individuals from both locations. Moreover, we HLA-typed HIV-1-infected individuals and demonstrated that the selected vaccine epitopes, when targeted, are restricted to the five most common HLA supertypes at both locations. Thus, the HLA supertype-directed approach achieved HLA coverage of 95% and 100% of the examined cohorts in Guinea-Bissau and Denmark, respectively. In conclusion, the selected vaccine epitopes match the host populations and HIV-1 strains of these two distant geographic regions, justifying clinical testing in both locations.

  13. HLA sensitization in islet transplantation.

    PubMed

    Rickels, Michael R; Kearns, Jane; Markmann, Eileen; Palanjian, Maral; Markmann, James F; Naji, Ali; Kamoun, Malek

    2006-01-01

    Islet transplantation is an emerging therapy for poorly controlled type 1 diabetes. Currently, islets isolated from multiple donors not HLA-matched to recipients are usually required to achieve insulin-independence. Subsequent HLA sensitization is common following a reduction or discontinuation of immunosuppressive drugs and may be responsible for deterioration in islet graft function. Based on the evidence available to date concerning HLA sensitization in islet transplant recipients, we recommend that future islet transplantation protocols consider the following: (1) minimizing the number of islet donors by, for example, infusing high quality islet preparations of sufficient yield from a single donor rather than pooling islet preparations from multiple donors since a greater number of HLA class I mismatches appears to be associated with increased risk for sensitization; (2) ensuring negative cross-matching of donor lymphocytes and recipient sera by testing prior to islet infusions; (3) avoiding donor-recipient antigen mismatches when an identifiable alloantibody is present pre-transplant (i.e., in the case of a positive PRA pretransplant) but excluding potential recipients who are highly sensitized (e.g., have a PRA > or = 20%); and (4) performing an assessment for HLA sensitization using a sensitive flow cytometric method for alloantibody detection any time there is a reduction in immunosuppressant drug levels or worsening of metabolic control.

  14. HLA-J, a second inactivated class I HLA gene related to HLA-G and HLA-A

    SciTech Connect

    Messer, G.; Weiss, E.H. ); Zemmour, J.; Parham, P. ); Orr, H.T. ); Girdlestone, J. )

    1992-06-15

    Ragoussis and co-workers previously described a class I HLA gene (now designated HLA-J) that maps to within 50 kb of HLA-A. The nucleotide sequences of three HLA-J alleles are reported here. Comparison of the nucleotide sequences of HLA-J alleles shows this gene is more related to HLA-G, A, and H than to HLA-B, C, E, and F. All four alleles of HLA-J are pseudogenes because of deleterious mutations that produce translation termination either in exon 2 or exon 4. Apart from these mutations. the predicted proteins have structures similar to those of HLA-A, B, and C molecules. There is, however, little polymorphism at HLA-J and none at functional positions of the Ag-recognition site. The polymorphism is less than found for HLA-H, another HLA-A-related pseudogene. HLA-J appears, like HLA-H, to be an inactivated gene that resulted from duplication of an Ag-presenting locus related to HLA-A. Nucleotide sequence comparisons show that the HLA-A, H, J, and G genes form a well defined group of [open quotes]HLA-A-related[close quotes] loci. Evolutionary relationships as assessed by construction of trees suggest the four modern loci, HLA-A, G, H, and J, were formed by successive duplications from a common ancestral gene. In this scheme one intermediate locus gave rise to HLA-A and H, the other to HLA-G and J. 33 refs., 6 figs., 4 tabs.

  15. Common oscillatory mechanisms across multiple memory systems

    NASA Astrophysics Data System (ADS)

    Headley, Drew B.; Paré, Denis

    2017-01-01

    The cortex, hippocampus, and striatum support dissociable forms of memory. While each of these regions contains specialized circuitry supporting their respective functions, all structure their activities across time with delta, theta, and gamma rhythms. We review how these oscillations are generated and how they coordinate distinct memory systems during encoding, consolidation, and retrieval. First, gamma oscillations occur in all regions and coordinate local spiking, compressing it into short population bursts. Second, gamma oscillations are modulated by delta and theta oscillations. Third, oscillatory dynamics in these memory systems can operate in either a "slow" or "fast" mode. The slow mode happens during slow-wave sleep and is characterized by large irregular activity in the hippocampus and delta oscillations in cortical and striatal circuits. The fast mode occurs during active waking and rapid eye movement (REM) sleep and is characterized by theta oscillations in the hippocampus and its targets, along with gamma oscillations in the rest of cortex. In waking, the fast mode is associated with the efficacious encoding and retrieval of declarative and procedural memories. Theta and gamma oscillations have similar relationships with encoding and retrieval across multiple forms of memory and brain regions, despite regional differences in microcircuitry and information content. Differences in the oscillatory coordination of memory systems during sleep might explain why the consolidation of some forms of memory is sensitive to slow-wave sleep, while others depend on REM. In particular, theta oscillations appear to support the consolidation of certain types of procedural memories during REM, while delta oscillations during slow-wave sleep seem to promote declarative and procedural memories.

  16. HLA-DRB1-DQB1 Haplotypes Confer Susceptibility and Resistance to Multiple Sclerosis in Sardinia

    PubMed Central

    Cocco, Eleonora; Sardu, Claudia; Pieroni, Enrico; Valentini, Maria; Murru, Raffaele; Costa, Gianna; Tranquilli, Stefania; Frau, Jessica; Coghe, Giancarlo; Carboni, Nicola; Floris, Matteo; Contu, Paolo; Marrosu, Maria Giovanna

    2012-01-01

    Introduction Genetic predisposition to multiple sclerosis (MS) in Sardinia (Italy) has been associated with five DRB1*-DQB1* haplotypes of the human leukocyte antigen (HLA). Given the complexity of these associations, an in-depth re-analysis was performed with the specific aims of confirming the haplotype associations; establishing the independence of the associated haplotypes; and assessing patients' genotypic risk of developing MS. Methods and Results A transmission disequilibrium test (TDT) of the DRB1*-DQB1* haplotypes in 943 trio families, confirmed a higher than expected transmission rate (over-transmission) of the *13:03-*03:01 (OR = 2.9, P = 7.6×10−3), *04:05-*03:01 (OR = 2.4, P = 4.4×10−6) and *03:01-*02:01 (OR = 2.1, P = 1.0×10−15) haplotype. In contrast, the *16:01-*05:02 (OR = 0.5, P = 5.4×10−11) and the *15:02-*06:01 (OR = 0.3, P = 1.5×10−3) haplotypes exhibited a lower than expected transmission rate (under-transmission). The independence of the transmission of each positively and negatively associated haplotype was confirmed relative to all positively associated haplotypes, and to the negatively associated *16:01-*05:02 haplotype. In patients, carriage of two predisposing haplotypes, or of protective haplotypes, respectively increased or decreased the patient's risk of developing MS. The risk of MS followed a multiplicative model of genotypes, which was, in order of decreasing ORs: *04:05-*0301/*03:01-*02:01 (OR = 4.5); *03:01-*02:01/*03:01-*02:01 (OR = 4.1); and the *16:01-*05:02/*16:01-*0502 (OR = 0.2) genotypes. Analysis of DRB1 and DQB1 protein chain residues showed that the Val/Gly residue at position 86 of the DRB1 chain was the only difference between the protective *16:01- *15:02 alleles and the predisposing *15:01 one. Similarly, the Ala/Val residue at position 38 of the DQB1 chain differentiated the positively associated *06:02 allele and the negatively associated *05

  17. Dense genotyping identifies and localizes multiple common and rare variant association signals in celiac disease

    PubMed Central

    Trynka, Gosia; Hunt, Karen A; Bockett, Nicholas A; Romanos, Jihane; Mistry, Vanisha; Szperl, Agata; Bakker, Sjoerd F; Bardella, Maria Teresa; Bhaw-Rosun, Leena; Castillejo, Gemma; de la Concha, Emilio G.; de Almeida, Rodrigo Coutinho; Dias, Kerith-Rae M; van Diemen, Cleo C.; Dubois, Patrick CA; Duerr, Richard H.; Edkins, Sarah; Franke, Lude; Fransen, Karin; Gutierrez, Javier; Heap, Graham AR; Hrdlickova, Barbara; Hunt, Sarah; Izurieta, Leticia Plaza; Izzo, Valentina; Joosten, Leo AB; Langford, Cordelia; Mazzilli, Maria Cristina; Mein, Charles A; Midah, Vandana; Mitrovic, Mitja; Mora, Barbara; Morelli, Marinita; Nutland, Sarah; Núñez, Concepción; Onengut-Gumuscu, Suna; Pearce, Kerra; Platteel, Mathieu; Polanco, Isabel; Potter, Simon; Ribes-Koninckx, Carmen; Ricaño-Ponce, Isis; Rich, Stephen S.; Rybak, Anna; Santiago, José Luis; Senapati, Sabyasachi; Sood, Ajit; Szajewska, Hania; Troncone, Riccardo; Varadé, Jezabel; Wallace, Chris; Wolters, Victorien M; Zhernakova, Alexandra; Thelma, B.K.; Cukrowska, Bozena; Urcelay, Elena; Bilbao, Jose Ramon; Mearin, M Luisa; Barisani, Donatella; Barrett, Jeffrey C; Plagnol, Vincent; Deloukas, Panos; Wijmenga, Cisca; van Heel, David A

    2011-01-01

    We densely genotyped, using 1000 Genomes Project pilot CEU and additional re-sequencing study variants, 183 reported immune-mediated disease non-HLA risk loci in 12,041 celiac disease cases and 12,228 controls. We identified 13 new celiac disease risk loci at genome wide significance, bringing the total number of known loci (including HLA) to 40. Multiple independent association signals are found at over a third of these loci, attributable to a combination of common, low frequency, and rare genetic variants. In comparison with previously available data such as HapMap3, our dense genotyping in a large sample size provided increased resolution of the pattern of linkage disequilibrium, and suggested localization of many signals to finer scale regions. In particular, 29 of 54 fine-mapped signals appeared localized to specific single genes - and in some instances to gene regulatory elements. We define a complex genetic architecture of risk regions, and refine risk signals, providing a next step towards elucidating causal disease mechanisms. PMID:22057235

  18. Comparison of exome-based HLA class I genotyping tools: identification of platform-specific genotyping errors

    PubMed Central

    Kiyotani, Kazuma; Mai, Tu H; Nakamura, Yusuke

    2017-01-01

    Accurate human leukocyte antigen (HLA) genotyping is critical in studies involving the immune system. Several algorithms to estimate HLA genotypes from whole-exome data were developed. We compared the accuracy of seven algorithms, including Optitype, Polysolver and PHLAT, as well as investigated patterns and possible causes of miscalls using 12 clinical samples and 961 individuals from the 1000 Genomes Project. Optitype showed the highest accuracy of 97.2% for HLA class I alleles at the second field resolution, followed by 94.0% in Polysolver and 85.6% in PHLAT. In Optitype, 34 (21.1%) of 161 miscalls were across different serological types, and common miscalls were HLA-A*26:01 to HLA-A*25:01, HLA-B*45:01 to HLA-B*44:15 and HLA-C*08:02 to HLA-C*05:01 with error rates of 4.1%, 10.0% and 4.1%, respectively. In Polysolver, 193 (55.9%) of 345 miscalls occurred across different serological alleles, and a specific pattern of genotyping error from HLA-A*25:01 to HLA-A*26:01 was observed in 93.3% of HLA-A*25:01 carriers, due to dropping of HLA-A*25:01 sequence reads during the extraction process of HLA reads. In PHLAT, 147 (59.8%) of 246 miscalls in HLA-A were due to erroneous assignment of multiple alleles to either HLA-A*01:22 or HLA-A*01:81. These results suggest that careful considerations needed to be taken when using exome-based HLA class I genotyping data and applying these results in clinical settings. PMID:27881843

  19. Small molecule inhibitor of antigen binding and presentation by HLA-DR2b as a therapeutic strategy for the treatment of multiple sclerosis.

    PubMed

    Ji, Niannian; Somanaboeina, Animesh; Dixit, Aakanksha; Kawamura, Kazuyuki; Hayward, Neil J; Self, Christopher; Olson, Gary L; Forsthuber, Thomas G

    2013-11-15

    The strong association of HLA-DR2b (DRB1*1501) with multiple sclerosis (MS) suggests this molecule as prime target for specific immunotherapy. Inhibition of HLA-DR2b-restricted myelin-specific T cells has the potential to selectively prevent CNS pathology mediated by these MHC molecules without undesired global immunosuppression. In this study, we report development of a highly selective small molecule inhibitor of peptide binding and presentation by HLA-DR2b. PV-267, the candidate molecule used in these studies, inhibited cytokine production and proliferation of myelin-specific HLA-DR2b-restricted T cells. PV-267 had no significant effect on T cell responses mediated by other MHC class II molecules, including HLA-DR1, -DR4, or -DR9. Importantly, PV-267 did not induce nonspecific immune activation of human PBMC. Lastly, PV-267 showed treatment efficacy both in preventing experimental autoimmune encephalomyelitis and in treating established disease. The results suggest that blocking the MS-associated HLA-DR2b allele with small molecule inhibitors may be a promising therapeutic strategy for the treatment of MS.

  20. A decrease in the estimated frequency of the extended HLA haplotype B18 CF130 DR3 DQw2 is common to non-insulin-dependent diabetes, juvenile rheumatoid arthritis, and Berger's disease.

    PubMed

    Regueiro, J R; Arnaiz-Villena, A; Vicario, J L; Martinez-Laso, J; Pacheco, A; Rivera-Guzman, J M

    1993-07-05

    Extended HLA haplotypes frequencies were estimated from the HLA, C2, Bf and C4 phenotypes of 74 patients with non-insulin-dependent diabetes (NIDD), 92 with juvenile rheumatoid arthritis (JRA), 44 with Berger's disease (BD), 83 with insulin-dependent diabetes (IDD), and 140 healthy controls. The extended HLA haplotype B18 CF130 DR3 DQw2, which is common (around 10% phenotype frequency) in healthy Spaniards and in other populations of paleo-North African origin, was found to be significantly less frequent in NIDD, JRA and BD, whereas its frequency was normal in IDD (although DR3 DQw2 haplotypes were increased in the latter disease). These data support the existence of a common HLA-linked pathogeneic mechanism in NIDD, JRA and BD, and point to a genetic difference between IDD and NIDD at the HLA level. This effect is readily detectable in our population because the uncommon BfF1 allele marks that haplotype instead of the more common BfS, which marks B8 CS01 DR3 DQw2 in other Caucasians. Our results support the hypothesis of strong selective pressures operating at the HLA level to preserve extended HLA haplotypes with advantageous gene sets from dilution by crossing-over. Imbalanced incomplete haplotypes may give rise to inappropriate T-cell repertoire selection in the thymus and/or antigen handling in the periphery, and be partly responsible for the pathogenesis of certain HLA-linked diseases (i.e. NIDD, JRA, and BD).

  1. Quantitative assessment of common genetic variations in HLA-DP with hepatitis B virus infection, clearance and hepatocellular carcinoma development

    PubMed Central

    Yu, Lei; Cheng, Yi-ju; Cheng, Ming-liang; Yao, Yu-mei; Zhang, Quan; Zhao, Xue-ke; Liu, Hua-juan; Hu, Ya-xin; Mu, Mao; Wang, Bi; Yang, Guo-zhen; Zhu, Li-li; Zhang, Shuai

    2015-01-01

    Hepatitis B virus (HBV) infection is the predominant risk factor for chronic hepatitis B (CHB), liver cirrhosis (LC) and hepatocellular carcinoma (HCC). Recently, genome-wide association studies have identified human leukocyte antigen (HLA)-DP polymorphisms (rs3077 and rs9277535) as a new chronic HBV infection susceptibility locus. Since then, the relationship between HLA-DP polymorphisms and various outcomes of HBV infection has been reported. However, the results have been inconclusive. To derive a more precise estimation of the relationship between HLA-DP polymorphisms and various outcomes of HBV infection, a meta-analysis of 62,050 subjects from 29 case-control studies was performed. We found that rs3077 and rs9277535 in HLA-DP significantly decreased HBV infection risks and increased HBV clearance possibility in a dose-dependent manner. In the subgroup analysis by ethnicity, study design and sample size, significant associations were found for these polymorphisms in almost all comparisons. Meanwhile, haplotype analyses of the two polymorphisms revealed a significant association between the combination of these alleles and HBV infection outcomes. However, no significant results were observed in HCC development. Our results further confirm that genetic variants in the HLA-DP locus are strongly associated with reduced HBV infection and increased the likelihood of spontaneous viral clearance. PMID:26462556

  2. Genotype-Phenotype Correlations in Multiple Sclerosis: "HLA" Genes Influence Disease Severity Inferred by [superscript 1]HMR Spectroscopy and MRI Measures

    ERIC Educational Resources Information Center

    Okuda, D. T.; Srinivasan, R.; Oksenberg, J. R.; Goodin, D. S.; Baranzini, S. E.; Beheshtian, A.; Waubant, E.; Zamvil, S. S.; Leppert, D.; Qualley, P.; Lincoln, R.; Gomez, R.; Caillier, S.; George, M.; Wang, J.; Nelson, S. J.; Cree, B. A. C.; Hauser, S. L.; Pelletier, D.

    2009-01-01

    Genetic susceptibility to multiple sclerosis (MS) is associated with the human leukocyte antigen (HLA) "DRB1*1501" allele. Here we show a clear association between DRB1*1501 carrier status and four domains of disease severity in an investigation of genotype-phenotype associations in 505 robust, clinically well characterized MS patients evaluated…

  3. Genotype-Phenotype Correlations in Multiple Sclerosis: "HLA" Genes Influence Disease Severity Inferred by [superscript 1]HMR Spectroscopy and MRI Measures

    ERIC Educational Resources Information Center

    Okuda, D. T.; Srinivasan, R.; Oksenberg, J. R.; Goodin, D. S.; Baranzini, S. E.; Beheshtian, A.; Waubant, E.; Zamvil, S. S.; Leppert, D.; Qualley, P.; Lincoln, R.; Gomez, R.; Caillier, S.; George, M.; Wang, J.; Nelson, S. J.; Cree, B. A. C.; Hauser, S. L.; Pelletier, D.

    2009-01-01

    Genetic susceptibility to multiple sclerosis (MS) is associated with the human leukocyte antigen (HLA) "DRB1*1501" allele. Here we show a clear association between DRB1*1501 carrier status and four domains of disease severity in an investigation of genotype-phenotype associations in 505 robust, clinically well characterized MS patients evaluated…

  4. HLA-DR 15 is associated with female sex and younger age at diagnosis in multiple sclerosis

    PubMed Central

    Hensiek, A; Sawcer, S; Feakes, R; Deans, J; Mander, A; Akesson, E; Roxburgh, R; Coraddu, F; Smith, S; Compston, D

    2002-01-01

    Background: The association between multiple sclerosis and class II alleles of the major histocompatibiliy complex, in particular the DRB1*1501-DQB1*0602 haplotype, is well established but their role in determining specific features of this clinically heterogeneous disease is unknown as few studies involving large sample sizes have been performed. Method: 729 patients with multiple sclerosis were typed for the HLA DR15 phenotype. All patients underwent clinical assessment and a detailed evaluation of their clinical records was undertaken. Results: The presence of DR15 was associated with younger age at diagnosis and female sex but there was no association with disease course (relapsing-remitting or secondary progressive v primary progressive type), disease outcome, specific clinical features (opticospinal v disseminated form), diagnostic certainty (clinically and laboratory supported definite v clinically probable multiple sclerosis), and paraclinical investigations including the presence of oligoclonal bands in the CSF or characteristic abnormalities on MRI imaging of the central nervous system. Conclusion:Even though DR15 carriers are more likely to be female and prone to an earlier disease onset, the results indicate that there is no association with other specific clinical outcomes or laboratory indices examined here. This suggests that DR15 exerts a susceptibility rather than disease modifying effect in multiple sclerosis. PMID:11796767

  5. KIR2DS5 allotypes that recognize the C2 epitope of HLA-C are common among Africans and absent from Europeans.

    PubMed

    Blokhuis, Jeroen H; Hilton, Hugo G; Guethlein, Lisbeth A; Norman, Paul J; Nemat-Gorgani, Neda; Nakimuli, Annettee; Chazara, Olympe; Moffett, Ashley; Parham, Peter

    2017-07-06

    KIR2DS5 is an activating human NK cell receptor of lineage III KIR. These include both inhibitory KIR2DL1, 2 and 3 and activating KIR2DS1 that recognize either the C1 or C2 epitope of HLA-C. In Europeans KIR2DS5 is essentially monomorphic, with KIR2DS5*002 being predominant. Pioneering investigations showed that KIR2DS5*002 has activating potential, but cannot recognize HLA-A, -B, or -C. Subsequent studies have shown that KIR2DS5 is highly polymorphic in Africans, and that KIR2DS5*006 protects pregnant Ugandan women from preeclampsia. Because inhibitory C2-specific KIR2DL1 correlates with preeclampsia, whereas activating C2-specific KIR2DS1 protects, this association pointed to KIR2DS5*006 being an activating C2-specific receptor. To test this hypothesis we made KIR-Fc fusion proteins from all ten KIR2DS5 allotypes and tested their binding to a representative set of HLA-A, -B and -C allotypes. Six African-specific KIR2DS5 bound to C2(+) HLA-C but not to other HLA class I. Their avidity for C2 is ∼20% that of C2-specific KIR2DL1 and ∼40% that of C2-specific KIR2DS1. Among the African C2 receptors is KIR2DS5*006, which protected a cohort of pregnant Ugandans from pre-eclampsia. Three African KIR2DS5 allotypes and KIR2DS5*002, bound no HLA-A, -B or -C. As a group the C2-binding KIR2DS5 allotypes protect against pre-eclampsia compared to the non-binding KIR2DS5 allotypes. Natural substitutions that contribute to loss or reduction of C2 receptor function are at positions 127, 158, and 176 in the D2 domain. KIR2DS5*005 has the KIR2DS5 consensus sequence, is the only allele found at both centromeric and telomeric locations of KIR2DS5, and is likely the common ancestor of all KIR2DS5 alleles. That KIR2DS5*005 has C2 receptor activity, points to KIR2DS5*002, and other allotypes lacking C2 receptor function, being products of attenuation, a characteristic feature of most KIR B haplotype genes. Alleles encoding attenuated and active KIR2DS5 are present in both centromeric

  6. Joint Estimation of Multiple Precision Matrices with Common Structures

    PubMed Central

    Lee, Wonyul; Liu, Yufeng

    2015-01-01

    Estimation of inverse covariance matrices, known as precision matrices, is important in various areas of statistical analysis. In this article, we consider estimation of multiple precision matrices sharing some common structures. In this setting, estimating each precision matrix separately can be suboptimal as it ignores potential common structures. This article proposes a new approach to parameterize each precision matrix as a sum of common and unique components and estimate multiple precision matrices in a constrained l1 minimization framework. We establish both estimation and selection consistency of the proposed estimator in the high dimensional setting. The proposed estimator achieves a faster convergence rate for the common structure in certain cases. Our numerical examples demonstrate that our new estimator can perform better than several existing methods in terms of the entropy loss and Frobenius loss. An application to a glioblastoma cancer data set reveals some interesting gene networks across multiple cancer subtypes. PMID:26568704

  7. The association between functional HLA-G 14bp insertion/deletion and +3142 C>G polymorphisms and susceptibility to multiple sclerosis.

    PubMed

    Ben Fredj, Nadia; Sakly, Kaouthar; Bortolotti, Daria; Aissi, Mouna; Frih-Ayed, Mahbouba; Rotola, Antonella; Caselli, Elisabetta; Cura, Franscesca; Sakly, Nabil; Aouni, Mahjoub; Di Luca, Dario; Rizzo, Roberta

    2016-12-01

    We aimed to investigate two main polymorphisms in the 3' untranslated region (3'UTR) of the HLA-G gene [14bp insertion/deletion (INS/DEL) and +3142 C>G] and to assess their impact on the soluble HLA-G (sHLA-G) production in patients with multiple sclerosis (MS). This study included 60 patients with relasping-remitting (RR) MS and 112 healthy donors (HD). Mutations were identified by PCR and PCR-RFLP, and serum sHLA-G quantification was performed by ELISA. For the 14bp INS/DEL polymorphism, variants frequencies were similar in patients and controls, whereas a significant increased frequency of the +3142 G allele was found in MS patients compared to HD (63.4% vs 52.3%, p=0.04; OR=1.58, 95%CI=1.003-2.48). In addition, an association was found between MS susceptibility and the haplotypes regrouping both studied polymorphisms. Indeed, the 14bp DEL/+3142 G haplotype frequency was significantly increased in MS patients compared to HD (20.8% vs 12.5%, p=0.04, OR=1.84). On the other hand, no associations were detected between both polymorphisms and clinical parameters, except the lower age of disease onset (ADO) in patients with the +3142 C/C genotype. Moreover, our study doesn't show any significant variation of sHLA-G serum levels between patients and controls. Our findings showed that the +3142 C>G, but not the 14bp INS/DEL, polymorphism may constitute a genetic susceptibility factor to MS in the Tunisian population. However, no association was found between the two polymorphisms and sHLA-G serum levels. Copyright © 2016 European Federation of Immunological Societies. Published by Elsevier B.V. All rights reserved.

  8. Multiple Sclerosis Risk Variant HLA-DRB1*1501 Associates with High Expression of DRB1 Gene in Different Human Populations

    PubMed Central

    Abad-Grau, María del Mar; Fedetz, María; Izquierdo, Guillermo; Lucas, Miguel; Fernández, Óscar; Ndagire, Dorothy; Catalá-Rabasa, Antonio; Ruiz, Agustín; Gayán, Javier; Delgado, Concepción; Arnal, Carmen

    2012-01-01

    The human leukocyte antigen (HLA) DRB1*1501 has been consistently associated with multiple sclerosis (MS) in nearly all populations tested. This points to a specific antigen presentation as the pathogenic mechanism though this does not fully explain the disease association. The identification of expression quantitative trait loci (eQTL) for genes in the HLA locus poses the question of the role of gene expression in MS susceptibility. We analyzed the eQTLs in the HLA region with respect to MS-associated HLA-variants obtained from genome-wide association studies (GWAS). We found that the Tag of DRB1*1501, rs3135388 A allele, correlated with high expression of DRB1, DRB5 and DQB1 genes in a Caucasian population. In quantitative terms, the MS-risk AA genotype carriers of rs3135388 were associated with 15.7-, 5.2- and 8.3-fold higher expression of DQB1, DRB5 and DRB1, respectively, than the non-risk GG carriers. The haplotype analysis of expression-associated variants in a Spanish MS cohort revealed that high expression of DRB1 and DQB1 alone did not contribute to the disease. However, in Caucasian, Asian and African American populations, the DRB1*1501 allele was always highly expressed. In other immune related diseases such as type 1 diabetes, inflammatory bowel disease, ulcerative colitis, asthma and IgA deficiency, the best GWAS-associated HLA SNPs were also eQTLs for different HLA Class II genes. Our data suggest that the DR/DQ expression levels, together with specific structural properties of alleles, seem to be the causal effect in MS and in other immunopathologies rather than specific antigen presentation alone. PMID:22253788

  9. Uncommon HLA alleles identified by hemizygous ultra-high Sanger sequencing: haplotype associations and reconsideration of their assignment in the Common and Well-Documented catalogue.

    PubMed

    Voorter, Christina E M; Groeneweg, Mathijs; Groeneveld, Lisette; Tilanus, Marcel G J

    2016-02-01

    Although the number of HLA alleles still increases, many of them have been reported being uncommon. This is partly due to lack of full length gene sequencing, especially for those alleles belonging to an allele ambiguity in which the first discovered allele has been assigned as the most frequent one. As members of the working group on Common and Well Documented (CWD) alleles and since we implemented full length group-specific sequencing as standard method routinely, we have investigated the presence of presumably rare alleles in our collection of HLA typing data. We identified 50 alleles, that were not previously encountered as Common or Well Documented. Sixteen of them should be added to the CWD catalogue, since we encountered them in 5 or more unrelated individuals. Another 11 could be added, based upon our results and the data present in the IMGT database and the rare allele section of the allele frequencies database. Furthermore, tight associations were observed between several different alleles even at the level of synonymous and non-coding sequences. In addition, in several cases the uncommon allele was found to be more frequent than its common counterpart.

  10. Multiple mismatches at the low expression HLA loci DP, DQ, and DRB3/4/5 associate with adverse outcomes in hematopoietic stem cell transplantation.

    PubMed

    Fernández-Viña, Marcelo A; Klein, John P; Haagenson, Michael; Spellman, Stephen R; Anasetti, Claudio; Noreen, Harriet; Baxter-Lowe, Lee Ann; Cano, Pedro; Flomenberg, Neal; Confer, Dennis L; Horowitz, Mary M; Oudshoorn, Machteld; Petersdorf, Effie W; Setterholm, Michelle; Champlin, Richard; Lee, Stephanie J; de Lima, Marcos

    2013-05-30

    A single mismatch in highly expressed HLA-A, -B, -C, and -DRB1 loci (HEL) is associated with worse outcomes in hematopoietic stem cell transplantation, while less is known about the cumulative impact of mismatches in the lesser expressed HLA loci DRB3/4/5, DQ, and DP (LEL). We studied whether accumulation of LEL mismatches is associated with deleterious effects in 3853 unrelated donor transplants stratified according to number of matches in the HEL. In the 8/8 matched HEL group, LEL mismatches were not associated with any adverse outcome. Mismatches at HLA-DRB1 were associated with occurrence of multiple LEL mismatches. In the 7/8 HEL group, patients with 3 or more LEL mismatches scored in the graft-versus-host vector had a significantly higher risk of mortality (1.45 and 1.43) and transplant-related mortality (1.68 and 1.54) than the subgroups with 0 or 1 LEL mismatches. No single LEL locus had a more pronounced effect on clinical outcome. Three or more LEL mismatches are associated with lower survival after 7/8 HEL matched transplantation. Prospective evaluation of matching for HLA-DRB3/4/5, -DQ, and -DP loci is warranted to reduce posttransplant risks in donor-recipient pairs matched for 7/8 HEL.

  11. Fine mapping analysis of HLA-DP/DQ gene clusters on chromosome 6 reveals multiple susceptibility loci for HBV infection.

    PubMed

    Tao, Jingjing; Su, Kunkai; Yu, Chengbo; Liu, Xiaoli; Wu, Wei; Xu, Wei; Jiang, Bingxun; Luo, Rui; Yao, Jian; Zhou, Jiawei; Zhan, Yan; Ye, Chao; Yuan, Wenji; Jiang, Xianzhong; Cui, Wenyan; Li, Ming D; Li, Lianjuan

    2015-12-01

    Recent genome-wide association studies have revealed the HLA region on chromosome 6p21 as a susceptibility locus for hepatitis B virus (HBV) infection, a finding subsequently replicated in independent samples. However, only limited single nucleotide polymorphisms (SNPs) were analyzed in most of these studies, and it remains to be determined which SNPs contribute to the detected association. After genotyping 140 SNPs within this genomic region in a total of 1657 HBV-positive patients and 1456 HBV-negative controls, we conducted a series of genetic epidemiological and bioinformatics analysis, including individual SNP-based association analysis, haplotype-based association analysis, and conditional analysis. We identified 76 SNPs and 5 LD blocks in HLA-DP/DQ clusters that are significantly associated with HBV infection, with the smallest P value being 3.88 × 10(-18) for rs9277535 in HLA-DPB1. With conditional analysis, we further revealed that the genes contributing to the effects of variants in HLA-DP/DQ on infection are independent of each other, and the LD block 5 in the 3'-UTR region of HLA-DPB1 had a predominant effect in the association of HLA-DP with HBV infection. We also found that the SNPs in the 3'-UTR region of HLA-DPB1 were significant between the subgroups of inactive HBV carrier, chronic hepatitis B, or hepatic cirrhosis from the case group and the spontaneous HBV-clearance subgroup from the control group. Finally, we did further association analysis of SNPs in this region with different subgroups from the case group, which revealed no association of these SNPs with the progression of HBV-related diseases. In sum, we showed, for the first time, that the HLA-DP/DQ clusters contribute independently to HBV infection, and the 3'-UTR region of HLA-DPB1 represents an important functional region involved in HBV infection.

  12. Multiple Pathway Quenchers: Efficient Quenching of Common Fluorophores

    PubMed Central

    Crisalli, Pete; Kool, Eric T.

    2011-01-01

    Fluorescence quenching groups are widely employed in biological detection, sensing, and imaging. To date, a relatively small number of such groups are in common use. Perhaps the most commonly used quencher, dabcyl, has limited efficiency with a broad range of fluorophores. Here we describe a molecular approach to improve the efficiency of quenchers by increasing their electronic complexity. Multiple pathway quenchers (MPQ) are designed to have multiple donor or acceptor groups in their structure, allowing for a multiplicity of conjugation pathways of varied length. This has the effect of broadening the absorption spectrum, which in turn can increase quenching efficiency and versatility. Six such MPQ derivatives are synthesized and tested for quenching efficiency in a DNA hybridization context. Duplexes placing quenchers and fluorophores within contact distance or beyond this distance are used to measure quenching via contact or FRET mechanisms. Results show that several of the quenchers are considerably more efficient than dabcyl at quenching a wider range of common fluorophores, and two quench fluorescein and TAMRA as well as or better than a Black Hole Quencher. PMID:22034828

  13. Latitude and HLA-DRB1*04:05 independently influence disease severity in Japanese multiple sclerosis: a cross-sectional study.

    PubMed

    Nakamura, Yuri; Matsushita, Takuya; Sato, Shinya; Niino, Masaaki; Fukazawa, Toshiyuki; Yoshimura, Satoshi; Hisahara, Shin; Isobe, Noriko; Shimohama, Shun; Watanabe, Mitsuru; Yoshida, Kazuto; Houzen, Hideki; Miyazaki, Yusei; Yamasaki, Ryo; Kikuchi, Seiji; Kira, Jun-Ichi

    2016-09-06

    Higher latitude and human leukocyte antigen (HLA)-DRB1*04:05 increase susceptibility to multiple sclerosis (MS) in the Japanese population, but their effects on disease severity are unknown. We aimed to clarify the effects of latitude and the HLA-DRB1 and HLA-DPB1 genes on disease severity in Japanese patients with MS. We enrolled 247 MS patients and 159 healthy controls (HCs) from the northernmost main island of Japan, Hokkaido Island (42-45° north), and 187 MS patients and 235 HCs from the southern half (33-35° north) of the Japanese archipelago (33-45° north). We genotyped HLA-DRB1 and HLA-DPB1 alleles, compared demographic features, and analyzed factors contributing to differences in clinical and laboratory findings between MS patients from southern and northern Japan. The Multiple Sclerosis Severity Score (MSSS), which adjusts the Kurtzke's Expanded Disability Status Scale score according to disease duration, was used to estimate disease severity. The HLA-DRB1*04:05 and DRB1*15:01 alleles conferred susceptibility to MS in our Japanese population (p (corr) = 0.0004 and p (corr) = 0.0019, respectively). Southern patients had higher MSSS scores than northern patients (p = 0.003). Northern patients had higher frequencies of brain lesions meeting the Barkhof criteria (Barkhof brain lesions) and cerebrospinal fluid (CSF) IgG abnormalities than southern patients (p = 0.0012 and p < 0.0001, respectively). DRB1*04:05-positive MS patients had lower MSSS scores and lower frequencies of Barkhof brain lesions and CSF IgG abnormalities than DRB1*04:05-negative MS patients (p = 0.0415, p = 0.0026, and p < 0.0001, respectively). Multivariate analyses revealed that latitude and DRB1*04:05 were independently associated with the lowest quartile of MSSS and that latitude was positively associated with Barkhof brain lesions and CSF IgG abnormalities. DRB1*04:05 was negatively associated with these parameters. MSSS was decreased by 0.57 per DRB1

  14. Susceptibility to Amoxicillin-Clavulanate-Induced Liver Injury is Influenced by Multiple HLA Class I and II Alleles

    PubMed Central

    Lucena, M. Isabel; Molokhia, Mariam; Shen, Yufeng; Urban, Thomas J.; Aithal, Guruprasad P.; Andrade, Raúl J.; Day, Christopher P.; Ruiz-Cabello, Francisco; Donaldson, Peter T.; Stephens, Camilla; Pirmohamed, Munir; Romero-Gomez, Manuel; Navarro, Jose Maria; Fontana, Robert J.; Miller, Michael; Groome, Max; Bondon-Guitton, Emmanuelle; Conforti, Anita; Stricker, Bruno H. C.; Carvajal, Alfonso; Ibanez, Luisa; Yue, Qun-Ying; Eichelbaum, Michel; Floratos, Aris; Pe’er, Itsik; Daly, Mark J.; Goldstein, David B.; Dillon, John F.; Nelson, Matthew R.; Watkins, Paul B.; Daly, Ann K.

    2011-01-01

    Background & Aims Drug-induced liver injury (DILI), especially from antimicrobial agents, is an important cause of serious liver disease. Amoxicillin-clavulanate (AC) is a leading cause of idiosyncratic DILI, but little is understood about genetic susceptibility to this adverse reaction. Methods We performed a genome-wide association study using 822,927 single-nucleotide polymorphism (SNP) markers from 201 White European and US cases of AC-DILI and 532 population controls, matched for genetic background. Results AC-DILI was associated with many loci in the major histocompatibility complex. The strongest effect was with a human leukocyte antigen (HLA) class II SNP (rs9274407, P=4.8×10−14), which correlated with rs3135388, a tag SNP of HLA-DRB1*1501-DQB1*0602 that was previously associated with AC-DILI. Conditioned on rs3135388, rs9274407 is still significant (P=1.1×10−4). An independent association was observed in the class I region (rs2523822, P=1.8×10−10), related to HLA-A*0201. The most significant class I and II SNPs showed statistical interaction (P=0.0015). High-resolution HLA genotyping (177 cases and 219 controls) confirmed associations of HLA-A*0201 (P=2×10−6) and HLA-DQB1*0602 (P=5×10−10), and their interaction (P=0.005). Additional, population-dependent effects were observed in HLA alleles with nominal significance. In an analysis of auto-immunerelated genes, rs2476601 in the gene PTPN22 was associated (P=1.3×10−4). Conclusions Class I and II HLA genotypes affect susceptibility to AC-DILI, indicating the importance of the adaptive immune response in pathogenesis. The HLA genotypes identified will be useful in studies of the pathogenesis of AC-DILI, but have limited utility as predictive or diagnostic biomarkers because of the low positive-predictive values. PMID:21570397

  15. A strategy to determine HLA class II restriction broadly covering the DR, DP and DQ allelic variants most commonly expressed in the general population

    PubMed Central

    McKinney, Denise M.; Southwood, Scott; Hinz, Denise; Oseroff, Carla; Lindestam Arlehamn, Cecilia S.; Schulten, Veronique; Taplitz, Randy; Broide, David; Hanekom, Willem A.; Scriba, Thomas J.; Wood, Robert; Alam, Rafeul; Peters, Bjoern; Sidney, John; Sette, Alessandro

    2013-01-01

    Classic ways to determine MHC restriction involve inhibition with locus specific antibodies and antigen presentation assays with panels of cell lines matched or mismatched at the various loci of interest. However, these determinations are often complicated by T-cell epitope degeneracy and promiscuity. We describe selection of 46 HLA DR, DQ and DP specificities that provide worldwide population (phenotypic) coverage of almost 90% at each locus, and account for over 66% of all genes at each locus. This panel afforded coverage of at least four HLA class II alleles in over 95% of the individuals in four study populations of diverse ethnicity from the US and South Africa. Next, a panel of single HLA class II transfected cell lines, corresponding to these 46 allelic variants was assembled, consisting of lines previously developed and 15 novel lines generated for the present study. The novel lines were validated by assessing their HLA class II expression by FACS analysis, the in vitro peptide binding activity of HLA molecules purified from the cell lines, and their antigen presenting capacity to T-cell lines of known restriction. We also show that these HLA class II transfected cell lines can be used to rapidly and unambiguously determine HLA restriction of epitopes recognized by an individual donor in a single experiment. This panel of lines will enable high throughput determination of HLA restriction, enabling better characterization of HLA class II-restricted T-cell responses and facilitating the development of HLA tetrameric staining reagents. PMID:23392739

  16. HLA-DRB1 rheumatoid arthritis risk in African Americans at multiple levels: Hierarchical classification systems, amino acid positions and residues

    PubMed Central

    Reynolds, Richard J.; Ahmed, Altan F.; Danila, Maria I.; Hughes, Laura B.; Gregersen, Peter K.; Raychaudhuri, Soumya; Plenge, Robert M.; Bridges, S. Louis

    2014-01-01

    Objective To evaluate African American rheumatoid arthritis HLA-DRB1 genetic risk by three validated allele classification systems, and by amino acid position and residue. To compare the genetic risk between African American and European ancestries. Methods Four-digit HLA-DRB1 genotyping was performed on 561 autoantibody-positive African American cases and 776 African American controls. Association analysis was performed on Tezenas du Montcel (TdM); de Vries (DV); and Mattey classification system alleles and separately by amino acid position and individual residues. Results TdM S2 and S3P alleles were associated with RA (odds ratios (95% CI) 2.8 (2.0, 3.9) and 2.1 (1.7, 2.7), respectively). The DV (P-value=3.2 x 10−12) and Mattey (P-value=6.5 x 10−13) system alleles were both protective in African Americans. Amino acid position 11 (permutation P-value < 0.00001) accounted for nearly all variability explained by HLA-DRB1, although conditional analysis demonstrated that position 57 was also significant (0.01<= permutation P-val <=0.05). The valine and aspartic acid residues at position 11 conferred the highest risk for RA in African Americans. Conclusion With some exceptions, the genetic risk conferred by HLA-DRB1 in African Americans is similar to European ancestry at multiple levels: classification system (e.g., TdM), amino acid position (e.g. 11) and residue (Val 11). Unlike that reported from European ancestry, amino acid position 57 was associated with RA in African Americans, but positions 71 and 74 were not. Asp11 (OR = 1 in European ancestry) corresponds to the four digit classical allele, *09:01, also a risk allele for RA in Koreans. PMID:25524867

  17. HLA-DRB1-associated rheumatoid arthritis risk at multiple levels in African Americans: hierarchical classification systems, amino acid positions, and residues.

    PubMed

    Reynolds, Richard J; Ahmed, Altan F; Danila, Maria I; Hughes, Laura B; Gregersen, Peter K; Raychaudhuri, Soumya; Plenge, Robert M; Bridges, S Louis

    2014-12-01

    To evaluate HLA-DRB1 genetic risk of rheumatoid arthritis (RA) in African Americans by 3 validated allele classification systems and by amino acid position and residue, and to compare genetic risk between African American and European ancestries. Four-digit HLA-DRB1 genotyping was performed on 561 autoantibody-positive African American cases and 776 African American controls. Association analysis was performed on Tezenas du Montcel (TdM), de Vries (DV), and Mattey classification system alleles and separately by amino acid position and individual residues. TdM S2 and S3P alleles were associated with RA (odds ratio [95% confidence interval] 2.8 [2.0-3.9] and 2.1 [1.7-2.7], respectively). The DV (P = 3.2 × 10(-12)) and Mattey (P = 6.5 × 10(-13)) system alleles were both protective in African Americans. Amino acid position 11 (permutation P < 0.00001) accounted for nearly all variability explained by HLA-DRB1, although conditional analysis demonstrated that position 57 was also significant (0.01 ≤ permutation P ≤ 0.05). The valine and aspartic acid residues at position 11 conferred the highest risk of RA in African Americans. With some exceptions, the genetic risk conferred by HLA-DRB1 in African Americans is similar to that in individuals of European ancestry at multiple levels: classification system (e.g., TdM), amino acid position (e.g., 11), and residue (Val11). Unlike that reported for individuals of European ancestry, amino acid position 57 was associated with RA in African Americans, but positions 71 and 74 were not. Asp11 (odds ratio 1 in European ancestry) corresponds to the 4-digit classical allele *09:01, which is also a risk allele for RA in Koreans. Copyright © 2014 by the American College of Rheumatology.

  18. Common pitfalls in statistical analysis: The perils of multiple testing

    PubMed Central

    Ranganathan, Priya; Pramesh, C. S.; Buyse, Marc

    2016-01-01

    Multiple testing refers to situations where a dataset is subjected to statistical testing multiple times - either at multiple time-points or through multiple subgroups or for multiple end-points. This amplifies the probability of a false-positive finding. In this article, we look at the consequences of multiple testing and explore various methods to deal with this issue. PMID:27141478

  19. Multiple cell common pressure vessel nickel hydrogen battery

    NASA Technical Reports Server (NTRS)

    Zagrodnik, Jeffrey P.; Jones, Kenneth R.

    1991-01-01

    A multiple cell common pressure vessel (CPV) nickel hydrogen battery was developed that offers significant weight, volume, cost, and interfacing advantages over the conventional individual pressure vessel (IPV) nickel hydrogen configuration that is currently used for aerospace applications. The baseline CPV design was successfully demonstrated though the testing of a 26 cell prototype, which completed over 7,000 44 percent depth of discharge LEO cycles. Two-cell boilerplate batteries have now exceeded 12,500 LEO cycles in ongoing laboratory tests. CPV batteries using both nominal 5 and 10 inch diameter vessels are currently available. The flexibility of the design allows these diameters to provide a broad capability for a variety of space applications.

  20. Prokaryotic Heme Biosynthesis: Multiple Pathways to a Common Essential Product.

    PubMed

    Dailey, Harry A; Dailey, Tamara A; Gerdes, Svetlana; Jahn, Dieter; Jahn, Martina; O'Brian, Mark R; Warren, Martin J

    2017-03-01

    The advent of heme during evolution allowed organisms possessing this compound to safely and efficiently carry out a variety of chemical reactions that otherwise were difficult or impossible. While it was long assumed that a single heme biosynthetic pathway existed in nature, over the past decade, it has become clear that there are three distinct pathways among prokaryotes, although all three pathways utilize a common initial core of three enzymes to produce the intermediate uroporphyrinogen III. The most ancient pathway and the only one found in the Archaea converts siroheme to protoheme via an oxygen-independent four-enzyme-step process. Bacteria utilize the initial core pathway but then add one additional common step to produce coproporphyrinogen III. Following this step, Gram-positive organisms oxidize coproporphyrinogen III to coproporphyrin III, insert iron to make coproheme, and finally decarboxylate coproheme to protoheme, whereas Gram-negative bacteria first decarboxylate coproporphyrinogen III to protoporphyrinogen IX and then oxidize this to protoporphyrin IX prior to metal insertion to make protoheme. In order to adapt to oxygen-deficient conditions, two steps in the bacterial pathways have multiple forms to accommodate oxidative reactions in an anaerobic environment. The regulation of these pathways reflects the diversity of bacterial metabolism. This diversity, along with the late recognition that three pathways exist, has significantly slowed advances in this field such that no single organism's heme synthesis pathway regulation is currently completely characterized.

  1. A Common HLA-DPA1 Variant Is Associated with Hepatitis B Virus Infection but Fails to Distinguish Active from Inactive Caucasian Carriers

    PubMed Central

    Vermehren, Johannes; Lötsch, Jörn; Susser, Simone; Wicker, Sabine; Berger, Annemarie; Zeuzem, Stefan; Sarrazin, Christoph; Doehring, Alexandra

    2012-01-01

    Background and Aims Chronic infection with the hepatitis B virus (HBV) is a major health issue worldwide. Recently, single nucleotide polymorphisms (SNPs) within the human leukocyte antigen (HLA)-DP locus were identified to be associated with HBV infection in Asian populations. Most significant associations were observed for the A alleles of HLA-DPA1 rs3077 and HLA-DPB1 rs9277535, which conferred a decreased risk for HBV infection. We assessed the implications of these variants for HBV infection in Caucasians. Methods Two HLA-DP gene variants (rs3077 and rs9277535) were analyzed for associations with persistent HBV infection and with different clinical outcomes, i.e., inactive HBsAg carrier status versus progressive chronic HBV (CHB) infection in Caucasian patients (n = 201) and HBsAg negative controls (n = 235). Results The HLA-DPA1 rs3077 C allele was significantly associated with HBV infection (odds ratio, OR = 5.1, 95% confidence interval, CI: 1.9–13.7; p = 0.00093). However, no significant association was seen for rs3077 with progressive CHB infection versus inactive HBsAg carrier status (OR = 2.7, 95% CI: 0.6–11.1; p = 0.31). In contrast, HLA-DPB1 rs9277535 was not associated with HBV infection in Caucasians (OR = 0.8, 95% CI: 0.4–1.9; p = 1). Conclusions A highly significant association of HLA-DPA1 rs3077 with HBV infection was observed in Caucasians. However, as a differentiation between different clinical courses of HBV infection was not possible, knowledge of the HLA-DPA1 genotype cannot be translated into personalized anti-HBV therapy approaches. PMID:22448225

  2. A common HLA-DPA1 variant is associated with hepatitis B virus infection but fails to distinguish active from inactive Caucasian carriers.

    PubMed

    Vermehren, Johannes; Lötsch, Jörn; Susser, Simone; Wicker, Sabine; Berger, Annemarie; Zeuzem, Stefan; Sarrazin, Christoph; Doehring, Alexandra

    2012-01-01

    Chronic infection with the hepatitis B virus (HBV) is a major health issue worldwide. Recently, single nucleotide polymorphisms (SNPs) within the human leukocyte antigen (HLA)-DP locus were identified to be associated with HBV infection in Asian populations. Most significant associations were observed for the A alleles of HLA-DPA1 rs3077 and HLA-DPB1 rs9277535, which conferred a decreased risk for HBV infection. We assessed the implications of these variants for HBV infection in Caucasians. Two HLA-DP gene variants (rs3077 and rs9277535) were analyzed for associations with persistent HBV infection and with different clinical outcomes, i.e., inactive HBsAg carrier status versus progressive chronic HBV (CHB) infection in Caucasian patients (n = 201) and HBsAg negative controls (n = 235). The HLA-DPA1 rs3077 C allele was significantly associated with HBV infection (odds ratio, OR = 5.1, 95% confidence interval, CI: 1.9-13.7; p = 0.00093). However, no significant association was seen for rs3077 with progressive CHB infection versus inactive HBsAg carrier status (OR = 2.7, 95% CI: 0.6-11.1; p = 0.31). In contrast, HLA-DPB1 rs9277535 was not associated with HBV infection in Caucasians (OR = 0.8, 95% CI: 0.4-1.9; p = 1). A highly significant association of HLA-DPA1 rs3077 with HBV infection was observed in Caucasians. However, as a differentiation between different clinical courses of HBV infection was not possible, knowledge of the HLA-DPA1 genotype cannot be translated into personalized anti-HBV therapy approaches.

  3. Frequencies of allele groups HLA-A, HLA-B and HLA-DRB1 in a population from the northwestern region of São Paulo State, Brazil.

    PubMed

    Ayo, C M; da Silveira Camargo, A V; Xavier, D H; Batista, M F; Carneiro, O A; Brandão de Mattos, C C; Ricci, O; de Mattos, L C

    2015-02-01

    The aim of this study was to estimate the HLA-A, HLA-B and HLA-DRB1 allele groups frequencies in a population of 1559 volunteer bone marrow donors from the northwestern region of São Paulo State grouped according to ethnicity. An additional objective was to compare the allele frequencies of the current study with data published for other Brazilian populations. The allele groups were characterized by the PCR-rSSO method using Luminex(®) technology. Twenty HLA-A, 32 HLA-B and 13 HLA-DRB1 allele groups were identified. The most common allele groups in European descent and mixed African and European descent samples were HLA-A*02, HLA-B*35 and HLA-DRB1*13, while HLA-A*02, HLA-B*35 and HLA-DRB1*11 were more common in African descent samples. The HLA-A*23, HLA-A*36, HLA-B*58 and HLA-B*81 allele groups were more common in sample from African descent than European descent, and the HLA-DRB1*08 was more common in mixed African and European descent than in European descent. Allele group frequencies were compared with samples from other Brazilian regions. The HLA-A*30 and HLA-A*23 were more common in this study than in the populations of Rio Grande do Sul and Paraná; and the HLA-A*01, HLA-B*18, HLA-B*57 and HLA-DRB1*11 were more common in this study than in the population of Piauí. The least frequent allele groups were HLA-A*31, HLA-B*15, HLA-B*40 and HLA-DRB1*08 for the population of Piauí, HLA-A*01 and HLA-A*11 for Parana, HLA-A*02 and -A*03 for Rio Grande do Sul and HLA-DRB1*04 for Paraná, Rio Grande do Sul and Piauí. These data provide an overview on the knowledge on HLA diversity in the population of the northwestern region of São Paulo State and show that the genes of this system are useful to distinguish different ethnic groups.

  4. Successful Simultaneous Liver-Kidney Transplantation in the Presence of Multiple High-Titered Class I and II Antidonor HLA Antibodies.

    PubMed

    Paterno, Flavio; Girnita, Alin; Brailey, Paul; Witte, David; Wang, Jiang; Cuffy, Madison C; Diwan, Tayyab; Tremblay, Simon; Revollo, Jane Y; Alloway, Rita R; Schoech, Michael R; Anwar, Nadim; Shah, Shimul A; Woodle, Steve E

    2016-12-01

    The results of simultaneous liver-kidney transplants in highly sensitized recipients have been controversial in terms of antibody-mediated rejection and kidney allograft outcomes. This case report provides a detailed and sophisticated documentation of histocompatibility and pathologic data in a simultaneous liver-kidney transplant performed in a recipient with multiple high-titered class I and II antidonor HLA antibodies and a strongly positive cytotoxic crossmatch. Patient received induction with steroids, rituximab, and eculizumab without lymphocyte depleting agents. The kidney transplant was delayed by 6 hours after the liver transplant to allow more time to the liver allograft to "absorb" donor-specific antibodies (DSA). Interestingly, the liver allograft did not prevent immediate antibody-mediated injury to the kidney allograft in this highly sensitized recipient. Anti-HLA single antigen bead analysis of liver and kidney allograft biopsy eluates revealed deposition of both class I and II DSA in both liver and kidney transplants during the first 2 weeks after transplant. Afterward, both liver and kidney allograft functions improved and remained normal after a year with progressive reduction in serum DSA values.

  5. Successful Simultaneous Liver-Kidney Transplantation in the Presence of Multiple High-Titered Class I and II Antidonor HLA Antibodies

    PubMed Central

    Paterno, Flavio; Girnita, Alin; Brailey, Paul; Witte, David; Wang, Jiang; Cuffy, Madison C.; Diwan, Tayyab; Tremblay, Simon; Revollo, Jane Y.; Alloway, Rita R.; Schoech, Michael R.; Anwar, Nadim; Shah, Shimul A.; Woodle, Steve E.

    2016-01-01

    Abstract The results of simultaneous liver-kidney transplants in highly sensitized recipients have been controversial in terms of antibody-mediated rejection and kidney allograft outcomes. This case report provides a detailed and sophisticated documentation of histocompatibility and pathologic data in a simultaneous liver-kidney transplant performed in a recipient with multiple high-titered class I and II antidonor HLA antibodies and a strongly positive cytotoxic crossmatch. Patient received induction with steroids, rituximab, and eculizumab without lymphocyte depleting agents. The kidney transplant was delayed by 6 hours after the liver transplant to allow more time to the liver allograft to “absorb” donor-specific antibodies (DSA). Interestingly, the liver allograft did not prevent immediate antibody-mediated injury to the kidney allograft in this highly sensitized recipient. Anti-HLA single antigen bead analysis of liver and kidney allograft biopsy eluates revealed deposition of both class I and II DSA in both liver and kidney transplants during the first 2 weeks after transplant. Afterward, both liver and kidney allograft functions improved and remained normal after a year with progressive reduction in serum DSA values. PMID:27990486

  6. Common genetic variant association with altered HLA expression, synergy with pyrethroid exposure, and risk for Parkinson’s disease: an observational and case–control study

    PubMed Central

    Kannarkat, G T; Cook, D A; Lee, J-K; Chang, J; Chung, J; Sandy, E; Paul, K C; Ritz, B; Bronstein, J; Factor, S A; Boss, J M; Tansey, M G

    2015-01-01

    Background: The common noncoding single-nucleotide polymorphism (SNP) rs3129882 in HLA-DRA is associated with risk for idiopathic Parkinson’s disease (PD). The location of the SNP in the major histocompatibility complex class II (MHC-II) locus implicates regulation of antigen presentation as a potential mechanism by which immune responses link genetic susceptibility to environmental factors in conferring lifetime risk for PD. Aims: The aim of this study was to determine the effect of this SNP on the MHC-II locus and its synergy with pesticide exposure. Methods: For immunophenotyping, blood cells from 81 subjects were analyzed by quantitative reverse transcription-PCR and flow cytometry. A case–control study was performed on a separate cohort of 962 subjects to determine association of pesticide exposure and the SNP with risk of PD. Results: Homozygosity for G at this SNP was associated with heightened baseline expression and inducibility of MHC class II molecules in B cells and monocytes from peripheral blood of healthy controls and PD patients. In addition, exposure to a commonly used class of insecticide, pyrethroids, synergized with the risk conferred by this SNP (odds ratio=2.48, P=0.007), thereby identifying a novel gene–environment interaction that promotes risk for PD via alterations in immune responses. Conclusions: In sum, these novel findings suggest that the MHC-II locus may increase susceptibility to PD through presentation of pathogenic, immunodominant antigens and/or a shift toward a more pro-inflammatory CD4+ T-cell response in response to specific environmental exposures, such as pyrethroid exposure through genetic or epigenetic mechanisms that modulate MHC-II gene expression. PMID:27148593

  7. Proteomic analysis uncovers common effects of IFN-γ and IL-27 on the HLA class I antigen presentation machinery in human cancer cells

    PubMed Central

    Inglese, Elvira; Lavarello, Chiara; Pistillo, Maria Pia; Rigo, Valentina; Croce, Michela; Longo, Luca; Martini, Stefania; Vacca, Paola

    2016-01-01

    IL-27, a member of the IL-12-family of cytokines, has shown anti-tumor activity in several pre-clinical models due to anti-proliferative, anti-angiogenic and immune-enhancing effects. On the other hand, IL-27 demonstrated immune regulatory activities and inhibition of auto-immunity in mouse models. Also, we reported that IL-27, similar to IFN-γ, induces the expression of IL-18BP, IDO and PD-L1 immune regulatory molecules in human cancer cells. Here, a proteomic analysis reveals that IL-27 and IFN-γ display a broad overlap of functions on human ovarian cancer cells. Indeed, among 990 proteins modulated by either cytokine treatment in SKOV3 cells, 814 showed a concordant modulation by both cytokines, while a smaller number (176) were differentially modulated. The most up-regulated proteins were common to both IFN-γ and IL-27. In addition, functional analysis of IL-27-regulated protein networks highlighted pathways of interferon signaling and regulation, antigen presentation, protection from natural killer cell-mediated cytotoxicity, regulation of protein polyubiquitination and proteasome, aminoacid catabolism and regulation of viral protein levels. Importantly, we found that IL-27 induced HLA class I molecule expression in human cancer cells of different histotypes, including tumor cells showing very low expression. IL-27 failed only in a cancer cell line bearing a homozygous deletion in the B2M gene. Altogether, these data point out to a broad set of activities shared by IL-27 and IFN-γ, which are dependent on the common activation of the STAT1 pathway. These data add further explanation to the anti-tumor activity of IL-27 and also to its dual role in immune regulation. PMID:27683036

  8. Common Language Effect Size for Multiple Treatment Comparisons

    ERIC Educational Resources Information Center

    Liu, Xiaofeng Steven

    2015-01-01

    Researchers who need to explain treatment effects to laypeople can translate Cohen's effect size (standardized mean difference) to a common language effect size--a probability of a random observation from one population being larger than a random observation from the other population. This common language effect size can be extended to represent…

  9. Common Language Effect Size for Multiple Treatment Comparisons

    ERIC Educational Resources Information Center

    Liu, Xiaofeng Steven

    2015-01-01

    Researchers who need to explain treatment effects to laypeople can translate Cohen's effect size (standardized mean difference) to a common language effect size--a probability of a random observation from one population being larger than a random observation from the other population. This common language effect size can be extended to represent…

  10. Improving coeliac disease risk prediction by testing non-HLA variants additional to HLA variants

    PubMed Central

    Romanos, Jihane; Rosén, Anna; Kumar, Vinod; Trynka, Gosia; Franke, Lude; Szperl, Agata; Gutierrez-Achury, Javier; van Diemen, Cleo C; Kanninga, Roan; Jankipersadsing, Soesma A; Steck, Andrea; Eisenbarth, Georges; van Heel, David A; Cukrowska, Bozena; Bruno, Valentina; Mazzilli, Maria Cristina; Núñez, Concepcion; Bilbao, Jose Ramon; Mearin, M Luisa; Barisani, Donatella; Rewers, Marian; Norris, Jill M; Ivarsson, Anneli; Boezen, H Marieke; Liu, Edwin; Wijmenga, Cisca

    2014-01-01

    Background The majority of coeliac disease (CD) patients are not being properly diagnosed and therefore remain untreated, leading to a greater risk of developing CD-associated complications. The major genetic risk heterodimer, HLA-DQ2 and DQ8, is already used clinically to help exclude disease. However, approximately 40% of the population carry these alleles and the majority never develop CD. Objective We explored whether CD risk prediction can be improved by adding non-HLA-susceptible variants to common HLA testing. Design We developed an average weighted genetic risk score with 10, 26 and 57 single nucleotide polymorphisms (SNP) in 2675 cases and 2815 controls and assessed the improvement in risk prediction provided by the non-HLA SNP. Moreover, we assessed the transferability of the genetic risk model with 26 non-HLA variants to a nested case–control population (n=1709) and a prospective cohort (n=1245) and then tested how well this model predicted CD outcome for 985 independent individuals. Results Adding 57 non-HLA variants to HLA testing showed a statistically significant improvement compared to scores from models based on HLA only, HLA plus 10 SNP and HLA plus 26 SNP. With 57 non-HLA variants, the area under the receiver operator characteristic curve reached 0.854 compared to 0.823 for HLA only, and 11.1% of individuals were reclassified to a more accurate risk group. We show that the risk model with HLA plus 26 SNP is useful in independent populations. Conclusions Predicting risk with 57 additional non-HLA variants improved the identification of potential CD patients. This demonstrates a possible role for combined HLA and non-HLA genetic testing in diagnostic work for CD. PMID:23704318

  11. Commonality.

    ERIC Educational Resources Information Center

    Beaton, Albert E., Jr.

    Commonality analysis is an attempt to understand the relative predictive power of the regressor variables, both individually and in combination. The squared multiple correlation is broken up into elements assigned to each individual regressor and to each possible combination of regressors. The elements have the property that the appropriate sums…

  12. Measles Virus Epitope Presentation by HLA: Novel Insights into Epitope Selection, Dominance, and Microvariation

    PubMed Central

    Schellens, Ingrid M.; Meiring, Hugo D.; Hoof, Ilka; Spijkers, Sanne N.; Poelen, Martien C. M.; van Gaans-van den Brink, Jacqueline A. M.; Costa, Ana I.; Vennema, Harry; Keşmir, Can; van Baarle, Debbie; van Els, Cécile A. C. M.

    2015-01-01

    Immunity to infections with measles virus (MV) can involve vigorous human leukocyte antigen (HLA) class I-restricted CD8+ cytotoxic T cell (CTL) responses. MV, albeit regarded monotypic, is known to undergo molecular evolution across its RNA genome. To address which regions of the MV proteome are eligible for recognition by CD8+ CTLs and how different HLA class I loci contribute to the epitope display, we interrogated the naturally processed and presented MV peptidome extracted from cell lines expressing in total a broad panel of 16 different common HLA-A, -B, and -C molecules. The repertoire and abundance of MV peptides were bona fide identified by nanoHPLC–MS/MS. ­Eighty-nine MV peptides were discovered and assignment to an HLA-A, -B, or -C allele, based on HLA-peptide affinity prediction, was in most cases successful. Length variation and presentation by multiple HLA class I molecules was common in the MV peptidome. More than twice as many unique MV epitopes were found to be restricted by HLA-B than by HLA-A, while MV peptides with supra-abundant expression rates (>5,000 cc) were rather associated with HLA-A and HLA-C. In total, 59 regions across the whole MV proteome were identified as targeted by HLA class I. Sequence coverage by epitopes was highest for internal proteins transcribed from the MV-P/V/C and -M genes and for hemagglutinin. At the genome level, the majority of the HLA class I-selected MV epitopes represented codons having a higher non-synonymous mutation rate than silent mutation rate, as established by comparison of a set of 58 unique full length MV genomes. Interestingly, more molecular variation was seen for the epitopes expressed at rates ≥1,000 cc. These data for the first time indicate that HLA class I broadly samples the MV proteome and that CTL pressure may contribute to the genomic evolution of MV. PMID:26579122

  13. Preclinical studies on targeted delivery of multiple IFNα2b to HLA-DR in diverse hematologic cancers

    PubMed Central

    Rossi, Diane L.; Cardillo, Thomas M.; Stein, Rhona; Chang, Chien-Hsing

    2011-01-01

    The short circulating half-life and side effects of IFNα affect its dosing schedule and efficacy. Fusion of IFNα to a tumor-targeting mAb (mAb-IFNα) can enhance potency because of increased tumor localization and improved pharmacokinetics. We used the Dock-and-Lock method to generate C2-2b-2b, a mAb-IFNα comprising tetrameric IFNα2b site-specifically linked to hL243 (humanized anti–HLA-DR). In vitro, C2-2b-2b inhibited various B-cell lymphoma leukemia and myeloma cell lines. In most cases, this immunocytokine was more effective than CD20-targeted mAb-IFNα or a mixture comprising the parental mAb and IFNα. Our findings indicate that responsiveness depends on HLA-DR expression/density and sensitivity to IFNα and hL243. C2-2b-2b induced more potent and longer-lasting IFNα signaling compared with nontargeted IFNα. Phosphorylation of STAT1 was more robust and persistent than that of STAT3, which may promote apoptosis. C2-2b-2b efficiently depleted lymphoma and myeloma cells from whole human blood but also exhibited some toxicity to B cells, monocytes, and dendritic cells. C2-2b-2b showed superior efficacy compared with nontargeting mAb-IFNα, peginterferonalfa-2a, or a combination of hL243 and IFNα, using human lymphoma and myeloma xenografts. These results suggest that C2-2b-2b should be useful in the treatment of various hematopoietic malignancies. PMID:21680794

  14. Theorizing University Identity Development: Multiple Perspectives and Common Goals

    ERIC Educational Resources Information Center

    MacDonald, Ginger Phillips

    2013-01-01

    Universities articulate their identities during moments of organizational change. The process of development of university identity is herein explored from multiple theoretical strands: (a) industrial/organizational psychology, (b) human development/social psychology, (c) marketing, and (d) postmodern sociological. This article provides an…

  15. Theorizing University Identity Development: Multiple Perspectives and Common Goals

    ERIC Educational Resources Information Center

    MacDonald, Ginger Phillips

    2013-01-01

    Universities articulate their identities during moments of organizational change. The process of development of university identity is herein explored from multiple theoretical strands: (a) industrial/organizational psychology, (b) human development/social psychology, (c) marketing, and (d) postmodern sociological. This article provides an…

  16. Paramyxovirus Fusion and Entry: Multiple Paths to a Common End

    PubMed Central

    Chang, Andres; Dutch, Rebecca E.

    2012-01-01

    The paramyxovirus family contains many common human pathogenic viruses, including measles, mumps, the parainfluenza viruses, respiratory syncytial virus, human metapneumovirus, and the zoonotic henipaviruses, Hendra and Nipah. While the expression of a type 1 fusion protein and a type 2 attachment protein is common to all paramyxoviruses, there is considerable variation in viral attachment, the activation and triggering of the fusion protein, and the process of viral entry. In this review, we discuss recent advances in the understanding of paramyxovirus F protein-mediated membrane fusion, an essential process in viral infectivity. We also review the role of the other surface glycoproteins in receptor binding and viral entry, and the implications for viral infection. Throughout, we concentrate on the commonalities and differences in fusion triggering and viral entry among the members of the family. Finally, we highlight key unanswered questions and how further studies can identify novel targets for the development of therapeutic treatments against these human pathogens. PMID:22590688

  17. HLA-A, HLA-B, and HLA-DRB1 allele distribution in a large Armenian population sample.

    PubMed

    Matevosyan, L; Chattopadhyay, S; Madelian, V; Avagyan, S; Nazaretyan, M; Hyussian, A; Vardapetyan, E; Arutunyan, R; Jordan, F

    2011-07-01

    Human leukocyte antigen (HLA)-A, HLA-B, and HLA-DRB1 gene frequencies were investigated in 4279 unrelated Armenian bone marrow donors. HLA alleles were defined by using PCR amplification with sequence specific primers (PCR-SSP) high- and low-resolution kits. The aim of this study was to examine the HLA diversity at the high-resolution level in a large Armenian population sample, and to compare HLA allele group distribution in Armenian subpopulations. The most frequently observed alleles in the HLA class I were HLA-A*0201, A*0101, A*2402, A*0301, HLA-B*5101, HLA-B*3501, and B*4901. Among DRB1 alleles, high frequencies of DRB1*1104 and DRB1*1501 were observed, followed by DRB1*1101 and DRB1*1401. The most common three-locus haplotype found in the Armenian population was A*33-B*14-DRB1*01, followed by A*03-B*35-DRB1*01. Our results show a similar distribution of alleles in Armenian subpopulations from different countries, and from different regions of the Republics of Armenia and Karabagh. The low level of genetic distances between subpopulations indicates a high level of population homogeneity, and the genetic distances between Armenians and other populations show Armenians as a distinct ethnic group relative to others, reflecting the fact that Armenians have been an 'isolated population' throughout centuries. This study is the first comprehensive investigation of HLA-allele group distribution in a subset of Armenian populations, and the first to provide HLA-allele and haplotype frequencies at a high-resolution level. It is a valuable reference for organ transplantation and for future studies of HLA-associated diseases in Armenian populations.

  18. Regulatory polymorphisms modulate the expression of HLA class II molecules and promote autoimmunity

    PubMed Central

    Raj, Prithvi; Rai, Ekta; Song, Ran; Khan, Shaheen; Wakeland, Benjamin E; Viswanathan, Kasthuribai; Arana, Carlos; Liang, Chaoying; Zhang, Bo; Dozmorov, Igor; Carr-Johnson, Ferdicia; Mitrovic, Mitja; Wiley, Graham B; Kelly, Jennifer A; Lauwerys, Bernard R; Olsen, Nancy J; Cotsapas, Chris; Garcia, Christine K; Wise, Carol A; Harley, John B; Nath, Swapan K; James, Judith A; Jacob, Chaim O; Tsao, Betty P; Pasare, Chandrashekhar; Karp, David R; Li, Quan Zhen; Gaffney, Patrick M; Wakeland, Edward K

    2016-01-01

    Targeted sequencing of sixteen SLE risk loci among 1349 Caucasian cases and controls produced a comprehensive dataset of the variations causing susceptibility to systemic lupus erythematosus (SLE). Two independent disease association signals in the HLA-D region identified two regulatory regions containing 3562 polymorphisms that modified thirty-seven transcription factor binding sites. These extensive functional variations are a new and potent facet of HLA polymorphism. Variations modifying the consensus binding motifs of IRF4 and CTCF in the XL9 regulatory complex modified the transcription of HLA-DRB1, HLA-DQA1 and HLA-DQB1 in a chromosome-specific manner, resulting in a 2.5-fold increase in the surface expression of HLA-DR and DQ molecules on dendritic cells with SLE risk genotypes, which increases to over 4-fold after stimulation. Similar analyses of fifteen other SLE risk loci identified 1206 functional variants tightly linked with disease-associated SNPs and demonstrated that common disease alleles contain multiple causal variants modulating multiple immune system genes. DOI: http://dx.doi.org/10.7554/eLife.12089.001 PMID:26880555

  19. Multiple mutations of lung squamous cell carcinoma shared common mechanisms

    PubMed Central

    Hu, Zhaoyan; Gu, Biao; Shi, Yan

    2016-01-01

    Lung squamous cell carcinoma (LUSC) is a subtype of non-small cell lung cancers which is the cause of 80% of all lung cancer deaths. The genes that highly mutated in patients with LUSC and their roles played in the tumorigenesis remains unknown. Data of patients with Lung squamous cell carcinoma (LUSC) were retrieved from The Cancer Genome Atlas (TCGA). Differentially expressed genes were identified between control and cancer samples. Patients and controls can be separated by mRNA expression level showing that the between-group variance and totally 1265 genes were differentially expressed between controls and patients. Top genes whose mutations highly occurred in patients with LUSC were identified, most of these genes were shown to be related with tumorigenesis in previous studies. All of the genes mostly mutated were independently correlated with expression levels of all genes. These mutations did not show the trend of co-occurrence. However, the influenced gene of these mutations had overlaps. After studying the intersection of these genes, a group of shared genes were identified. The shared pathways enriched which played critical role in LUSC were identified based on these shared genes. Different mutations had contribution to the progression of LUSC. Though these genes involved different specific mechanisms, most of them may share a common mechanism which is critical for LUSC. The results may suggest a neglected mechanism and also indicate a potential target for therapies. PMID:27835590

  20. Localization of type 1 diabetes susceptibility to the MHC class I genes HLA-B and HLA-A

    PubMed Central

    Nejentsev, Sergey; Howson, Joanna M. M.; Walker, Neil M.; Szeszko, Jeffrey; Field, Sarah F.; Stevens, Helen E.; Reynolds, Pamela; Hardy, Matthew; King, Erna; Masters, Jennifer; Hulme, John; Maier, Lisa M.; Smyth, Deborah; Bailey, Rebecca; Cooper, Jason D.; Ribas, Gloria; Campbell, R. Duncan; Clayton, David G.; Todd, John A.

    2009-01-01

    The major histocompatibility complex (MHC) on chromosome 6 is associated with susceptibility to more common diseases than any other region of the human genome, including almost all disorders classified as autoimmune. In type 1 diabetes the major genetic susceptibility determinants have been mapped to the MHC class II genes HLA-DQB1 and HLA-DRB1 (refs 1-3), but these genes cannot completely explain the association between type 1 diabetes and the MHC region4-11. Owing to the region’s extreme gene density, the multiplicity of disease-associated alleles, strong associations between alleles, limited genotyping capability, and inadequate statistical approaches and sample sizes, which, and how many, loci within the MHC determine susceptibility remains unclear. Here, in several large type 1 diabetes data sets, we analyse a combined total of 1,729 polymorphisms, and apply statistical methods—recursive partitioning and regression—to pinpoint disease susceptibility to the MHC class I genes HLA-B and HLA-A (risk ratios>1.5; Pcombined=2.01×10-19 and 2.35×10-13, respectively) in addition to the established associations of the MHC class II genes. Other loci with smaller and/or rarer effects might also be involved, but to find these, future searches must take into account both the HLA class II and class I genes and use even larger samples. Taken together with previous studies4-8,10-16, we conclude that MHC-class-I-mediated events, principally involving HLA-B*39, contribute to the aetiology of type 1 diabetes. PMID:18004301

  1. Vitamin D responsive elements within the HLA-DRB1 promoter region in Sardinian multiple sclerosis associated alleles.

    PubMed

    Cocco, Eleonora; Meloni, Alessandra; Murru, Maria Rita; Corongiu, Daniela; Tranquilli, Stefania; Fadda, Elisabetta; Murru, Raffaele; Schirru, Lucia; Secci, Maria Antonietta; Costa, Gianna; Asunis, Isadora; Cuccu, Stefania; Fenu, Giuseppe; Lorefice, Lorena; Carboni, Nicola; Mura, Gioia; Rosatelli, Maria Cristina; Marrosu, Maria Giovanna

    2012-01-01

    Vitamin D response elements (VDREs) have been found in the promoter region of the MS-associated allele HLA-DRB1*15:01, suggesting that with low vitamin D availability VDREs are incapable of inducing *15:01 expression allowing in early life autoreactive T-cells to escape central thymic deletion. The Italian island of Sardinia exhibits a very high frequency of MS and high solar radiation exposure. We test the contribution of VDREs analysing the promoter region of the MS-associated DRB1 *04:05, *03:01, *13:01 and *15:01 and non-MS-associated *16:01, *01, *11, *07:01 alleles in a cohort of Sardinians (44 MS patients and 112 healthy subjects). Sequencing of the DRB1 promoter region revealed a homozygous canonical VDRE in all *15:01, *16:01, *11 and in 45/73 *03:01 and in heterozygous state in 28/73 *03:01 and all *01 alleles. A new mutated homozygous VDRE was found in all *13:03, *04:05 and *07:01 alleles. Functionality of mutated and canonical VDREs was assessed for its potential to modulate levels of DRB1 gene expression using an in vitro transactivation assay after stimulation with active vitamin D metabolite. Vitamin D failed to increase promoter activity of the *04:05 and *03:01 alleles carrying the new mutated VDRE, while the *16:01 and *03:01 alleles carrying the canonical VDRE sequence showed significantly increased transcriptional activity. The ability of VDR to bind the mutant VDRE in the DRB1 promoter was evaluated by EMSA. Efficient binding of VDR to the VDRE sequence found in the *16:01 and in the *15:01 allele reduced electrophoretic mobility when either an anti-VDR or an anti-RXR monoclonal antibody was added. Conversely, the Sardinian mutated VDRE sample showed very low affinity for the RXR/VDR heterodimer. These data seem to exclude a role of VDREs in the promoter region of the DRB1 gene in susceptibility to MS carried by DRB1* alleles in Sardinian patients.

  2. Vitamin D Responsive Elements within the HLA-DRB1 Promoter Region in Sardinian Multiple Sclerosis Associated Alleles

    PubMed Central

    Murru, Maria Rita; Corongiu, Daniela; Tranquilli, Stefania; Fadda, Elisabetta; Murru, Raffaele; Schirru, Lucia; Secci, Maria Antonietta; Costa, Gianna; Asunis, Isadora; Cuccu, Stefania; Fenu, Giuseppe; Lorefice, Lorena; Carboni, Nicola; Mura, Gioia; Rosatelli, Maria Cristina; Marrosu, Maria Giovanna

    2012-01-01

    Vitamin D response elements (VDREs) have been found in the promoter region of the MS-associated allele HLA-DRB1*15∶01, suggesting that with low vitamin D availability VDREs are incapable of inducing *15∶01 expression allowing in early life autoreactive T-cells to escape central thymic deletion. The Italian island of Sardinia exhibits a very high frequency of MS and high solar radiation exposure. We test the contribution of VDREs analysing the promoter region of the MS-associated DRB1 *04∶05, *03∶01, *13∶01 and *15∶01 and non-MS-associated *16∶01, *01, *11, *07∶01 alleles in a cohort of Sardinians (44 MS patients and 112 healthy subjects). Sequencing of the DRB1 promoter region revealed a homozygous canonical VDRE in all *15∶01, *16∶01, *11 and in 45/73 *03∶01 and in heterozygous state in 28/73 *03∶01 and all *01 alleles. A new mutated homozygous VDRE was found in all *13∶03, *04∶05 and *07∶01 alleles. Functionality of mutated and canonical VDREs was assessed for its potential to modulate levels of DRB1 gene expression using an in vitro transactivation assay after stimulation with active vitamin D metabolite. Vitamin D failed to increase promoter activity of the *04∶05 and *03∶01 alleles carrying the new mutated VDRE, while the *16∶01 and *03∶01 alleles carrying the canonical VDRE sequence showed significantly increased transcriptional activity. The ability of VDR to bind the mutant VDRE in the DRB1 promoter was evaluated by EMSA. Efficient binding of VDR to the VDRE sequence found in the *16∶01 and in the *15∶01 allele reduced electrophoretic mobility when either an anti-VDR or an anti-RXR monoclonal antibody was added. Conversely, the Sardinian mutated VDRE sample showed very low affinity for the RXR/VDR heterodimer. These data seem to exclude a role of VDREs in the promoter region of the DRB1 gene in susceptibility to MS carried by DRB1* alleles in Sardinian patients. PMID:22848563

  3. HLA-DPB1 and HLA Class I Confer Risk of and Protection from Narcolepsy

    PubMed Central

    Ollila, Hanna M.; Ravel, Jean-Marie; Han, Fang; Faraco, Juliette; Lin, Ling; Zheng, Xiuwen; Plazzi, Giuseppe; Dauvilliers, Yves; Pizza, Fabio; Hong, Seung-Chul; Jennum, Poul; Knudsen, Stine; Kornum, Birgitte R.; Dong, Xiao Song; Yan, Han; Hong, Heeseung; Coquillard, Cristin; Mahlios, Joshua; Jolanki, Otto; Einen, Mali; Lavault, Sophie; Högl, Birgit; Frauscher, Birgit; Crowe, Catherine; Partinen, Markku; Huang, Yu Shu; Bourgin, Patrice; Vaarala, Outi; Désautels, Alex; Montplaisir, Jacques; Mack, Steven J.; Mindrinos, Michael; Fernandez-Vina, Marcelo; Mignot, Emmanuel

    2015-01-01

    Type 1 narcolepsy, a disorder caused by a lack of hypocretin (orexin), is so strongly associated with human leukocyte antigen (HLA) class II HLA-DQA1∗01:02-DQB1∗06:02 (DQ0602) that very few non-DQ0602 cases have been reported. A known triggering factor for narcolepsy is pandemic 2009 influenza H1N1, suggesting autoimmunity triggered by upper-airway infections. Additional effects of other HLA-DQ alleles have been reported consistently across multiple ethnic groups. Using over 3,000 case and 10,000 control individuals of European and Chinese background, we examined the effects of other HLA loci. After careful matching of HLA-DR and HLA-DQ in case and control individuals, we found strong protective effects of HLA-DPA1∗01:03-DPB1∗04:02 (DP0402; odds ratio [OR] = 0.51 [0.38–0.67], p = 1.01 × 10−6) and HLA-DPA1∗01:03-DPB1∗04:01 (DP0401; OR = 0.61 [0.47–0.80], p = 2.07 × 10−4) and predisposing effects of HLA-DPB1∗05:01 in Asians (OR = 1.76 [1.34–2.31], p = 4.71 × 10−05). Similar effects were found by conditional analysis controlling for HLA-DR and HLA-DQ with DP0402 (OR = 0.45 [0.38–0.55] p = 8.99 × 10−17) and DP0501 (OR = 1.38 [1.18–1.61], p = 7.11 × 10−5). HLA-class-II-independent associations with HLA-A∗11:01 (OR = 1.32 [1.13–1.54], p = 4.92 × 10−4), HLA-B∗35:03 (OR = 1.96 [1.41–2.70], p = 5.14 × 10−5), and HLA-B∗51:01 (OR = 1.49 [1.25–1.78], p = 1.09 × 10−5) were also seen across ethnic groups in the HLA class I region. These effects might reflect modulation of autoimmunity or indirect effects of HLA class I and HLA-DP alleles on response to viral infections such as that of influenza. PMID:25574827

  4. The Humoral Theory of Transplantation: Epitope Analysis and the Pathogenicity of HLA Antibodies

    PubMed Central

    Farber, John L.

    2016-01-01

    Central to the humoral theory of transplantation is production of antibodies by the recipient against mismatched HLA antigens in the donor organ. Not all mismatches result in antibody production, however, and not all antibodies are pathogenic. Serologic HLA matching has been the standard for solid organ allocation algorithms in current use. Antibodies do not recognize whole HLA molecules but rather polymorphic residues on the surface, called epitopes, which may be shared by multiple serologic HLA antigens. Data are accumulating that epitope analysis may be a better way to determine organ compatibility as well as the potential immunogenicity of given HLA mismatches. Determination of the pathogenicity of alloantibodies is evolving. Potential features include antibody strength (as assessed by antibody titer or, more commonly and inappropriately, mean fluorescence intensity) and ability to fix complement (in vitro by C1q or C3d assay or by IgG subclass analysis). Technical issues with the use of solid phase assays are also of prime importance, such as denaturation of HLA antigens and manufacturing and laboratory variability. Questions and controversies remain, and here we review new relevant data. PMID:28070526

  5. Structural basis of cross-allele presentation by HLA-A*0301 and HLA-A*1101 revealed by two HIV-derived peptide complexes.

    PubMed

    Zhang, Shihong; Liu, Jun; Cheng, Hao; Tan, Shuguang; Qi, Jianxun; Yan, Jinghua; Gao, George F

    2011-10-01

    Human leukocyte antigens (HLA) are initially classified by serotyping but recently can be re-grouped by their peptide-presentation characteristics into supertypes. Both HLA-A*0301 and HLA-A*1101 are grouped into A3 supertype. Although a number of cross-presented T cell epitopes of HLA-A*0301 and HLA-A*1101 have been identified, the molecular mechanisms of cross-presentation remain elusive. Herein, the structures of HLA-A*0301 with two HIV-derived immunodominant T cell epitopes were solved and their characteristics in comparison with HLA-A*1101 presenting the same peptides were analyzed. The comparable structures of HLA-A*0301 and HLA-A*1101 with subtle differences illustrate the common modes of cross-presented peptides and the strict HLA-restriction of T cell receptor (TCR)-recognition.

  6. 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.

  7. The HLA genes and their diverse polymorphism.

    PubMed

    Mehra, N K

    2000-08-01

    Advanced DNA level studies based on HLA class II sequence analysis have revealed considerable diversity in HLA among Asian Indians. High resolution typing of specific alleles such as DR2 and DR4 in the HLA class II region by PCR-SSP or SSOP hybridization and their associated DR-DQ haplotypes have helped to detect unique haplotypes and novel alleles which have subsequently been confirmed by sequencing. Incidentally, remarkable stability has been maintained in several other DRB1 alleles viz. DR1, DR7, DR9 and DR10. The ARMS-PCR technology has been found to be particularly useful for typing HLA-A, HLA-B and HLA-Cw alleles. These technologies are far superior over serological methods. Our studies have shown remarkable heterogeneity of common HLA-A and B alleles in Asian Indians. Molecular subtyping of HLA-A2 revealed that subtype A(*)0211 is found only in Indian population and may be the result of selection pressure in this population. Investigations into polymorphism in the HLA-B27 gene revealed that subtypes common both to the western caucasians and orientals occur in the Indian population. It is apparent that the population of the Indian subcontinent, placed as it is between the Caucasoids and Negroids on one hand and Australoids and Mongoloids on the other, provides a rich source of many HLA haplotypes. While the most frequent Caucasian haplotypes occur with a reasonable frequency in Asian Indians, those found predominantly in other ethnic groups (e.g., australian Aborigines and populations of Oceania, China and Japan) are also detected. Knowledge on this is most important for donor selection during organ and bone marrow transplantation and for designing MHC targeted vaccines in specific diseases.

  8. Beyond Multiple Regression: Using Commonality Analysis to Better Understand R[superscript 2] Results

    ERIC Educational Resources Information Center

    Warne, Russell T.

    2011-01-01

    Multiple regression is one of the most common statistical methods used in quantitative educational research. Despite the versatility and easy interpretability of multiple regression, it has some shortcomings in the detection of suppressor variables and for somewhat arbitrarily assigning values to the structure coefficients of correlated…

  9. Induction of CD8 T-cell responses restricted to multiple HLA class I alleles in a cancer patient by immunization with a 20-mer NY-ESO-1f (NY-ESO-1 91-110) peptide.

    PubMed

    Eikawa, Shingo; Kakimi, Kazuhiro; Isobe, Midori; Kuzushima, Kiyotaka; Luescher, Immanuel; Ohue, Yoshihiro; Ikeuchi, Kazuhiro; Uenaka, Akiko; Nishikawa, Hiroyoshi; Udono, Heiichiro; Oka, Mikio; Nakayama, Eiichi

    2013-01-15

    Immunogenicity of a long 20-mer NY-ESO-1f peptide vaccine was evaluated in a lung cancer patient TK-f01, immunized with the peptide with Picibanil OK-432 and Montanide ISA-51. We showed that internalization of the peptide was necessary to present CD8 T-cell epitopes on APC, contrasting with the direct presentation of the short epitope. CD8 T-cell responses restricted to all five HLA class I alleles were induced in the patient after the peptide vaccination. Clonal analysis showed that B*35:01 and B*52:01-restricted CD8 T-cell responses were the two dominant responses. The minimal epitopes recognized by A*24:02, B*35:01, B*52:01 and C*12:02-restricted CD8 T-cell clones were defined and peptide/HLA tetramers were produced. NY-ESO-1 91-101 on A*24:02, NY-ESO-1 92-102 on B*35:01, NY-ESO-1 96-104 on B*52:01 and NY-ESO-1 96-104 on C*12:02 were new epitopes first defined in this study. Identification of the A*24:02 epitope is highly relevant for studying the Japanese population because of its high expression frequency (60%). High affinity CD8 T-cells recognizing tumor cells naturally expressing the epitopes and matched HLA were induced at a significant level. The findings suggest the usefulness of a long 20-mer NY-ESO-1f peptide harboring multiple CD8 T-cell epitopes as an NY-ESO-1 vaccine. Characterization of CD8 T-cell responses in immunomonitoring using peptide/HLA tetramers revealed that multiple CD8 T-cell responses comprised the dominant response. Copyright © 2012 UICC.

  10. The most common Chinese rhesus macaque MHC class I molecule shares peptide binding repertoire with the HLA-B7 supertype

    PubMed Central

    Solomon, Christopher; Southwood, Scott; Hoof, Ilka; Rudersdorf, Richard; Peters, Bjoern; Sidney, John; Pinilla, Clemencia; Marcondes, Maria Cecilia Garibaldi; Ling, Binhua; Marx, Preston; Sette, Alessandro

    2010-01-01

    Of the two rhesus macaque subspecies used for AIDS studies, the Simian immunodeficiency virus-infected Indian rhesus macaque (Macaca mulatta) is the most established model of HIV infection, providing both insight into pathogenesis and a system for testing novel vaccines. Despite the Chinese rhesus macaque potentially being a more relevant model for AIDS outcomes than the Indian rhesus macaque, the Chinese-origin rhesus macaques have not been well-characterized for their major histocompatibility complex (MHC) composition and function, reducing their greater utilization. In this study, we characterized a total of 50 unique Chinese rhesus macaques from several varying origins for their entire MHC class I allele composition and identified a total of 58 unique complete MHC class I sequences. Only nine of the sequences had been associated with Indian rhesus macaques, and 28/58 (48.3%) of the sequences identified were novel. From all MHC alleles detected, we prioritized Mamu-A1*02201 for functional characterization based on its higher frequency of expression. Upon the development of MHC/peptide binding assays and definition of its associated motif, we revealed that this allele shares peptide binding characteristics with the HLA-B7 supertype, the most frequent supertype in human populations. These studies provide the first functional characterization of an MHC class I molecule in the context of Chinese rhesus macaques and the first instance of HLA-B7 analogy for rhesus macaques. Electronic supplementary material The online version of this article (doi:10.1007/s00251-010-0450-3) contains supplementary material, which is available to authorized users. PMID:20480161

  11. 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

  12. Identification of independent susceptible and protective HLA alleles in Japanese autoimmune thyroid disease and their epistasis.

    PubMed

    Ueda, Sho; Oryoji, Daisuke; Yamamoto, Ken; Noh, Jaeduk Yoshimura; Okamura, Ken; Noda, Mitsuhiko; Kashiwase, Koichi; Kosuga, Yuka; Sekiya, Kenichi; Inoue, Kaori; Yamada, Hisakata; Oyamada, Akiko; Nishimura, Yasuharu; Yoshikai, Yasunobu; Ito, Koichi; Sasazuki, Takehiko

    2014-02-01

    Autoimmune thyroid disease (AITD) includes Graves disease (GD) and Hashimoto thyroiditis (HT), which partially share immunological features. Determining the genetic basis that distinguishes GD and HT is a key to understanding the differences between these 2 related diseases. The aims of this study were to identify HLA antigens that can explain the immunopathological difference between GD and HT and to elucidate epistatic interactions between protective and susceptible HLA alleles, which can delineate the distinct function of HLA in AITD etiology. We genotyped 991 patients with AITD (547 patients with GD and 444 patients with HT) and 481 control subjects at the HLA-A, HLA-C, HLA-B, DRB1, DQB1, and DPB1 loci. A direct comparison of HLA antigen frequencies between GD and HT was performed. We further analyzed an epistatic interaction between the susceptible and protective HLA alleles in the development of GD and HT. We identified 4 and 2 susceptible HLA molecules primarily associated with GD and HT, respectively, HLA-B*35:01, HLA-B*46:01, HLA-DRB1*14:03, and HLA-DPB1*05:01 for GD and HLA-A*02:07 and HLA-DRB4 for HT. In a direct comparison between GD and HT, we identified GD-specific susceptible class II molecules, HLA-DP5 (HLA-DPB1*05:01; Pc = 1.0 × 10(-9)) and HLA-DR14 (HLA-DRB*14:03; Pc = .0018). In contrast, HLA components on 3 common haplotypes in Japanese showed significant protective effects against the development of GD and HT (HLA-A*24:02-C*12:02-B*52:01-DRB1*15:02-DQB1*06:01-DPB1*09:01 and HLA-A*24:02-C*07:02-B*07:02-DRB1*01:01-DQB1*05:01-DPB1*04:02 haplotypes for GD and HLA-A*33:03-C*14:03-B*44:03-DRB1*13:02-DQB1*06:04-DPB1*04:01 haplotype for GD and HT). Interestingly, the representative protective HLA, HLA-DR13 (HLA-DRB1*13:02), was epistatic to susceptible HLA-DP5 in controlling the development of GD. We show that HLA exerts a dual function, susceptibility and resistance, in controlling the development of GD and HT. We also show that the protective HLA

  13. HLA class I, NKG2D, and natural cytotoxicity receptors regulate multiple myeloma cell recognition by natural killer cells.

    PubMed

    Carbone, Ennio; Neri, Paola; Mesuraca, Maria; Fulciniti, Mariateresa T; Otsuki, Takemi; Pende, Daniela; Groh, Veronika; Spies, Thomas; Pollio, Giuditta; Cosman, David; Catalano, Lucio; Tassone, Pierfrancesco; Rotoli, Bruno; Venuta, Salvatore

    2005-01-01

    The role of natural killer (NK) cells in multiple myeloma is not fully understood. Here, NK susceptibility of myeloma cells derived from distinct disease stages was evaluated in relation to major histocompatibility complex (MHC) class I, MHC class I chain-related protein A (MICA), MHC class I chain-related protein B (MICB), and UL16 binding protein (ULBP) expression. MHC class I molecules were hardly detectable on bone marrow cells of early-stage myeloma, while late-stage pleural effusion-derived cell lines showed a strong MHC class I expression. Conversely, a high MICA level was found on bone marrow myeloma cells, while it was low or not measurable on pleural effusion myeloma cells. The reciprocal surface expression of these molecules on bone marrow- and pleural effusion-derived cell was confirmed at mRNA levels. While bone marrow-derived myeloma cells were readily recognized by NK cells, pleural effusion-derived lines were resistant. NK protection of pleural effusion cells was MHC class I dependent. Receptor blocking experiments demonstrated that natural cytotoxicity receptor (NCR) and NK receptor member D of the lectin-like receptor family (NKG2D) were the key NK activating receptors for bone marrow-derived myeloma cell recognition. In ex vivo experiments patient's autologous fresh NK cells recognized bone marrow-derived myeloma cells. Our data support the hypothesis that NK cell cytotoxicity could sculpture myeloma and represents an important immune effector mechanism in controlling its intramedullary stages.

  14. HLA-DQA1 and HLA-DQB1 alleles and haplotypes in two Brazilian Indian tribes: evidence of conservative evolution of HLA-DQ.

    PubMed

    Sotomaior, V S; Faucz, F R; Schafhauser, C; Janzen-Dück, M; Boldt, A B; Petzl-Erler, M L

    1998-08-01

    Nucleotide sequence polymorphism of the HLA-DQA1 and HLA-DQB1 class II genes was analyzed in the Kaingang and Guarani Amerindians from southern Brazil using PCR sequence-specific oligonucleotide typing methods. Four different DQA1-DQB1 haplotypes were found: DQA1*0401-DQB1*0402 (associated with DRB1*0802, DRB1*08041, and DRB1*0807), DQA1*0501-DQB1*0301 (associated with DRB1*1602, DRB1*1413, and DRB1*1402), DQA1*03-DQB1*0302 (associated with DRB1*0404 and DRB1*0411), and DQA1*03-DQB1*03032 (associated with DRB1*09012). These HLA-DQA1 and HLA-DQB1 alleles and haplotypes are common in many other populations of all major ethnic groups. Alleles and haplotypes introduced into the populations by post-Columbian admixture were seen at low frequency both in the Kaingang (3.2%) and in the Guarani (3.8%). No novel HLA-DQA1 and HLA-DQB1 alleles have thus far been identified in Amerindians. This differs from previous results for HLA-DRB1, another class II locus presenting novel alleles (i.e., alleles not found in other ethnic groups and probably generated after migration of paleo-Indians to the Americas) in the Guarani and in other South American Indian populations. The distribution of the HLA-DQ alleles and haplotypes in Amerindians indicates a weaker diversifying selective pressure on the HLA-DQ genes compared with HLA-DRB1 and HLA-B. The more conservative evolution of HLA-DQA1 and HLA-DQB1 compared with HLA-DRB1 is strong evidence of (still not well-defined) functional differences of these class II genes.

  15. The CIITA genetic polymorphism rs4774*C in combination with the HLA-DRB1*15:01 allele as a putative susceptibility factor to multiple sclerosis in Brazilian females.

    PubMed

    Paradela, Eduardo R; Alves-Leon, Soniza V; Figueiredo, André L S; Pereira, Valéria C S R; Malfetano, Fabíola; Mansur, Letícia F; Scherpenhuijzen, Simone; Agostinho, Luciana A; Rocha, Catielly F; Rueda-Lopes, Fernanda; Gasparetto, Emerson; Paiva, Carmen L A

    2015-04-01

    The objective of this study was to investigate the association between the HLA alleles at the DQA1, DQB1 and DRB1 loci, the CIITA genetic polymorphisms -168A/G and +1614G/C, and susceptibility to multiple sclerosis (MS) in a sample from Rio de Janeiro State, Brazil. Furthermore, we wished to determine whether any of these associations might be more significant in women compared with men. DNA samples from 52 relapsing-remitting MS (RRMS) patients and 126 healthy controls matched for sex and age were analyzed. We identified a significant HLA-DRB1*15:01-MS association that was female-specific (Odds Ratio (OR) = 4.78; p = 0.001). Furthermore, we observed that the +1614G/C mutation in combination with the HLA-DRB1*15:01 allele increased susceptibility to MS in females (OR = 4.55; p = 0.01). Together, these findings highlight the polygenic nature of MS.

  16. HLA polymorphism in the Havasupai: Evidence for balancing selection

    SciTech Connect

    Markow, T.; Hedrick, P.W.; Armstrong, C.; Martin, J. ); Zuerlein, K. ); Vyvial, T.; Danilov, J.

    1993-10-01

    The characterization and analysis of genetic variation at the HLA loci provides important insight for population geneticists trying to understand the evolutionary forces that have shaped human populations. This study describes the HLA-A and HLA-B loci serotyping and statistical analysis on an isolated Native American population, the Havasupai of Arizona. Four alleles at the HLA-A locus were identified, while eight alleles were found at the HLA-B locus. These variants were present as 20 of 32 potential two-locus haplotypes, with five of the six most common haplotypes exhibiting high positive linkage disequilibrium. Significant homozygote deficiency (heterozygosity excess) was detected both at HLA-A and at HLA-B. This deviation from Hardy-Weinberg proportions was not attributable to nonselective causes such as different alleles at both HLA-A and HLA-B was more even than expected from neutrality theory; that is, the observed Hardy-Weinberg homozygosity was only 62.4% of that expected under neutrality. These observations suggest that balancing selection is of major importance in maintaining genetic variation at HLA-A and HLA-B. 52 refs., 5 tabs.

  17. In Silico Prediction of Peptides Binding to Multiple HLA-DR Molecules Accurately Identifies Immunodominant Epitopes from gp43 of Paracoccidioides brasiliensis Frequently Recognized in Primary Peripheral Blood Mononuclear Cell Responses from Sensitized Individuals

    PubMed Central

    Iwai, Leo Kei; Yoshida, Márcia; Sidney, John; Shikanai-Yasuda, Maria Aparecida; Goldberg, Anna Carla; Juliano, Maria Aparecida; Hammer, Jurgen; Juliano, Luiz; Sette, Alessandro; Kalil, Jorge; Travassos, Luiz Rodolpho; Cunha-Neto, Edecio

    2003-01-01

    One of the major drawbacks limiting the use of synthetic peptide vaccines in genetically distinct populations is the fact that different epitopes are recognized by T cells from individuals displaying distinct major histocompatibility complex molecules. Immunization of mice with peptide (181-195) from the immunodominant 43 kDa glycoprotein of Paracoccidioides brasiliensis (gp43), the causative agent of Paracoccidioidomycosis (PCM), conferred protection against infectious challenge by the fungus. To identify immunodominant and potentially protective human T-cell epitopes in gp43, we used the TEPITOPE algorithm to select peptide sequences that would most likely bind multiple HLA-DR molecules and tested their recognition by T cells from sensitized individuals. The 5 most promiscuous peptides were selected from the gp43 sequence and the actual promiscuity of HLA binding was assessed by direct binding assays to 9 prevalent HLA-DR molecules. Synthetic peptides were tested in proliferation assays with peripheral blood mononuclear cells (PBMC) from PCM patients after chemotherapy and healthy controls. PBMC from 14 of 19 patients recognized at least one of the promiscuous peptides, whereas none of the healthy controls recognized the gp43 promiscuous peptides. Peptide gp43(180-194) was recognized by 53% of patients, whereas the other promiscuous gp43 peptides were recognized by 32% to 47% of patients. The frequency of peptide binding and peptide recognition correlated with the promiscuity of HLA-DR binding, as determined by TEPITOPE analysis. In silico prediction of promiscuous epitopes led to the identification of naturally immunodominant epitopes recognized by PBMC from a significant proportion of a genetically heterogeneous patient population exposed to P. brasiliensis. The combination of several such epitopes may increase the frequency of positive responses and allow the immunization of genetically distinct populations. PMID:15208742

  18. A genome-wide association study of hepatitis B vaccine response in an Indonesian population reveals multiple independent risk variants in the HLA region.

    PubMed

    Png, Eileen; Thalamuthu, Anbupalam; Ong, Rick T H; Snippe, Harm; Boland, Greet J; Seielstad, Mark

    2011-10-01

    We performed a two-stage genome-wide association study (GWAS) of antibody titer in 3614 hepatitis B vaccine recipients from Indonesia's Riau Archipelago, leading to the identification of at least three independent signals within the human leukocyte antigen (HLA) complex. These appear to implicate HLA-DR [rs3135363; P= 6.53 × 10(-22); odds ratio (OR) = 1.53, 95% confidence interval (CI) = 1.35-1.74]; HLA-DP, previously associated with the risk of chronic hepatitis B infection (rs9277535; P= 2.91 × 10(-12); OR = 0.72, 95% CI = 0.63-0.81); and a gene rich HLA Class III interval (rs9267665; P = 1.24 × 10(-17); OR = 2.05, CI = 1.64-2.57). The substantial overlap of these variants and those identified by GWAS of chronic hepatitis B infection confirms vaccine response as a model for infection, while suggesting that the vaccine is least effective in those most at risk of lifelong infection, following exposure to the virus.

  19. Genome-wide Association Study Identifies Five Susceptibility Loci for Follicular Lymphoma outside the HLA Region

    PubMed Central

    Skibola, Christine F.; Berndt, Sonja I.; Vijai, Joseph; Conde, Lucia; Wang, Zhaoming; Yeager, Meredith; de Bakker, Paul I.W.; Birmann, Brenda M.; Vajdic, Claire M.; Foo, Jia-Nee; Bracci, Paige M.; Vermeulen, Roel C.H.; Slager, Susan L.; de Sanjose, Silvia; Wang, Sophia S.; Linet, Martha S.; Salles, Gilles; Lan, Qing; Severi, Gianluca; Hjalgrim, Henrik; Lightfoot, Tracy; Melbye, Mads; Gu, Jian; Ghesquières, Hervé; Link, Brian K.; Morton, Lindsay M.; Holly, Elizabeth A.; Smith, Alex; Tinker, Lesley F.; Teras, Lauren R.; Kricker, Anne; Becker, Nikolaus; Purdue, Mark P.; Spinelli, John J.; Zhang, Yawei; Giles, Graham G.; Vineis, Paolo; Monnereau, Alain; Bertrand, Kimberly A.; Albanes, Demetrius; Zeleniuch-Jacquotte, Anne; Gabbas, Attilio; Chung, Charles C.; Burdett, Laurie; Hutchinson, Amy; Lawrence, Charles; Montalvan, Rebecca; Liang, Liming; Huang, Jinyan; Ma, Baoshan; Liu, Jianjun; Adami, Hans-Olov; Glimelius, Bengt; Ye, Yuanqing; Nowakowski, Grzegorz S.; Dogan, Ahmet; Thompson, Carrie A.; Habermann, Thomas M.; Novak, Anne J.; Liebow, Mark; Witzig, Thomas E.; Weiner, George J.; Schenk, Maryjean; Hartge, Patricia; De Roos, Anneclaire J.; Cozen, Wendy; Zhi, Degui; Akers, Nicholas K.; Riby, Jacques; Smith, Martyn T.; Lacher, Mortimer; Villano, Danylo J.; Maria, Ann; Roman, Eve; Kane, Eleanor; Jackson, Rebecca D.; North, Kari E.; Diver, W. Ryan; Turner, Jenny; Armstrong, Bruce K.; Benavente, Yolanda; Boffetta, Paolo; Brennan, Paul; Foretova, Lenka; Maynadie, Marc; Staines, Anthony; McKay, James; Brooks-Wilson, Angela R.; Zheng, Tongzhang; Holford, Theodore R.; Chamosa, Saioa; Kaaks, Rudolph; Kelly, Rachel S.; Ohlsson, Bodil; Travis, Ruth C.; Weiderpass, Elisabete; Clavel, Jacqueline; Giovannucci, Edward; Kraft, Peter; Virtamo, Jarmo; Mazza, Patrizio; Cocco, Pierluigi; Ennas, Maria Grazia; Chiu, Brian C.H.; Fraumeni, Joseph F.; Nieters, Alexandra; Offit, Kenneth; Wu, Xifeng; Cerhan, James R.; Smedby, Karin E.; Chanock, Stephen J.; Rothman, Nathaniel

    2014-01-01

    Genome-wide association studies (GWASs) of follicular lymphoma (FL) have previously identified human leukocyte antigen (HLA) gene variants. To identify additional FL susceptibility loci, we conducted a large-scale two-stage GWAS in 4,523 case subjects and 13,344 control subjects of European ancestry. Five non-HLA loci were associated with FL risk: 11q23.3 (rs4938573, p = 5.79 × 10−20) near CXCR5; 11q24.3 (rs4937362, p = 6.76 × 10−11) near ETS1; 3q28 (rs6444305, p = 1.10 × 10−10) in LPP; 18q21.33 (rs17749561, p = 8.28 × 10−10) near BCL2; and 8q24.21 (rs13254990, p = 1.06 × 10−8) near PVT1. In an analysis of the HLA region, we identified four linked HLA-DRβ1 multiallelic amino acids at positions 11, 13, 28, and 30 that were associated with FL risk (pomnibus = 4.20 × 10−67 to 2.67 × 10−70). Additional independent signals included rs17203612 in HLA class II (odds ratio [ORper-allele] = 1.44; p = 4.59 × 10−16) and rs3130437 in HLA class I (ORper-allele = 1.23; p = 8.23 × 10−9). Our findings further expand the number of loci associated with FL and provide evidence that multiple common variants outside the HLA region make a significant contribution to FL risk. PMID:25279986

  20. Very long haplotype tracts characterized at high resolution from HLA homozygous cell lines

    PubMed Central

    Norman, Paul J.; Norberg, Steve; Nemat-Gorgani, Neda; Royce, Thomas; Hollenbach, Jill A.; Won, Melissa Shults; Guethlein, Lisbeth A.; Gunderson, Kevin L.; Ronaghi, Mostafa; Parham, Peter

    2015-01-01

    The HLA region of chromosome 6 contains the most polymorphic genes in humans. Spanning ~5Mbp the densely packed region encompasses approximately 175 expressed genes including the highly polymorphic HLA class I and II loci. Most of the other genes and functional elements are also polymorphic, and many of them are directly implicated in immune function or immune-related disease. For these reasons this complex genomic region is subject to intense scrutiny by researchers with the common goal of aiding further understanding and diagnoses of multiple immune-related diseases and syndromes. To aid assay development and characterization of the classical loci, a panel of cell lines partially or fully homozygous for HLA class I and II was assembled over time by the International Histocompatibility Working Group (IHWG). Containing a minimum of 88 unique HLA haplotypes, we show this panel represents a significant proportion of European HLA allelic and haplotype diversity (60–95%). Using a high-density whole genome array that includes 13,331 HLA region SNPs, we analyzed 99 IHWG cells to map the coordinates of the homozygous tracts at a fine scale. The mean homozygous tract length within chromosome 6 from these individuals is 21Mbp. Within HLA the mean haplotype length is 4.3Mbp, and 65% of the cell lines were shown to be homozygous throughout the entire region. In addition, four cell lines are homozygous throughout the complex KIR region of chromosome 19 (~250kbp). The data we describe will provide a valuable resource for characterizing haplotypes, designing and refining imputation algorithms and developing assay controls. PMID:26198775

  1. Very long haplotype tracts characterized at high resolution from HLA homozygous cell lines.

    PubMed

    Norman, Paul J; Norberg, Steve J; Nemat-Gorgani, Neda; Royce, Thomas; Hollenbach, Jill A; Shults Won, Melissa; Guethlein, Lisbeth A; Gunderson, Kevin L; Ronaghi, Mostafa; Parham, Peter

    2015-09-01

    The HLA region of chromosome 6 contains the most polymorphic genes in humans. Spanning ~5 Mbp the densely packed region encompasses approximately 175 expressed genes including the highly polymorphic HLA class I and II loci. Most of the other genes and functional elements are also polymorphic, and many of them are directly implicated in immune function or immune-related disease. For these reasons, this complex genomic region is subject to intense scrutiny by researchers with the common goal of aiding further understanding and diagnoses of multiple immune-related diseases and syndromes. To aid assay development and characterization of the classical loci, a panel of cell lines partially or fully homozygous for HLA class I and II was assembled over time by the International Histocompatibility Working Group (IHWG). Containing a minimum of 88 unique HLA haplotypes, we show that this panel represents a significant proportion of European HLA allelic and haplotype diversity (60-95 %). Using a high-density whole genome array that includes 13,331 HLA region SNPs, we analyzed 99 IHWG cells to map the coordinates of the homozygous tracts at a fine scale. The mean homozygous tract length within chromosome 6 from these individuals is 21 Mbp. Within HLA, the mean haplotype length is 4.3 Mbp, and 65 % of the cell lines were shown to be homozygous throughout the entire region. In addition, four cell lines are homozygous throughout the complex KIR region of chromosome 19 (~250 kbp). The data we describe will provide a valuable resource for characterizing haplotypes, designing and refining imputation algorithms and developing assay controls.

  2. Common source-multiple load vs. separate source-individual load photovoltaic system

    NASA Technical Reports Server (NTRS)

    Appelbaum, Joseph

    1989-01-01

    A comparison of system performance is made for two possible system setups: (1) individual loads powered by separate solar cell sources; and (2) multiple loads powered by a common solar cell source. A proof for resistive loads is given that shows the advantage of a common source over a separate source photovoltaic system for a large range of loads. For identical loads, both systems perform the same.

  3. Seven novel HLA alleles reflect different mechanisms involved in the evolution of HLA diversity: description of the new alleles and review of the literature.

    PubMed

    Adamek, Martina; Klages, Cornelia; Bauer, Manuela; Kudlek, Evelina; Drechsler, Alina; Leuser, Birte; Scherer, Sabine; Opelz, Gerhard; Tran, Thuong Hien

    2015-01-01

    The human leukocyte antigen (HLA) loci are among the most polymorphic genes in the human genome. The diversity of these genes is thought to be generated by different mechanisms including point mutation, gene conversion and crossing-over. During routine HLA typing, we discovered seven novel HLA alleles which were probably generated by different evolutionary mechanisms. HLA-B*41:21, HLA-DQB1*02:10 and HLA-DQA1*01:12 likely emerged from the common alleles of their groups by point mutations, all of which caused non-synonymous amino acid substitutions. In contrast, a deletion of one nucleotide leading to a frame shift with subsequent generation of a stop codon is responsible for the appearance of a null allele, HLA-A*01:123N. Whereas HLA-B*35:231 and HLA-B*53:31 were probably products of intralocus gene conversion between HLA-B alleles, HLA-C*07:294 presumably evolved by interlocus gene conversion between an HLA-C and an HLA-B allele. Our analysis of these novel alleles illustrates the different mechanisms which may have contributed to the evolution of HLA polymorphism.

  4. Genomic evaluation of HLA-DR3+ haplotypes associated with type 1 diabetes.

    PubMed

    Kumar, Neeraj; Kaur, Gurvinder; Tandon, Nikhil; Kanga, Uma; Mehra, Narinder K

    2013-04-01

    We have defined three sets of HLA-DR3(+) haplotypes that provide maximum risk of type 1 disease development in Indians: (1) a diverse array of B8-DR3 haplotypes, (2) A33-B58-DR3 haplotype, and (3) A2-B50-DR3 occurring most predominantly in this population. Further analysis has revealed extensive diversity in B8-DR3 haplotypes, particularly at the HLA-A locus, in contrast to the single fixed HLA-A1-B8-DR3 haplotype (generally referred to as AH8.1) reported in Caucasians. However, the classical AH8.1 haplotype was rare and differed from the Caucasian counterpart at multiple loci. In our study, HLA-A26-B8-DR3 (AH8.2) was the most common B8-DR3 haplotype constituting >50% of the total B8-DR3 haplotypes. Further, A2-B8-DR3 contributed the maximum risk (RR = 48.7) of type 1 diabetes, followed by A2-B50-DR3 (RR = 9.4), A33-B58-DR3 (RR = 6.6), A24-B8-DR3 (RR = 4.5), and A26-B8-DR3 (RR = 4.2). Despite several differences, the disease-associated haplotypes in Indian and Caucasian populations share a frozen DR3-DQ2 block, suggesting a common ancestor from which multiple haplotypes evolved independently. © 2013 The New York Academy of Sciences.

  5. On Studying Common Factor Variance in Multiple-Component Measuring Instruments

    ERIC Educational Resources Information Center

    Raykov, Tenko; Pohl, Steffi

    2013-01-01

    A method for examining common factor variance in multiple-component measuring instruments is outlined. The procedure is based on an application of the latent variable modeling methodology and is concerned with evaluating observed variance explained by a global factor and by one or more additional component-specific factors. The approach furnishes…

  6. On Studying Common Factor Variance in Multiple-Component Measuring Instruments

    ERIC Educational Resources Information Center

    Raykov, Tenko; Pohl, Steffi

    2013-01-01

    A method for examining common factor variance in multiple-component measuring instruments is outlined. The procedure is based on an application of the latent variable modeling methodology and is concerned with evaluating observed variance explained by a global factor and by one or more additional component-specific factors. The approach furnishes…

  7. Supporting Student's Ability in Understanding Least Common Multiple (LCM) Concept Using Storytelling

    ERIC Educational Resources Information Center

    Triyani, Septi; Putri, Ratu Ilma Indra; Darmawijoyo

    2012-01-01

    Several researches showed that students had difficulty in understanding the concept of Least Common Multiple (LCM) in Elementary School. This underlies the researcher to design a learning of LCM using storytelling, Legend "Putri Dayang Merindu" (LPDM), which contains situational problem related to LCM. The purposes of this study are to…

  8. 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

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

    PubMed

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

    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 devel-opment, 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.

  10. An investigation of commonly prescribed stretches of the ankle plantarflexors in people with Multiple Sclerosis.

    PubMed

    Ofori, J; Freeman, J; Logan, A; Rapson, R; Zajieck, J; Hobart, J; Marsden, J

    2016-08-01

    Stretches are often prescribed to manage increased limb stiffness in people with Multiple Sclerosis. This study determined the ankle plantarflexor torque magnitude that people with Multiple Sclerosis can apply during four commonly prescribed stretches and determined the relationship between the applied torque and functional ability. People with Multiple Sclerosis (N=27) were compared to healthy control participants (n=15). Four stretches were investigated; stretching in step standing; using a step; pulling the ankle into dorsiflexion and standing in a frame. Joint position and forces were measured using 3D motion analysis and torque transducers. Baseline ankle strength and stiffness was measured using motor driven ankle perturbations. People with Multiple Sclerosis (N=27) had higher stretch reflex amplitudes and lower strength compared to the control group (n=15). People with Multiple Sclerosis achieved less lengthening of the plantarflexor muscle-tendon complex when stretching but similar ankle torques compared to controls. While stretching people with Multiple Sclerosis showed greater muscle activation in the ankle plantarflexors. Stretches in weight bearing positions produced higher plantarflexor torques. People with Multiple Sclerosis with lower functional ability preferred the more supported stretches (ankle pull and standing frame). Stretches in weight bearing positions achieve higher ankle torques but this is in part due to increased postural activity in people with Multiple Sclerosis. Functional ability may limit stretch effectiveness. Copyright © 2016 Elsevier Ltd. All rights reserved.

  11. Multiple HLA A11-restricted cytotoxic T-lymphocyte epitopes of different immunogenicities in the Epstein-Barr virus-encoded nuclear antigen 4.

    PubMed

    Gavioli, R; Kurilla, M G; de Campos-Lima, P O; Wallace, L E; Dolcetti, R; Murray, R J; Rickinson, A B; Masucci, M G

    1993-03-01

    Epstein-Barr virus (EBV), a ubiquitous herpesvirus, induces potent HLA class I-restricted cytotoxic T-lymphocyte (CTL) responses. Analyses of target antigen choice have shown that the very strong CTL responses which are often observed through the HLA A11 allele map are due almost entirely to a single transformation-associated EBV protein, the nuclear antigen EBNA4. Here, we sought to determine the number and relative immunogenicities of HLA A11-restricted epitopes within this 938-amino-acid protein. An initial screening with a series of recombinant vaccinia virus vectors encoding progressively truncated forms of EBNA4 was followed by peptide sensitization experiments using overlapping 14- or 15-mers from the entire sequence. These two approaches allowed the identification of five epitope regions located between residues 101 and 115, 416 and 429, 396 and 410, 481 and 495, and 551 and 564 of the EBNA4 molecule. CTL preparations from all seven HLA A11-positive donors tested had demonstrable reactivities against the 416-to-429 peptide, whereas reactivities against the other epitopes either tended to be lost on serial passage or, for some of the donors, were never detected. The immunodominance of the 416-to-429 epitope was further supported by peptide dilution assays using polyclonal effectors and by CTL cloning experiments. Analysis of the 416-to-429 region identified the nanomer 416-424 (IVTDFSVIK) as the cognate peptide. This peptide was able to sensitize targets to lysis by A11-restricted CTL clones at concentrations as low as 5 x 10(-14) M.

  12. Limited common origins of multiple adult health-related behaviors: Evidence from U.S. twins.

    PubMed

    Sudharsanan, Nikkil; Behrman, Jere R; Kohler, Hans-Peter

    2016-12-01

    Health-related behaviors are significant contributors to morbidity and mortality in the United States, yet evidence on the underlying causes of the vast within-population variation in behaviors is mixed. While many potential causes of health-related behaviors have been identified-such as schooling, genetics, and environments-little is known on how much of the variation across multiple behaviors is due to a common set of causes. We use three separate datasets on U.S. twins to investigate the degree to which multiple health-related behaviors correlate and can be explained by a common set of factors. We find that aside from smoking and drinking, most behaviors are not strongly correlated among individuals. Based on the results of both within-identical-twins regressions and multivariate behavioral genetics models, we find some evidence that schooling may be related to smoking but not to the covariation between multiple behaviors. Similarly, we find that a large fraction of the variance in each of the behaviors is consistent with genetic factors; however, we do not find strong evidence that a single common set of genes explains variation in multiple behaviors. We find, however, that a large portion of the correlation between smoking and heavy drinking is consistent with common, mostly childhood, environments. This suggests that the initiation and patterns of these two behaviors might arise from a common childhood origin. Research and policy to identify and modify this source may provide a strong way to reduce the population health burden of smoking and heavy drinking. Copyright © 2016 Elsevier Ltd. All rights reserved.

  13. Vital transfusion in patients with multiple antibodies against common erythrocyte antigens.

    PubMed

    Grífols, Joan-Ramon; Serrano, Alfons; Ester, Anna; Juncà, Jordi; Muñiz, Eduard

    2009-04-01

    The transfusion of blood components could be needed in certain types of surgical procedures. Blood type components and the requested number of units will depend on the estimated loss of blood, type of surgery, surgical technique to be employed and risk factors for bleeding. Problems can appear when multiple antibodies against common erythrocyte antigens are detected in blood samples and this situation worsens if blood units are requested as quickly as possible. We report a case of a patient with a non frequent erythrocytic phenotype where multiple antibodies acting against high-frequency antigens were detected and who required urgent surgery.

  14. Attitude control of an object commonly held by multiple robot arms - A Lyapunov approach

    NASA Technical Reports Server (NTRS)

    Kreutz, Kenneth; Wen, John T.

    1988-01-01

    Multiple robot arms moving a commonly held object can be viewed as complex actuators whose purpose is to provide net forces and moments to the object. These forces and moments can be used to control the orientation, or attitude, of the object via the Euler equation describing attitude evolution in response to applied moments at the mass center. In contrast to the common approach that feedback-linearizes the attitude dynamics to a double integrator form with respect to some three-parameter local representation of orientation, the authors control the object using a globally nonsingular representation. Using an energy-motivated Liapunov function, globally stable control of attitude is shown.

  15. Attitude control of an object commonly held by multiple robot arms - A Lyapunov approach

    NASA Technical Reports Server (NTRS)

    Kreutz, Kenneth; Wen, John T.

    1988-01-01

    Multiple robot arms moving a commonly held object can be viewed as complex actuators whose purpose is to provide net forces and moments to the object. These forces and moments can be used to control the orientation, or attitude, of the object via the Euler equation describing attitude evolution in response to applied moments at the mass center. In contrast to the common approach that feedback-linearizes the attitude dynamics to a double integrator form with respect to some three-parameter local representation of orientation, the authors control the object using a globally nonsingular representation. Using an energy-motivated Liapunov function, globally stable control of attitude is shown.

  16. HLA Genes in Mayos Population from Northeast Mexico

    PubMed Central

    Arnaiz-Villena, A; Moscoso, J; Granados, J; Serrano-Vela, J.I; de la Peña, A.; Reguera, R; Ferri, A; Seclen, E; Izaguirre, R; Perez-Hernandez, N; Vargas-Alarcon, G

    2007-01-01

    HLA class I and class II alleles have been studied in 60 unrelated people belonging to Mayos ethnic group, which lives in the Mexican Pacific Sinaloa State. Mayos HLA profile was compared to other Amerindians and worldwide populations’ profile. A total of 14,896 chromosomes were used for comparisons. Genetic distances between populations, Neigbour-Joining dendrograms and correspondence analyses were performed to determine the genetic relationship among population. The new specific Mayo HLA haplotypes found are: HLA-A*02-B*35-DRB1*1406-DQB1*0301; HLA-A*02-B*48-DRB1*0404-DQB1*0302; HLA-A*24-B*51-DRB1*0407-DQB1*0302 and HLA-A*02-B*08-DRB1*0407-DQB1*0302. However, the typical Meso American HLADRB1*0407 represents a 40% of all DRB1 alleles. While common HLA characteristics are found in Amerindian distant ethnic groups, still new group specific HLA haplotypes are being found, suggesting that a common founder effect (i.e. high DRB1*0407) is noticed. Moreover, new HLA haplotypes are almost certainly appearing along time probably due to specific pathogen (?) selection for diversity. Mayo language is close to the Tarahumara one (another geographically close group); notwithstanding both groups are not genetically close according to our results, showing again the different evolution of genes and languages, which do not correlate. Finally, Sinaloa is one of the Mexican States in which more European genes are found. However, the results presented in this paper, where no European HLA genes are seen in Mayos, should have a bearing in establishing transplant programs and in HLA and disease studies. PMID:19412332

  17. Extensible Adaptable Simulation Systems: Supporting Multiple Fidelity Simulations in a Common Environment

    NASA Technical Reports Server (NTRS)

    McLaughlin, Brian J.; Barrett, Larry K.

    2012-01-01

    Common practice in the development of simulation systems is meeting all user requirements within a single instantiation. The Joint Polar Satellite System (JPSS) presents a unique challenge to establish a simulation environment that meets the needs of a diverse user community while also spanning a multi-mission environment over decades of operation. In response, the JPSS Flight Vehicle Test Suite (FVTS) is architected with an extensible infrastructure that supports the operation of multiple observatory simulations for a single mission and multiple mission within a common system perimeter. For the JPSS-1 satellite, multiple fidelity flight observatory simulations are necessary to support the distinct user communities consisting of the Common Ground System development team, the Common Ground System Integration & Test team, and the Mission Rehearsal Team/Mission Operations Team. These key requirements present several challenges to FVTS development. First, the FVTS must ensure all critical user requirements are satisfied by at least one fidelity instance of the observatory simulation. Second, the FVTS must allow for tailoring of the system instances to function in diverse operational environments from the High-security operations environment at NOAA Satellite Operations Facility (NSOF) to the ground system factory floor. Finally, the FVTS must provide the ability to execute sustaining engineering activities on a subset of the system without impacting system availability to parallel users. The FVTS approach of allowing for multiple fidelity copies of observatory simulations represents a unique concept in simulator capability development and corresponds to the JPSS Ground System goals of establishing a capability that is flexible, extensible, and adaptable.

  18. Error Rates Resulting From Anemia Can Be Corrected in Multiple Commonly Used Point of Care Glucometers

    DTIC Science & Technology

    2008-01-01

    Error Rates Resulting From Anemia can be Corrected in Multiple Commonly Used Point-of-Care Glucometers Elizabeth A. Mann, MS, RN, Jose Salinas, PhD...strategies, increasing the prevalence of both hypoglycemia and anemia in the ICU.14–20 The change in allogeneic blood transfusion practices occurred in...transfusion-related risk. As physicians adopted practices that resulted in permissive anemia , the number of critically ill patients at risk of inappropriate

  19. Definition of the region on NS3 which contains multiple epitopes recognized by dengue virus serotype-cross-reactive and flavivirus-cross-reactive, HLA-DPw2-restricted CD4+ T cell clones.

    PubMed

    Okamoto, Y; Kurane, I; Leporati, A M; Ennis, F A

    1998-04-01

    The epitopes recognized by six CD4+ CD8- cytotoxic T lymphocyte (CTL) clones established from a dengue-3 virus-immune donor were defined. (i) Three CTL clones, JK10, JK34 and JK39, were cross-reactive for dengue virus types 1-4. (ii) One clone, JK28, was cross-reactive for dengue virus types 1-4 and West Nile virus. (iii) Two clones, JK26 and JK49, were cross-reactive for dengue virus types 1-4, West Nile virus and yellow fever virus. The clones, except for JK49, recognized the same epitope on NS3 in an HLA-DPw2-restricted fashion. The smallest synthetic peptide recognized by the five CTL clones was a 10 aa peptide which comprises aa 255-264 on dengue virus NS3. JK49 recognized the overlapping epitope which comprises aa 257-266 in an HLA-DPw2-restricted fashion. Analysis of T cell receptor (TCR) usage by these T cell clones revealed that (i) JK10 and JK34 use V alpha11, and JK34 and JK28 use V beta23, and (ii) the amino acid sequences of the V(D)J junctional region of the TCR were different among these five CTL clones. There were, however, single amino acid conservations among TCRs of some of these T cell clones. These results indicate that the region on NS3 which comprises aa 255-266 contains multiple epitopes recognized by dengue serotype-cross-reactive and flavivirus-cross-reactive CD4+ CTL in an HLA-DPw2-restricted fashion and that a single epitope can be recognized by T cells which have heterogeneous virus specificities.

  20. Mold sensitization is common amongst patients with severe asthma requiring multiple hospital admissions.

    PubMed

    O'Driscoll, B Ronan; Hopkinson, Linda C; Denning, David W

    2005-02-18

    Multiple studies have linked fungal exposure to asthma, but the link to severe asthma is controversial. We studied the relationship between asthma severity and immediate type hypersensitivity to mold (fungal) and non-mold allergens in 181 asthmatic subjects. We recruited asthma patients aged 16 to 60 years at a University hospital and a nearby General Practice. Patients were categorized according to the lifetime number of hospital admissions for asthma (82 never admitted, 53 one admission, 46 multiple admissions). All subjects had allergy skin prick tests performed for 5 mold allergens (Aspergillus, Alternaria, Cladosporium, Penicillium and Candida) and 4 other common inhalant allergens (D. pteronyssinus, Grass Pollen, Cat and Dog). Skin reactivity to all allergens was commonest in the group with multiple admissions. This trend was strongest for mold allergens and dog allergen and weakest for D. pteronyssinus. 76% of patients with multiple admissions had at least one positive mold skin test compared with 16%-19% of other asthma patients; (Chi squared p < 0.0001). Multiple mold reactions were also much commoner in the group with multiple admissions (50% V 5% and 6%; p < 0.0001). The number of asthma admissions was related to the number and size of positive mold skin allergy tests (Spearman Correlation Coefficient r = 0.60, p < 0.0001) and less strongly correlated to the number and size of non-mold allergy tests (r = 0.34, p = 0.0005). Hospital admissions for asthma patients aged 16-40 were commonest during the mold spore season (July to October) whereas admissions of patients aged above 40 peaked in November-February (Chi Squared, p < 0.02). These findings support previous suggestions that mold sensitization may be associated with severe asthma attacks requiring hospital admission.

  1. Ecologically relevant levels of multiple, common marine stressors suggest antagonistic effects.

    PubMed

    Lange, Rolanda; Marshall, Dustin

    2017-07-24

    Stressors associated with global change will be experienced simultaneously and may act synergistically, so attempts to estimate the capacity of marine systems to cope with global change requires a multi-stressor approach. Because recent evidence suggests that stressor effects can be context-dependent, estimates of how stressors are experienced in ecologically realistic settings will be particularly valuable. To enhance our understanding of the interplay between environmental effects and the impact of multiple stressors from both natural and anthropogenic sources, we conducted a field experiment. We explored the impact of multiple, functionally varied stressors from both natural and anthropogenic sources experienced during early life history in a common sessile marine invertebrate, Bugula neritina. Natural spatial environmental variation induced differences in conspecific densities, allowing us to test for density-driven context-dependence of stressor effects. We indeed found density-dependent effects. Under high conspecific density, individual survival increased, which offset part of the negative effects of experiencing stressors. Experiencing multiple stressors early in life history translated to a decreased survival in the field, albeit the effects were not as drastic as we expected: our results are congruent with antagonistic stressor effects. We speculate that when individual stressors are more subtle, stressor synergies become less common.

  2. 21-inch common large-area display set for multiple military command and control workstation applications

    NASA Astrophysics Data System (ADS)

    Gorenflo, Ronald L.; Hermann, David J.

    1996-05-01

    Battelle is under contract with Warner Robins Air Logistics Center to design a common large area display set (CLADS) for use in multiple airborne C4I applications that currently use unique 19 inch CRTs. Engineers at Battelle have determined that by taking advantage of the latest flat panel display technology and the commonality between C4I applications, one display head (21 inch diagonal, 1280 by 1024) can be used in multiple applications. In addition, common modules are being designed by Battelle to reduce the number of installation- specific circuit card assemblies required for a particular application. Initial USAF applications include replacements for the E-3 AWACS color monitor assembly, E-8 Joint STARS graphics display unit, and ABCCC airborne color display. Initial U. S. Navy applications include the E-2C ACIS display. For these applications reliability and maintainability are key objectives. The common design reduces the number of unique subassemblies in the USAF inventory by 56 to 66%. In addition to total module reductions, CLADs module/subassembly re-use across nine potential applications is estimated to be 73%. As more platforms implement CLADS, the percentage of module re-use increases. The new design is also expected to have a MTBF of at least 3350 hours, an order of magnitude better than one of the current systems. In the Joint STARS installation, more than 1400 pounds can be eliminated from the aircraft. In the E-3 installation, the CLADs is estimated to provide a power reduction of approximately 1750 watts per aircraft. This paper discuses the common large area display set design and it use in a variety of C4I applications that require a large area, high resolution, full color display.

  3. The nucleotide sequence of HLA-B{sup *}2704 reveals a new amino acid substitution in exon 4 which is also present in HLA-B{sup *}2706

    SciTech Connect

    Rudwaleit, M.; Bowness, P.; Wordsworth, P.

    1996-12-31

    The HLA-B27 subtype HLA-B{sup *}2704 is virtually absent in Caucasians but common in Orientals, where it is associated with ankylosing spondylitis. The amino acid sequence of HLA-B{sup *}2704 has been established by peptide mapping and was shown to differ by two amino acids from HLA-B{sup *}2705, HLA-B{sup *}2704 is characterized by a serine for aspartic acid substitution at position 77 and glutamic acid for valine at position 152. To date, however, no nucleotide sequence confirming these changes at the DNA level has been published. 13 refs., 2 figs.

  4. Cutting Edge: Allele-specific and peptide-dependent interactions between KIR3DL1 and HLA-A and HLA-B.

    PubMed

    Thananchai, Hathairat; Gillespie, Geraldine; Martin, Maureen P; Bashirova, Arman; Yawata, Nobuyo; Yawata, Makoto; Easterbrook, Philippa; McVicar, Daniel W; Maenaka, Katsumi; Parham, Peter; Carrington, Mary; Dong, Tao; Rowland-Jones, Sarah

    2007-01-01

    Although it is clear that KIR3DL1 recognizes Bw4(+) HLA-B, the role of Bw4(+) HLA-A allotypes as KIR3DL1 ligands is controversial. We therefore examined the binding of tetrameric HLA-A and -B complexes, including HLA*2402, a common Bw4(+) HLA-A allotype, to KIR3DL1*001, *005, *007, and *1502 allotypes. Only Bw4(+) tetramers bound KIR3DL1. Three of four HLA-A*2402 tetramers bound one or more KIR3DL1 allotypes and all four KIR3DL1 allotypes bound to one or more HLA-A*2402 tetramers, but with different binding specificities. Only KIR3DL1*005 bound both HLA-A*2402 and HLA-B*5703 tetramers. HLA-A*2402-expressing target cells were resistant to lysis by NK cells expressing KIR3DL1*001 or *005. This study shows that HLA-A*2402 is a ligand for KIR3DL1 and demonstrates how the binding of KIR3DL1 to Bw4(+) ligands depends upon the bound peptide as well as HLA and KIR3DL1 polymorphism.

  5. Parasites and health affect multiple sexual signals in male common wall lizards, Podarcis muralis

    NASA Astrophysics Data System (ADS)

    Martín, José; Amo, Luisa; López, Pilar

    2008-04-01

    Multiple advertising sexual traits may either advertise different characteristics of male condition or be redundant to reinforce reliability of signals. Research has focused on multiple visual traits. However, in animals that use different multiple additional sensory systems, such as chemoreception, different types of traits might have evolved to signal similar characteristics of a male quality using different sensory channels. We examined whether ventral coloration and chemicals in femoral gland secretions of male common wall lizards, Podarcis muralis, are affected by their health state (blood-parasite load and cell-mediated immune response). Our results indicated that less parasitized lizards had brighter and more yellowish ventral colorations and also femoral secretions with higher proportions of two esters of octadecenoic acid. In addition, lizards with a greater immune response had more saturated coloration and secretions with higher proportions of octadecenoic acid methyl ester. We suggest that these signals would be reliable because only healthier males seemed able to allocate more carotenoids to coloration and presumably costly chemicals to secretions. The use of multiple sensory channels may provide more opportunities to signal a male quality under different circumstances, but also may reinforce the reliability of the signal when both types of traits may be perceived simultaneously.

  6. Cloacal Bacterial Diversity Increases with Multiple Mates: Evidence of Sexual Transmission in Female Common Lizards

    PubMed Central

    White, Joël; Richard, Murielle; Massot, Manuel; Meylan, Sandrine

    2011-01-01

    Sexually transmitted diseases have often been suggested as a potential cost of multiple mating and as playing a major role in the evolution of mating systems. Yet there is little empirical data relating mating strategies to sexually transmitted microorganisms in wild populations. We investigated whether mating behaviour influences the diversity and composition of cloacal assemblages by comparing bacterial communities in the cloaca of monandrous and polyandrous female common lizards Zootoca vivipara sampled after the mating period. We found that polyandrous females harboured more diverse communities and differed more in community composition than did monandrous females. Furthermore, cloacal diversity and variability were found to decrease with age in polyandrous females. Our results suggest that the higher bacterial diversity found in polyandrous females is due to the sexual transmission of bacteria by multiple mates. The impact of mating behaviour on the cloacal microbiota may have fitness consequences for females and may comprise a selective pressure shaping the evolution of mating systems. PMID:21811590

  7. Cloacal bacterial diversity increases with multiple mates: evidence of sexual transmission in female common lizards.

    PubMed

    White, Joël; Richard, Murielle; Massot, Manuel; Meylan, Sandrine

    2011-01-01

    Sexually transmitted diseases have often been suggested as a potential cost of multiple mating and as playing a major role in the evolution of mating systems. Yet there is little empirical data relating mating strategies to sexually transmitted microorganisms in wild populations. We investigated whether mating behaviour influences the diversity and composition of cloacal assemblages by comparing bacterial communities in the cloaca of monandrous and polyandrous female common lizards Zootoca vivipara sampled after the mating period. We found that polyandrous females harboured more diverse communities and differed more in community composition than did monandrous females. Furthermore, cloacal diversity and variability were found to decrease with age in polyandrous females. Our results suggest that the higher bacterial diversity found in polyandrous females is due to the sexual transmission of bacteria by multiple mates. The impact of mating behaviour on the cloacal microbiota may have fitness consequences for females and may comprise a selective pressure shaping the evolution of mating systems.

  8. Recessive mutations in a common pathway block thymocyte apoptosis induced by multiple signals

    PubMed Central

    1994-01-01

    The glucocorticoid receptor (GR) is a ligand-regulated transcription factor that controls genes necessary to initiate glucocorticoid-induced thymocyte apoptosis. We have performed a genetic analysis of thymocyte cell death by isolating and characterizing a panel of GR+ dexamethasone- resistant mutants of the murine WEHI7.2 thymocyte cell line. These apoptosis-defective (Apt-) mutants were used to identify previously unknown early steps in the apoptotic pathway. The Apt- mutants contain nonglucocorticoid receptor, recessive mutations in genes that represent multiple complementation groups. These mutations block apoptosis induced by dexamethasone, gamma irradiation, and c-AMP treatment before the point where Bcl-2 exerts its protective effect. We propose that different signals share a common apoptotic pathway, and that the induction of apoptosis involves multiple precommitment steps that can be blocked by recessive mutations. PMID:7798323

  9. SISEQ: manipulation of multiple sequence and large database files for common platforms.

    PubMed

    Sato, N

    2000-02-01

    A multiple sequence file converter for common platforms, SISEQ,is described, which performs extraction of DNA sequences that correspond to CDS or RNA field of a large database file as well as subsequent multi-sequence conversions for phylogenetic or molecular biological analysis. Command-line interface as well as a GUI and a script-driven operation mode are provided. The program is freely available to academic users in the form of Macintosh FAT binary, DOS executable, or UNIX source code at http://www.molbiol.saitama-u.ac.jp/ñaoki/ Software.html. naokisat@molbiol.saitama-u.ac.jp

  10. Multiple malignancies in a female patient with common variable immunodeficiency syndrome.

    PubMed

    Todorovic, Milena; Balint, Bela; Andjelic, Bosko; Mihaljevic, Biljana

    2014-10-01

    We herein present the case of a 55-year-old woman with a previous history of malignancies--uterine adenocarcinoma, basal cell carcinoma (which occurred twice consecutively), recurrent respiratory infections due to common variable immunodeficiency (CVID), and systemic granulomatous disease diagnosed at a later age. The patient suffered from diffuse large B cell lymphoma (DLBCL), which was successfully treated with R-CHOP chemotherapy, and continued with immunoglobulin supplementation. The patient was free of lymphoma and infectious complications for over 20 months despite her persistent immunodeficiency, but eventually developed colorectal adenocarcinoma. To the best of our knowledge, this is the first reported case of CVID associated with multiple solid tumours and DLBCL.

  11. 40 CFR 75.82 - Monitoring of Hg mass emissions and heat input at common and multiple stacks.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... heat input at common and multiple stacks. 75.82 Section 75.82 Protection of Environment ENVIRONMENTAL... Provisions § 75.82 Monitoring of Hg mass emissions and heat input at common and multiple stacks. (a) Unit... systems and perform the Hg emission testing described under § 75.81(b). If reporting of the unit heat...

  12. 40 CFR 75.16 - Special provisions for monitoring emissions from common, bypass, and multiple stacks for SO 2...

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... emissions from common, bypass, and multiple stacks for SO 2 emissions and heat input determinations. 75.16... emissions from common, bypass, and multiple stacks for SO 2 emissions and heat input determinations. (a) (b... by the Administrator, such that these emissions are not underestimated. (e) Heat input rate. The...

  13. 40 CFR 75.16 - Special provisions for monitoring emissions from common, bypass, and multiple stacks for SO2...

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... emissions from common, bypass, and multiple stacks for SO2 emissions and heat input determinations. 75.16... emissions from common, bypass, and multiple stacks for SO2 emissions and heat input determinations. (a) (b... by the Administrator, such that these emissions are not underestimated. (e) Heat input rate. The...

  14. 40 CFR 75.16 - Special provisions for monitoring emissions from common, bypass, and multiple stacks for SO 2...

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... emissions from common, bypass, and multiple stacks for SO 2 emissions and heat input determinations. 75.16... emissions from common, bypass, and multiple stacks for SO 2 emissions and heat input determinations. (a) (b... by the Administrator, such that these emissions are not underestimated. (e) Heat input rate. The...

  15. 40 CFR 75.16 - Special provisions for monitoring emissions from common, bypass, and multiple stacks for SO2...

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... emissions from common, bypass, and multiple stacks for SO2 emissions and heat input determinations. 75.16... emissions from common, bypass, and multiple stacks for SO2 emissions and heat input determinations. (a) (b... missing for the hour. The maximum potential SO2 concentration may be specific to the type of...

  16. Estimating the proportion of variation in susceptibility to multiple sclerosis captured by common SNPs

    NASA Astrophysics Data System (ADS)

    Watson, Corey T.; Disanto, Giulio; Breden, Felix; Giovannoni, Gavin; Ramagopalan, Sreeram V.

    2012-10-01

    Multiple sclerosis (MS) is a complex disease with underlying genetic and environmental factors. Although the contribution of alleles within the major histocompatibility complex (MHC) are known to exert strong effects on MS risk, much remains to be learned about the contributions of loci with more modest effects identified by genome-wide association studies (GWASs), as well as loci that remain undiscovered. We use a recently developed method to estimate the proportion of variance in disease liability explained by 475,806 single nucleotide polymorphisms (SNPs) genotyped in 1,854 MS cases and 5,164 controls. We reveal that ~30% of MS genetic liability is explained by SNPs in this dataset, the majority of which is accounted for by common variants. These results suggest that the unaccounted for proportion could be explained by variants that are in imperfect linkage disequilibrium with common GWAS SNPs, highlighting the potential importance of rare variants in the susceptibility to MS.

  17. Hubble Legacy Archive (HLA) Pipeline Progression

    NASA Astrophysics Data System (ADS)

    Anderson, Rachel E.; Casertano, S.; Lindsay, K.

    2013-01-01

    The HLA maintains a strong commitment to continuing improvement of our Hubble Space Telescope data processing pipelines with the goal of generating better science-ready data products. The HLA image processing pipeline is transitioning from the use of MultiDrizzle to AstroDrizzle for image registration and combination. It is expected that this change will allow for the creation of higher quality science products with improved astrometric solutions. Headerlets, a newly developed tool for AstroDrizzle, will be utilized and made available to simplify access to multiple astrometric solutions for a given data set. The capabilities of AstroDrizzle will allow for functionally simplified data processing, standardizing and streamlining the data reduction process and making it easier for users to reproduce our results. We are beginning with the HLA WFC3 data processing pipeline, and then plan to extend its application to other HST instrument data.

  18. Multiple linear combination (MLC) regression tests for common variants adapted to linkage disequilibrium structure

    PubMed Central

    Yoo, Yun Joo; Sun, Lei; Poirier, Julia G.; Paterson, Andrew D.

    2016-01-01

    ABSTRACT By jointly analyzing multiple variants within a gene, instead of one at a time, gene‐based multiple regression can improve power, robustness, and interpretation in genetic association analysis. We investigate multiple linear combination (MLC) test statistics for analysis of common variants under realistic trait models with linkage disequilibrium (LD) based on HapMap Asian haplotypes. MLC is a directional test that exploits LD structure in a gene to construct clusters of closely correlated variants recoded such that the majority of pairwise correlations are positive. It combines variant effects within the same cluster linearly, and aggregates cluster‐specific effects in a quadratic sum of squares and cross‐products, producing a test statistic with reduced degrees of freedom (df) equal to the number of clusters. By simulation studies of 1000 genes from across the genome, we demonstrate that MLC is a well‐powered and robust choice among existing methods across a broad range of gene structures. Compared to minimum P‐value, variance‐component, and principal‐component methods, the mean power of MLC is never much lower than that of other methods, and can be higher, particularly with multiple causal variants. Moreover, the variation in gene‐specific MLC test size and power across 1000 genes is less than that of other methods, suggesting it is a complementary approach for discovery in genome‐wide analysis. The cluster construction of the MLC test statistics helps reveal within‐gene LD structure, allowing interpretation of clustered variants as haplotypic effects, while multiple regression helps to distinguish direct and indirect associations. PMID:27885705

  19. Multiple linear combination (MLC) regression tests for common variants adapted to linkage disequilibrium structure.

    PubMed

    Yoo, Yun Joo; Sun, Lei; Poirier, Julia G; Paterson, Andrew D; Bull, Shelley B

    2017-02-01

    By jointly analyzing multiple variants within a gene, instead of one at a time, gene-based multiple regression can improve power, robustness, and interpretation in genetic association analysis. We investigate multiple linear combination (MLC) test statistics for analysis of common variants under realistic trait models with linkage disequilibrium (LD) based on HapMap Asian haplotypes. MLC is a directional test that exploits LD structure in a gene to construct clusters of closely correlated variants recoded such that the majority of pairwise correlations are positive. It combines variant effects within the same cluster linearly, and aggregates cluster-specific effects in a quadratic sum of squares and cross-products, producing a test statistic with reduced degrees of freedom (df) equal to the number of clusters. By simulation studies of 1000 genes from across the genome, we demonstrate that MLC is a well-powered and robust choice among existing methods across a broad range of gene structures. Compared to minimum P-value, variance-component, and principal-component methods, the mean power of MLC is never much lower than that of other methods, and can be higher, particularly with multiple causal variants. Moreover, the variation in gene-specific MLC test size and power across 1000 genes is less than that of other methods, suggesting it is a complementary approach for discovery in genome-wide analysis. The cluster construction of the MLC test statistics helps reveal within-gene LD structure, allowing interpretation of clustered variants as haplotypic effects, while multiple regression helps to distinguish direct and indirect associations. © 2016 The Authors Genetic Epidemiology Published by Wiley Periodicals, Inc.

  20. HLA/KIR Restraint of HIV: Surviving the Fittest

    PubMed Central

    Bashirova, Arman A.; Thomas, Rasmi; Carrington, Mary

    2013-01-01

    Multiple epidemiological studies have demonstrated associations between the human leukocyte antigen (HLA) loci and human immunodeficiency virus (HIV) disease, and more recently the killer cell immunoglobulin-like (KIR) locus has been implicated in differential responses to the virus. Genome-wide association studies have convincingly shown that the HLA class I locus is the most significant host genetic contributor to the variation in HIV control, underscoring a central role for CD8 T cells in resistance to the virus. However, both genetic and functional data indicate that part of the HLA effect on HIV is due to interactions between KIR and HLA genes, also implicating natural killer cells in defense against viral infection and viral expansion prior to initiation of an adaptive response. We review the HLA and KIR associations with HIV disease and the progress that has been made in understanding the mechanisms that explain these associations. PMID:21219175

  1. Reversal of Refractory Ulcerative Colitis and Severe Chronic Fatigue Syndrome Symptoms Arising from Immune Disturbance in an HLA-DR/DQ Genetically Susceptible Individual with Multiple Biotoxin Exposures.

    PubMed

    Gunn, Shelly R; Gunn, G Gibson; Mueller, Francis W

    2016-05-11

    Patients with multisymptom chronic conditions, such as refractory ulcerative colitis (RUC) and chronic fatigue syndrome (CFS), present diagnostic and management challenges for clinicians, as well as the opportunity to recognize and treat emerging disease entities. In the current case we report reversal of co-existing RUC and CFS symptoms arising from biotoxin exposures in a genetically susceptible individual. A 25-year-old previously healthy male with new-onset refractory ulcerative colitis (RUC) and chronic fatigue syndrome (CFS) tested negative for autoimmune disease biomarkers. However, urine mycotoxin panel testing was positive for trichothecene group and air filter testing from the patient's water-damaged rental house identified the toxic mold Stachybotrys chartarum. HLA-DR/DQ testing revealed a multisusceptible haplotype for development of chronic inflammation, and serum chronic inflammatory response syndrome (CIRS) biomarker testing was positive for highly elevated TGF-beta and a clinically undetectable level of vasoactive intestinal peptide (VIP). Following elimination of biotoxin exposures, VIP replacement therapy, dental extractions, and implementation of a mind body intervention-relaxation response (MBI-RR) program, the patient's symptoms resolved. He is off medications, back to work, and resuming normal exercise. This constellation of RUC and CFS symptoms in an HLA-DR/DQ genetically susceptible individual with biotoxin exposures is consistent with the recently described CIRS disease pathophysiology. Chronic immune disturbance (turbatio immuno) can be identified with clinically available CIRS biomarkers and may represent a treatable underlying disease etiology in a subset of genetically susceptible patients with RUC, CFS, and other immune disorders.

  2. T-cell memory responses elicited by yellow fever vaccine are targeted to overlapping epitopes containing multiple HLA-I and -II binding motifs.

    PubMed

    de Melo, Andréa Barbosa; Nascimento, Eduardo J M; Braga-Neto, Ulisses; Dhalia, Rafael; Silva, Ana Maria; Oelke, Mathias; Schneck, Jonathan P; Sidney, John; Sette, Alessandro; Montenegro, Silvia M L; Marques, Ernesto T A

    2013-01-01

    The yellow fever vaccines (YF-17D-204 and 17DD) are considered to be among the safest vaccines and the presence of neutralizing antibodies is correlated with protection, although other immune effector mechanisms are known to be involved. T-cell responses are known to play an important role modulating antibody production and the killing of infected cells. However, little is known about the repertoire of T-cell responses elicited by the YF-17DD vaccine in humans. In this report, a library of 653 partially overlapping 15-mer peptides covering the envelope (Env) and nonstructural (NS) proteins 1 to 5 of the vaccine was utilized to perform a comprehensive analysis of the virus-specific CD4(+) and CD8(+) T-cell responses. The T-cell responses were screened ex-vivo by IFN-γ ELISPOT assays using blood samples from 220 YF-17DD vaccinees collected two months to four years after immunization. Each peptide was tested in 75 to 208 separate individuals of the cohort. The screening identified sixteen immunodominant antigens that elicited activation of circulating memory T-cells in 10% to 33% of the individuals. Biochemical in-vitro binding assays and immunogenetic and immunogenicity studies indicated that each of the sixteen immunogenic 15-mer peptides contained two or more partially overlapping epitopes that could bind with high affinity to molecules of different HLAs. The prevalence of the immunogenicity of a peptide in the cohort was correlated with the diversity of HLA-II alleles that they could bind. These findings suggest that overlapping of HLA binding motifs within a peptide enhances its T-cell immunogenicity and the prevalence of the response in the population. In summary, the results suggests that in addition to factors of the innate immunity, "promiscuous" T-cell antigens might contribute to the high efficacy of the yellow fever vaccines.

  3. Multiple coloured ornaments in male common kestrels: different mechanisms to convey quality

    NASA Astrophysics Data System (ADS)

    Vergara, Pablo; Fargallo, Juan A.

    2011-04-01

    The simultaneous exhibition of more than one secondary sexual trait is a widespread phenomenon in nature, though it has rarely been explored. It has been proposed that different ornaments may convey complementary or back-up information about a single aspect of individual quality (redundancy hypothesis) or that each ornament may convey unique information (multiple-messages hypothesis). During a 5-year period, we measured several carotenoid-based (eye ring, bill cere and tarsi skin) and melanin-based (head, back, rump and tail feathers) potential ornamental colours in male common kestrels. We analysed whether multiple ornaments can convey different or related information about individual quality. We explored whether different ornaments can express different information depending on the pigment (carotenoids or melanins), the time-scale over which the ornament can change (dynamic vs. static) and the season of the year when the ornament is formed. We found that both melanin- and carotenoid- based traits correlated with indexes of quality, including body condition, body condition of their partners and laying date. However, not all ornaments correlated with the same measures of quality. In addition, some ornaments were intercorrelated within the same individuals while others were not. These results suggest that different ornaments can convey information about different qualities, as predicted by the multiple-messages hypothesis. In addition, this study suggests that the predominant pigment (e.g. carotenoid vs. melanin, eumelanin vs. pheomelanin), the time-scale over which the trait is developed (static feathers vs. dynamic skin) and the season of the year at which the ornament is produced can be potential mechanisms to convey different messages in male common kestrels.

  4. Multiple coloured ornaments in male common kestrels: different mechanisms to convey quality.

    PubMed

    Vergara, Pablo; Fargallo, Juan A

    2011-04-01

    The simultaneous exhibition of more than one secondary sexual trait is a widespread phenomenon in nature, though it has rarely been explored. It has been proposed that different ornaments may convey complementary or back-up information about a single aspect of individual quality (redundancy hypothesis) or that each ornament may convey unique information (multiple-messages hypothesis). During a 5-year period, we measured several carotenoid-based (eye ring, bill cere and tarsi skin) and melanin-based (head, back, rump and tail feathers) potential ornamental colours in male common kestrels. We analysed whether multiple ornaments can convey different or related information about individual quality. We explored whether different ornaments can express different information depending on the pigment (carotenoids or melanins), the time-scale over which the ornament can change (dynamic vs. static) and the season of the year when the ornament is formed. We found that both melanin- and carotenoid- based traits correlated with indexes of quality, including body condition, body condition of their partners and laying date. However, not all ornaments correlated with the same measures of quality. In addition, some ornaments were intercorrelated within the same individuals while others were not. These results suggest that different ornaments can convey information about different qualities, as predicted by the multiple-messages hypothesis. In addition, this study suggests that the predominant pigment (e.g. carotenoid vs. melanin, eumelanin vs. pheomelanin), the time-scale over which the trait is developed (static feathers vs. dynamic skin) and the season of the year at which the ornament is produced can be potential mechanisms to convey different messages in male common kestrels.

  5. The structure of HLA-DR52c: Comparison to other HLA-DRB3 alleles

    SciTech Connect

    Dai, Shaodong; Crawford, Frances; Marrack, Philippa; Kappler, John W.

    2008-09-05

    Class II major histocompatibility complex (MHCII) molecules present antigens to CD4{sup +} T cells. In addition to the most commonly studied human MHCII isotype, HLA-DR, whose {beta} chain is encoded by the HLA-DRB1 locus, several other isotypes that use the same {alpha} chain but have {beta} chains encoded by other genes. These other DR molecules also are expressed in antigen-presenting cells and are known to participate in peptide presentation to T cells and to be recognized as alloantigens by other T cells. Like some of the HLA-DRB1 alleles, several of these alternate DR molecules have been associated with specific autoimmune diseases and T cell hypersensitivity. Here we present the structure of an HLA-DR molecule (DR52c) containing one of these alternate {beta} chains (HLA-DRB3*0301) bound to a self-peptide derived from the Tu elongation factor. The molecule shares structurally conserved elements with other MHC class II molecules but has some unique features in the peptide-binding groove. Comparison of the three major HLA-DBR3 alleles (DR52a, b, and c) suggests that they were derived from one another by recombination events that scrambled the four major peptide-binding pockets at peptide positions 1, 4, 6, and 9 but left virtually no polymorphisms elsewhere in the molecules.

  6. 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.

  7. Most Common Types of Physical Activity Self-Selected by People with Multiple Sclerosis

    PubMed Central

    Weikert, Madeline; Dlugonski, Deirdre; Balantrapu, Swathi

    2011-01-01

    The promotion of physical activity for people with multiple sclerosis (MS) would benefit from information about the common types of physical activity self-selected by this population. This study examined the most frequent types of physical activity self-reported by a large sample of people with MS. The data were collected as part of the baseline assessment of a longitudinal investigation of physical activity in relapsing-remitting MS (RRMS). The participants (N = 272) were sent a battery of questionnaires through the US Postal Service that included the Modifiable Activity Questionnaire for assessing types of physical activity performed during the previous year. Walking was ranked number 1 for both the first and second most common types of physical activity self-selected by people with MS, and it was ranked number 4 as the third most common type of self-selected physical activity. Collectively, 79% of the sample reported walking as a frequent form of self-selected physical activity in the previous year. Other notable types of physical activities self-selected by people with MS were gardening (44%), weight training (34%), bicycling (30%), and calisthenics (20%). This information may assist clinicians and practitioners in the development of physical activity programs and recommendations for people with MS. PMID:24453701

  8. Most common types of physical activity self-selected by people with multiple sclerosis.

    PubMed

    Weikert, Madeline; Dlugonski, Deirdre; Balantrapu, Swathi; Motl, Robert W

    2011-01-01

    The promotion of physical activity for people with multiple sclerosis (MS) would benefit from information about the common types of physical activity self-selected by this population. This study examined the most frequent types of physical activity self-reported by a large sample of people with MS. The data were collected as part of the baseline assessment of a longitudinal investigation of physical activity in relapsing-remitting MS (RRMS). The participants (N = 272) were sent a battery of questionnaires through the US Postal Service that included the Modifiable Activity Questionnaire for assessing types of physical activity performed during the previous year. Walking was ranked number 1 for both the first and second most common types of physical activity self-selected by people with MS, and it was ranked number 4 as the third most common type of self-selected physical activity. Collectively, 79% of the sample reported walking as a frequent form of self-selected physical activity in the previous year. Other notable types of physical activities self-selected by people with MS were gardening (44%), weight training (34%), bicycling (30%), and calisthenics (20%). This information may assist clinicians and practitioners in the development of physical activity programs and recommendations for people with MS.

  9. Mutational and structural analysis of KIR3DL1 reveals a lineage-defining allotypic dimorphism that impacts both HLA and peptide sensitivity.

    PubMed

    O'Connor, Geraldine M; Vivian, Julian P; Widjaja, Jacqueline M; Bridgeman, John S; Gostick, Emma; Lafont, Bernard A P; Anderson, Stephen K; Price, David A; Brooks, Andrew G; Rossjohn, Jamie; McVicar, Daniel W

    2014-03-15

    Killer Ig-like receptors (KIRs) control the activation of human NK cells via interactions with peptide-laden HLAs. KIR3DL1 is a highly polymorphic inhibitory receptor that recognizes a diverse array of HLA molecules expressing the Bw4 epitope, a group with multiple polymorphisms incorporating variants within the Bw4 motif. Genetic studies suggest that KIR3DL1 variation has functional significance in several disease states, including HIV infection. However, owing to differences across KIR3DL1 allotypes, HLA-Bw4, and associated peptides, the mechanistic link with biological outcome remains unclear. In this study, we elucidated the impact of KIR3DL1 polymorphism on peptide-laden HLA recognition. Mutational analysis revealed that KIR residues involved in water-mediated contacts with the HLA-presented peptide influence peptide binding specificity. In particular, residue 282 (glutamate) in the D2 domain underpins the lack of tolerance of negatively charged C-terminal peptide residues. Allotypic KIR3DL1 variants, defined by neighboring residue 283, displayed differential sensitivities to HLA-bound peptide, including the variable HLA-B*57:01-restricted HIV-1 Gag-derived epitope TW10. Residue 283, which has undergone positive selection during the evolution of human KIRs, also played a central role in Bw4 subtype recognition by KIR3DL1. Collectively, our findings uncover a common molecular regulator that controls HLA and peptide discrimination without participating directly in peptide-laden HLA interactions. Furthermore, they provide insight into the mechanics of interaction and generate simple, easily assessed criteria for the definition of KIR3DL1 functional groupings that will be relevant in many clinical applications, including bone marrow transplantation.

  10. 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.

  11. Multiple origins of the determinate growth habit in domesticated common bean (Phaseolus vulgaris)

    PubMed Central

    Kwak, Myounghai; Toro, Orlando; Debouck, Daniel G.; Gepts, Paul

    2012-01-01

    Background and Aims The actual number of domestications of a crop is one of the key questions in domestication studies. Answers to this question have generally been based on relationships between wild progenitors and domesticated descendants determined with anonymous molecular markers. In this study, this question was investigated by determining the number of instances a domestication phenotype had been selected in a crop species. One of the traits that appeared during domestication of common bean (Phaseolus vulgaris) is determinacy, in which stems end with a terminal inflorescence. It has been shown earlier that a homologue of the arabidopsis TFL1 gene – PvTFL1y – controls determinacy in a naturally occurring variation of common bean. Methods Sequence variation was analysed for PvTFL1y in a sample of 46 wild and domesticated accessions that included determinate and indeterminate accessions. Key Results Indeterminate types – wild and domesticated – showed only synonymous nucleotide substitutions. Determinate types – observed only among domesticated accessions – showed, in addition to synonymous substitutions, non-synonymous substitutions, indels, a putative intron-splicing failure, a retrotransposon insertion and a deletion of the entire locus. The retrotransposon insertion was observed in 70 % of determinate cultivars, in the Americas and elsewhere. Other determinate mutants had a more restricted distribution in the Americas only, either in the Andean or in the Mesoamerican gene pool of common bean. Conclusions Although each of the determinacy haplotypes probably does not represent distinct domestication events, they are consistent with the multiple (seven) domestication pattern in the genus Phaseolus. The predominance of determinacy in the Andean gene pool may reflect domestication of common bean prior to maize introduction in the Andes. PMID:23019270

  12. Behçet’s disease in HLA-B*51 negative Germans and Turks shows association with HLA-Bw4-80I

    PubMed Central

    2014-01-01

    Introduction Behçet’s disease (BD) as systemic vasculitis of unknown etiology is associated with HLA-B*51 in European and Asian populations. HLA-A*26 was claimed as an additional BD susceptibility marker in Japanese and Greek patients. This study was performed to test for HLA associations in HLA-B*51 negative German and Turkish BD populations. Methods In total, 65 German and 46 Turkish patients lacking HLA-B*51 were analyzed in comparison to healthy HLA-B*51 negative Germans (n = 1500) and Turks (n = 130). HLA-A/B genotypes were determined by SSOP. P-values with correction for multiple testing (pc), χ2-test and odds ratio (OR) were used for statistical evaluation. Results HLA-A*26 was significantly more frequent in HLA-B*51− German patients [pc = 0.0076, OR = 3.23, 95% CI 1.63 to 6.39] than in respective controls. HLA-A*26 was also elevated in a smaller group of Turkish patients versus the controls. Significant association of HLA-Bw4 with isoleucine at amino-acid position 80 (HLA-Bw4-80I) was found in the HLA-B*51− German cohort of BD patients [pc = 0.0042, OR = 2.35, 95% CI 1.41 to 3.93) and in the Turkish patients in comparison to the respective controls [p = 0.025, OR = 2.17, 95% CI 1.09 to 4.31]. On the contrary, HLA-Bw4-80 T was reduced in both HLA-B*51− BD patient cohorts. Conclusions The study shows a significant association of HLA-Bw4-80I present on HLA-B*51 as well as on other B-locus molecules with BD. This indicates that distinctive Bw4 epitopes on HLA-B locus molecules could play a role in BD pathogenesis. The study also indicates an association with HLA-A*26 in German and Turkish BD patients as a genetic risk factor independent of HLA-B*51. PMID:24887019

  13. Behçet's disease in HLA-B*51 negative Germans and Turks shows association with HLA-Bw4-80I.

    PubMed

    Kuranov, Alexandr Borisovich; Kötter, Ina; Henes, Jörg Christoph; Abisheva, Saule Tleubaevna; Steiert, Ingeborg; Riewerts, Florian; Momynaliev, Kuvat Temirgalievich; Müller, Claudia Anna

    2014-05-26

    Behçet's disease (BD) as systemic vasculitis of unknown etiology is associated with HLA-B*51 in European and Asian populations. HLA-A*26 was claimed as an additional BD susceptibility marker in Japanese and Greek patients. This study was performed to test for HLA associations in HLA-B*51 negative German and Turkish BD populations. In total, 65 German and 46 Turkish patients lacking HLA-B*51 were analyzed in comparison to healthy HLA-B*51 negative Germans (n = 1500) and Turks (n = 130). HLA-A/B genotypes were determined by SSOP. P-values with correction for multiple testing (p(c)), χ2-test and odds ratio (OR) were used for statistical evaluation. HLA-A*26 was significantly more frequent in HLA-B*51- German patients [p(c) = 0.0076, OR = 3.23, 95% CI 1.63 to 6.39] than in respective controls. HLA-A*26 was also elevated in a smaller group of Turkish patients versus the controls. Significant association of HLA-Bw4 with isoleucine at amino-acid position 80 (HLA-Bw4-80I) was found in the HLA-B*51(-) German cohort of BD patients [p(c) = 0.0042, OR = 2.35, 95% CI 1.41 to 3.93) and in the Turkish patients in comparison to the respective controls [p = 0.025, OR = 2.17, 95% CI 1.09 to 4.31]. On the contrary, HLA-Bw4-80 T was reduced in both HLA-B*51(-) BD patient cohorts. The study shows a significant association of HLA-Bw4-80I present on HLA-B*51 as well as on other B-locus molecules with BD. This indicates that distinctive Bw4 epitopes on HLA-B locus molecules could play a role in BD pathogenesis. The study also indicates an association with HLA-A*26 in German and Turkish BD patients as a genetic risk factor independent of HLA-B*51.

  14. Soluble HLA-G and HLA-E Levels in Bone Marrow Plasma Samples Are Related to Disease Stage in Neuroblastoma Patients

    PubMed Central

    Pozzi, Sarah; Carlini, Barbara; Amoroso, Loredana; Corrias, Maria Valeria

    2016-01-01

    The role of nonclassical HLA-class Ib molecules HLA-G and HLA-E in the progression of Neuroblastoma (NB), the most common pediatric extracranial solid tumor, has been characterized in the last years. Since BM infiltration by NB cells is an adverse prognostic factor, we have here analyzed for the first time the concentration of soluble (s)HLA-G and HLA-E in bone marrow (BM) plasma samples from NB patients at diagnosis and healthy donors. sHLA-G and sHLA-E are present in BM plasma samples, and their levels were similar between NB patients and controls, thus suggesting that these molecules are physiologically released by resident or stromal BM cell populations. This hypothesis was supported by the finding that sHLA-G and sHLA-E levels did not correlate with BM infiltration and other adverse prognostic factors (MYCN amplification and age at diagnosis). In contrast, BM plasma levels of both molecules were higher in patients with metastatic disease than in patients with localized NB, thus suggesting that concentration of these molecules might be correlated with disease progression. The prognostic role of sHLA-G and sHLA-E concentration in the BM plasma for NB patients will be evaluated in future studies, by analyzing the clinical outcome of the same NB patients at follow-up. PMID:27610393

  15. 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.

  16. Multiple independent autonomous hydraulic oscillators driven by a common gravity head

    PubMed Central

    Kim, Sung-Jin; Yokokawa, Ryuji; Lesher-Perez, Sasha Cai; Takayama, Shuichi

    2015-01-01

    Self-switching microfluidic circuits that are able to perform biochemical experiments in a parallel and autonomous manner similar to instruction-embedded electronics, are rarely implemented. Here, we present design principles and demonstrations for gravity-driven, integrated, microfluidic pulsatile flow circuits. With a common gravity-head as the only driving force, these fluidic oscillator arrays realize a wide range of periods (0.4 s – 2 h) and flow rates (0.10 – 63 μL min−1) with completely independent timing between the multiple oscillator sub-circuits connected in parallel. As a model application, we perform systematic, parallel analysis of endothelial cell elongation response to different fluidic shearing patterns generated by the autonomous microfluidic pulsed flow generation system. PMID:26073884

  17. Multiple independent autonomous hydraulic oscillators driven by a common gravity head.

    PubMed

    Kim, Sung-Jin; Yokokawa, Ryuji; Lesher-Perez, Sasha Cai; Takayama, Shuichi

    2015-06-15

    Self-switching microfluidic circuits that are able to perform biochemical experiments in a parallel and autonomous manner, similar to instruction-embedded electronics, are rarely implemented. Here, we present design principles and demonstrations for gravity-driven, integrated, microfluidic pulsatile flow circuits. With a common gravity head as the only driving force, these fluidic oscillator arrays realize a wide range of periods (0.4 s-2 h) and flow rates (0.10-63 μl min(-1)) with completely independent timing between the multiple oscillator sub-circuits connected in parallel. As a model application, we perform systematic, parallel analysis of endothelial cell elongation response to different fluidic shearing patterns generated by the autonomous microfluidic pulsed flow generation system.

  18. Multiple malignancies in a female patient with common variable immunodeficiency syndrome

    PubMed Central

    Todorovic, Milena; Balint, Bela; Andjelic, Bosko; Mihaljevic, Biljana

    2014-01-01

    We herein present the case of a 55-year-old woman with a previous history of malignancies – uterine adenocarcinoma, basal cell carcinoma (which occurred twice consecutively), recurrent respiratory infections due to common variable immunodeficiency (CVID), and systemic granulomatous disease diagnosed at a later age. The patient suffered from diffuse large B cell lymphoma (DLBCL), which was successfully treated with R-CHOP chemotherapy, and continued with immunoglobulin supplementation. The patient was free of lymphoma and infectious complications for over 20 months despite her persistent immunodeficiency, but eventually developed colorectal adenocarcinoma. To the best of our knowledge, this is the first reported case of CVID associated with multiple solid tumours and DLBCL. PMID:25631905

  19. Texture analysis of common renal masses in multiple MR sequences for prediction of pathology

    NASA Astrophysics Data System (ADS)

    Hoang, Uyen N.; Malayeri, Ashkan A.; Lay, Nathan S.; Summers, Ronald M.; Yao, Jianhua

    2017-03-01

    This pilot study performs texture analysis on multiple magnetic resonance (MR) images of common renal masses for differentiation of renal cell carcinoma (RCC). Bounding boxes are drawn around each mass on one axial slice in T1 delayed sequence to use for feature extraction and classification. All sequences (T1 delayed, venous, arterial, pre-contrast phases, T2, and T2 fat saturated sequences) are co-registered and texture features are extracted from each sequence simultaneously. Random forest is used to construct models to classify lesions on 96 normal regions, 87 clear cell RCCs, 8 papillary RCCs, and 21 renal oncocytomas; ground truths are verified through pathology reports. The highest performance is seen in random forest model when data from all sequences are used in conjunction, achieving an overall classification accuracy of 83.7%. When using data from one single sequence, the overall accuracies achieved for T1 delayed, venous, arterial, and pre-contrast phase, T2, and T2 fat saturated were 79.1%, 70.5%, 56.2%, 61.0%, 60.0%, and 44.8%, respectively. This demonstrates promising results of utilizing intensity information from multiple MR sequences for accurate classification of renal masses.

  20. Heme Oxygenase-1 and 2 Common Genetic Variants and Risk for Multiple Sclerosis.

    PubMed

    Agúndez, José A G; García-Martín, Elena; Martínez, Carmen; Benito-León, Julián; Millán-Pascual, Jorge; Díaz-Sánchez, María; Calleja, Patricia; Pisa, Diana; Turpín-Fenoll, Laura; Alonso-Navarro, Hortensia; Pastor, Pau; Ortega-Cubero, Sara; Ayuso-Peralta, Lucía; Torrecillas, Dolores; García-Albea, Esteban; Plaza-Nieto, José Francisco; Jiménez-Jiménez, Félix Javier

    2016-02-12

    Several neurochemical, neuropathological, and experimental data suggest a possible role of oxidative stress in the ethiopathogenesis of multiple sclerosis(MS). Heme-oxygenases(HMOX) are an important defensive mechanism against oxidative stress, and HMOX1 is overexpressed in the brain and spinal cord of MS patients and in experimental autoimmune encephalomyelitis(EAE). We analyzed whether common polymorphisms affecting the HMOX1 and HMOX2 genes are related with the risk to develop MS. We analyzed the distribution of genotypes and allelic frequencies of the HMOX1 rs2071746, HMOX1 rs2071747, HMOX2 rs2270363, and HMOX2 rs1051308 SNPs, as well as the presence of Copy number variations(CNVs) of these genes in 292 subjects MS and 533 healthy controls, using TaqMan assays. The frequencies of HMOX2 rs1051308AA genotype and HMOX2 rs1051308A and HMOX1 rs2071746A alleles were higher in MS patients than in controls, although only that of the SNP HMOX2 rs1051308 in men remained as significant after correction for multiple comparisons. None of the studied polymorphisms was related to the age at disease onset or with the MS phenotype. The present study suggests a weak association between HMOX2 rs1051308 polymorphism and the risk to develop MS in Spanish Caucasian men and a trend towards association between the HMOX1 rs2071746A and MS risk.

  1. Gene and Network Analysis of Common Variants Reveals Novel Associations in Multiple Complex Diseases.

    PubMed

    Nakka, Priyanka; Raphael, Benjamin J; Ramachandran, Sohini

    2016-10-01

    Genome-wide association (GWA) studies typically lack power to detect genotypes significantly associated with complex diseases, where different causal mutations of small effect may be present across cases. A common, tractable approach for identifying genomic elements associated with complex traits is to evaluate combinations of variants in known pathways or gene sets with shared biological function. Such gene-set analyses require the computation of gene-level P-values or gene scores; these gene scores are also useful when generating hypotheses for experimental validation. However, commonly used methods for generating GWA gene scores are computationally inefficient, biased by gene length, imprecise, or have low true positive rate (TPR) at low false positive rates (FPR), leading to erroneous hypotheses for functional validation. Here we introduce a new method, PEGASUS, for analytically calculating gene scores. PEGASUS produces gene scores with as much as 10 orders of magnitude higher numerical precision than competing methods. In simulation, PEGASUS outperforms existing methods, achieving up to 30% higher TPR when the FPR is fixed at 1%. We use gene scores from PEGASUS as input to HotNet2 to identify networks of interacting genes associated with multiple complex diseases and traits; this is the first application of HotNet2 to common variation. In ulcerative colitis and waist-hip ratio, we discover networks that include genes previously associated with these phenotypes, as well as novel candidate genes. In contrast, existing methods fail to identify these networks. We also identify networks for attention-deficit/hyperactivity disorder, in which GWA studies have yet to identify any significant SNPs.

  2. Testing Multiple Psychological Processes for Common Neural Mechanisms Using EEG and Independent Component Analysis.

    PubMed

    Wessel, Jan R

    2016-03-08

    Temporal independent component analysis (ICA) is applied to an electrophysiological signal mixture (such as an EEG recording) to disentangle the independent neural source signals-independent components-underlying said signal mixture. When applied to scalp EEG, ICA is most commonly used either as a pre-processing step (e.g., to isolate physiological processes from non-physiological artifacts), or as a data-reduction step (i.e., to focus on one specific neural process with increased signal-to-noise ratio). However, ICA can be used in an even more powerful way that fundamentally expands the inferential utility of scalp EEG. The core assumption of EEG-ICA-namely, that individual independent components represent separable neural processes-can be leveraged to derive the following inferential logic: If a specific independent component shows activity related to multiple psychological processes within the same dataset (e.g., elicited by different experimental events), it follows that those psychological processes involve a common, non-separable neural mechanism. As such, this logic allows testing a class of hypotheses that is beyond the reach of regular EEG analyses techniques, thereby crucially increasing the inferential utility of the EEG. In the current article, this logic will be referred to as the 'common independent process identification' (CIPI) approach. This article aims to provide a tutorial into the application of this powerful approach, targeted at researchers that have a basic understanding of standard EEG analysis. Furthermore, the article aims to exemplify the usage of CIPI by outlining recent studies that successfully applied this approach to test neural theories of mental functions.

  3. Gene and Network Analysis of Common Variants Reveals Novel Associations in Multiple Complex Diseases

    PubMed Central

    Nakka, Priyanka; Raphael, Benjamin J.; Ramachandran, Sohini

    2016-01-01

    Genome-wide association (GWA) studies typically lack power to detect genotypes significantly associated with complex diseases, where different causal mutations of small effect may be present across cases. A common, tractable approach for identifying genomic elements associated with complex traits is to evaluate combinations of variants in known pathways or gene sets with shared biological function. Such gene-set analyses require the computation of gene-level P-values or gene scores; these gene scores are also useful when generating hypotheses for experimental validation. However, commonly used methods for generating GWA gene scores are computationally inefficient, biased by gene length, imprecise, or have low true positive rate (TPR) at low false positive rates (FPR), leading to erroneous hypotheses for functional validation. Here we introduce a new method, PEGASUS, for analytically calculating gene scores. PEGASUS produces gene scores with as much as 10 orders of magnitude higher numerical precision than competing methods. In simulation, PEGASUS outperforms existing methods, achieving up to 30% higher TPR when the FPR is fixed at 1%. We use gene scores from PEGASUS as input to HotNet2 to identify networks of interacting genes associated with multiple complex diseases and traits; this is the first application of HotNet2 to common variation. In ulcerative colitis and waist–hip ratio, we discover networks that include genes previously associated with these phenotypes, as well as novel candidate genes. In contrast, existing methods fail to identify these networks. We also identify networks for attention-deficit/hyperactivity disorder, in which GWA studies have yet to identify any significant SNPs. PMID:27489002

  4. [Immunogenetic HLA markers of chronic viral hepatitis].

    PubMed

    Popov, E A; Levitan, B N; Alekseev, L P; Pronina, O A; Suchkov, S V

    2005-01-01

    To study possible immunogenetic HLA markers of chronic viral hepatitides. Using the reaction of complement-dependent cytotoxicity by Terasaki, we analysed distribution of leukocytic HLA antigens (loci A, B and C) in 179 patients with chronic viral hepatitides B, C and D in Russians and Kazakhs living in the Astrakhan Region. In the Russian population we discovered a significant positive association of CVHB with HLA-B18, HLA-B35, HLA-B40, HLA-Cw3 antigens, and negative one--with HLA-A2. In Kazakhs with CVHB there was a positive association with HLA-A3, HLA-B18 and negative one--with HLA-A11. Alleles HLA-A10, HLA-B35, HLA-B40 and HLA-Cw3 mark CVHC in Russians. HLA-Cw4 specificity acts as protector in development of chronic HCV-infection. A correlation was found between carriage of some specificities and haplotypes of HLA and activity of chronic HBV and HCV infection. A high risk of chronic delta infection in Russians is associated with HLA-B8 and HLA-B35, in Kazakhs--with HLA-B35 and HLA-D40. There are significant associations between CVHB, CVHC, chronic delta infection and some HLA haplotypes. A universal role of HLA-B35 specificity in development of CVH irrespective of hepatotropic virus and patients' nationality is shown.

  5. An HLA matched donor! An HLA matched donor? What do you mean by: HLA matched donor?

    PubMed

    van Rood, J J; Oudshoorn, M

    1998-07-01

    The term 'an HLA matched donor' is in general used without giving exact information on the level of resolution of the HLA typing. This can lead to misunderstandings. A proposal is formulated to agree on using six match categories according to the HLA typing technique used to indicate the level of confidence of the matching.

  6. Coding Variants at Hexa-allelic Amino Acid 13 of HLA-DRB1 Explain Independent SNP Associations with Follicular Lymphoma Risk

    PubMed Central

    Foo, Jia Nee; Smedby, Karin E.; Akers, Nicholas K.; Berglund, Mattias; Irwan, Ishak D.; Jia, Xiaoming; Li, Yi; Conde, Lucia; Darabi, Hatef; Bracci, Paige M.; Melbye, Mads; Adami, Hans-Olov; Glimelius, Bengt; Khor, Chiea Chuen; Hjalgrim, Henrik; Padyukov, Leonid; Humphreys, Keith; Enblad, Gunilla; Skibola, Christine F.; de Bakker, Paul I.W.; Liu, Jianjun

    2013-01-01

    Non-Hodgkin lymphoma represents a diverse group of blood malignancies, of which follicular lymphoma (FL) is a common subtype. Previous genome-wide association studies (GWASs) have identified in the human leukocyte antigen (HLA) class II region multiple independent SNPs that are significantly associated with FL risk. To dissect these signals and determine whether coding variants in HLA genes are responsible for the associations, we conducted imputation, HLA typing, and sequencing in three independent populations for a total of 689 cases and 2,446 controls. We identified a hexa-allelic amino acid polymorphism at position 13 of the HLA-DR beta chain that showed the strongest association with FL within the major histocompatibility complex (MHC) region (multiallelic p = 2.3 × 10−15). Out of six possible amino acids that occurred at that position within the population, we classified two as high risk (Tyr and Phe), two as low risk (Ser and Arg), and two as moderate risk (His and Gly). There was a 4.2-fold difference in risk (95% confidence interval = 2.9–6.1) between subjects carrying two alleles encoding high-risk amino acids and those carrying two alleles encoding low-risk amino acids (p = 1.01 × 10−14). This coding variant might explain the complex SNP associations identified by GWASs and suggests a common HLA-DR antigen-driven mechanism for the pathogenesis of FL and rheumatoid arthritis. PMID:23791106

  7. Coding variants at hexa-allelic amino acid 13 of HLA-DRB1 explain independent SNP associations with follicular lymphoma risk.

    PubMed

    Foo, Jia Nee; Smedby, Karin E; Akers, Nicholas K; Berglund, Mattias; Irwan, Ishak D; Jia, Xiaoming; Li, Yi; Conde, Lucia; Darabi, Hatef; Bracci, Paige M; Melbye, Mads; Adami, Hans-Olov; Glimelius, Bengt; Khor, Chiea Chuen; Hjalgrim, Henrik; Padyukov, Leonid; Humphreys, Keith; Enblad, Gunilla; Skibola, Christine F; de Bakker, Paul I W; Liu, Jianjun

    2013-07-11

    Non-Hodgkin lymphoma represents a diverse group of blood malignancies, of which follicular lymphoma (FL) is a common subtype. Previous genome-wide association studies (GWASs) have identified in the human leukocyte antigen (HLA) class II region multiple independent SNPs that are significantly associated with FL risk. To dissect these signals and determine whether coding variants in HLA genes are responsible for the associations, we conducted imputation, HLA typing, and sequencing in three independent populations for a total of 689 cases and 2,446 controls. We identified a hexa-allelic amino acid polymorphism at position 13 of the HLA-DR beta chain that showed the strongest association with FL within the major histocompatibility complex (MHC) region (multiallelic p = 2.3 × 10⁻¹⁵). Out of six possible amino acids that occurred at that position within the population, we classified two as high risk (Tyr and Phe), two as low risk (Ser and Arg), and two as moderate risk (His and Gly). There was a 4.2-fold difference in risk (95% confidence interval = 2.9-6.1) between subjects carrying two alleles encoding high-risk amino acids and those carrying two alleles encoding low-risk amino acids (p = 1.01 × 10⁻¹⁴). This coding variant might explain the complex SNP associations identified by GWASs and suggests a common HLA-DR antigen-driven mechanism for the pathogenesis of FL and rheumatoid arthritis.

  8. HIBAG--HLA genotype imputation with attribute bagging.

    PubMed

    Zheng, X; Shen, J; Cox, C; Wakefield, J C; Ehm, M G; Nelson, M R; Weir, B S

    2014-04-01

    Genotyping of classical human leukocyte antigen (HLA) alleles is an essential tool in the analysis of diseases and adverse drug reactions with associations mapping to the major histocompatibility complex (MHC). However, deriving high-resolution HLA types subsequent to whole-genome single-nucleotide polymorphism (SNP) typing or sequencing is often cost prohibitive for large samples. An alternative approach takes advantage of the extended haplotype structure within the MHC to predict HLA alleles using dense SNP genotypes, such as those available from genome-wide SNP panels. Current methods for HLA imputation are difficult to apply or may require the user to have access to large training data sets with SNP and HLA types. We propose HIBAG, HLA Imputation using attribute BAGging, that makes predictions by averaging HLA-type posterior probabilities over an ensemble of classifiers built on bootstrap samples. We assess the performance of HIBAG using our study data (n=2668 subjects of European ancestry) as a training set and HLA data from the British 1958 birth cohort study (n≈1000 subjects) as independent validation samples. Prediction accuracies for HLA-A, B, C, DRB1 and DQB1 range from 92.2% to 98.1% using a set of SNP markers common to the Illumina 1M Duo, OmniQuad, OmniExpress, 660K and 550K platforms. HIBAG performed well compared with the other two leading methods, HLA*IMP and BEAGLE. This method is implemented in a freely available HIBAG R package that includes pre-fit classifiers for European, Asian, Hispanic and African ancestries, providing a readily available imputation approach without the need to have access to large training data sets.

  9. Association of HLA-A and Non-Classical HLA Class I Alleles

    PubMed Central

    Carlini, Federico; Ferreira, Virginia; Buhler, Stéphane; Tous, Audrey; Eliaou, Jean-François; René, Céline; Chiaroni, Jacques; Picard, Christophe; Di Cristofaro, Julie

    2016-01-01

    The HLA-A locus is surrounded by HLA class Ib genes: HLA-E, HLA-H, HLA-G and HLA-F. HLA class Ib molecules are involved in immuno-modulation with a central role for HLA-G and HLA-E, an emerging role for HLA-F and a yet unknown function for HLA-H. Thus, the principal objective of this study was to describe the main allelic associations between HLA-A and HLA-H, -G, -F and -E. Therefore, HLA-A, -E, -G, -H and -F coding polymorphisms, as well as HLA-G UnTranslated Region haplotypes (referred to as HLA-G UTRs), were explored in 191 voluntary blood donors. Allelic frequencies, Global Linkage Disequilibrium (GLD), Linkage Disequilibrium (LD) for specific pairs of alleles and two-loci haplotype frequencies were estimated. We showed that HLA-A, HLA-H, HLA-F, HLA-G and HLA-G UTRs were all in highly significant pairwise GLD, in contrast to HLA-E. Moreover, HLA-A displayed restricted associations with HLA-G UTR and HLA-H. We also confirmed several associations that were previously found to have a negative impact on transplantation outcome. In summary, our results suggest complex functional and clinical implications of the HLA-A genetic region. PMID:27701438

  10. Genetic link between Asians and native Americans: evidence from HLA genes and haplotypes.

    PubMed

    Tokunaga, K; Ohashi, J; Bannai, M; Juji, T

    2001-09-01

    We have been studying polymorphisms of HLA class I and II genes in East Asians including Buryat in Siberia, Mongolian, Han Chinese, Man Chinese, Korean Chinese, South Korean, and Taiwan indigenous populations in collaboration with many Asian scientists. Regional populations in Japan, Hondo-Japanese, Ryukyuan, and Ainu, were also studied. HLA-A, -B, and -DRB1 gene frequencies were subjected to the correspondence analysis and calculation of DA distances. The correspondence analysis demonstrated several major clusters of human populations in the world. "Mongoloid" populations were highly diversified, in which several clusters such as Northeast Asians, Southeast Asians, Oceanians, and Native Americans were observed. Interestingly, an indigenous population in North Japan, Ainu, was placed relatively close to Native Americans in the correspondence analysis. Distribution of particular HLA-A, -B, -DRB1 alleles and haplotypes was also analyzed in relation to migration and dispersal routes of ancestral populations. A number of alleles and haplotypes showed characteristic patterns of regional distribution. For example, B39-HR5-DQ7 (B*3901-DRB1*1406-DQB1*0301) was shared by Ainu and Native Americans. A24-Cw8-B48 was commonly observed in Taiwan indigenous populations, Maori in New Zealand, Orochon in Northeast China, Inuit, and Tlingit. These findings further support the genetic link between East Asians and Native Americans. We have proposed that various ancestral populations in East Asia, marked by different HLA haplotypes, had migrated and dispersed through multiple routes. Moreover, relatively small genetic distances and the sharing of several HLA haplotypes between Ainu and Native Americans suggest that these populations are descendants of some Upper Paleolithic populations of East Asia.

  11. How similar are commonly combined criteria for EDSS progression in multiple sclerosis?

    PubMed

    Kragt, J J; Nielsen, I M; van der Linden, F A H; Uitdehaag, B M J; Polman, C H

    2006-12-01

    Measuring disease progression is an important aspect of multiple sclerosis (MS) clinical trials. Commonly applied disability endpoints include time to clinically meaningful Expanded Disability Status Scale (EDSS) change, or the number of patients in whom such a change has occurred. Typically, clinically meaningful EDSS change has been defined as a change of 1.0 point on Kurtzke's EDSS in patients with an entry EDSS score of 5.5 or lower, or 0.5 point in patients with a higher EDSS score. Our goal was to evaluate whether these changes can be considered as similar. Therefore, we compared EDSS changes to corresponding changes in the Guy's Neurological Disability Scale (GNDS), which is a measure of patient perceived disability, and the Multiple Sclerosis Functional Composite (MSFC), which is an examination-based quantitative scoring of neurological impairment. From a large longitudinal database, we selected two groups of patients with a clinically meaningful change in EDSS score according to the usual criteria: patients with EDSS change > or = 1.0 for baseline EDSS < or = 5.5 and patients with EDSS change > or = 0.5 for baseline EDSS > or = 6.0. We compared changes in GNDS sum score and in MSFC score between both groups. In the group with baseline EDSS > or = 6.0, GNDS and MSFC changes were higher than in patients with baseline EDSS < or = 5.5. The difference in change was 1.00 (95% confidence interval (CI): -0.35 to 2.36) for the GNDS and 0.412 (95% CI: 0.300-0.525) for the MSFC. Our results indicate that a 0.5 point EDSS change in patients with baseline EDSS > or = 6.0 cannot be considered equal to a 1.0 point change in patients with baseline EDSS < or = 5.5.

  12. Feasibility and utility of applications of the common data model to multiple, disparate observational health databases.

    PubMed

    Voss, Erica A; Makadia, Rupa; Matcho, Amy; Ma, Qianli; Knoll, Chris; Schuemie, Martijn; DeFalco, Frank J; Londhe, Ajit; Zhu, Vivienne; Ryan, Patrick B

    2015-05-01

    To evaluate the utility of applying the Observational Medical Outcomes Partnership (OMOP) Common Data Model (CDM) across multiple observational databases within an organization and to apply standardized analytics tools for conducting observational research. Six deidentified patient-level datasets were transformed to the OMOP CDM. We evaluated the extent of information loss that occurred through the standardization process. We developed a standardized analytic tool to replicate the cohort construction process from a published epidemiology protocol and applied the analysis to all 6 databases to assess time-to-execution and comparability of results. Transformation to the CDM resulted in minimal information loss across all 6 databases. Patients and observations excluded were due to identified data quality issues in the source system, 96% to 99% of condition records and 90% to 99% of drug records were successfully mapped into the CDM using the standard vocabulary. The full cohort replication and descriptive baseline summary was executed for 2 cohorts in 6 databases in less than 1 hour. The standardization process improved data quality, increased efficiency, and facilitated cross-database comparisons to support a more systematic approach to observational research. Comparisons across data sources showed consistency in the impact of inclusion criteria, using the protocol and identified differences in patient characteristics and coding practices across databases. Standardizing data structure (through a CDM), content (through a standard vocabulary with source code mappings), and analytics can enable an institution to apply a network-based approach to observational research across multiple, disparate observational health databases. © The Author 2015. Published by Oxford University Press on behalf of the American Medical Informatics Association.

  13. Feasibility and utility of applications of the common data model to multiple, disparate observational health databases

    PubMed Central

    Makadia, Rupa; Matcho, Amy; Ma, Qianli; Knoll, Chris; Schuemie, Martijn; DeFalco, Frank J; Londhe, Ajit; Zhu, Vivienne; Ryan, Patrick B

    2015-01-01

    Objectives To evaluate the utility of applying the Observational Medical Outcomes Partnership (OMOP) Common Data Model (CDM) across multiple observational databases within an organization and to apply standardized analytics tools for conducting observational research. Materials and methods Six deidentified patient-level datasets were transformed to the OMOP CDM. We evaluated the extent of information loss that occurred through the standardization process. We developed a standardized analytic tool to replicate the cohort construction process from a published epidemiology protocol and applied the analysis to all 6 databases to assess time-to-execution and comparability of results. Results Transformation to the CDM resulted in minimal information loss across all 6 databases. Patients and observations excluded were due to identified data quality issues in the source system, 96% to 99% of condition records and 90% to 99% of drug records were successfully mapped into the CDM using the standard vocabulary. The full cohort replication and descriptive baseline summary was executed for 2 cohorts in 6 databases in less than 1 hour. Discussion The standardization process improved data quality, increased efficiency, and facilitated cross-database comparisons to support a more systematic approach to observational research. Comparisons across data sources showed consistency in the impact of inclusion criteria, using the protocol and identified differences in patient characteristics and coding practices across databases. Conclusion Standardizing data structure (through a CDM), content (through a standard vocabulary with source code mappings), and analytics can enable an institution to apply a network-based approach to observational research across multiple, disparate observational health databases. PMID:25670757

  14. Strain-based HLA association analysis identified HLA-DRB1*09:01 associated with modern strain tuberculosis.

    PubMed

    Toyo-Oka, L; Mahasirimongkol, S; Yanai, H; Mushiroda, T; Wattanapokayakit, S; Wichukchinda, N; Yamada, N; Smittipat, N; Juthayothin, T; Palittapongarnpim, P; Nedsuwan, S; Kantipong, P; Takahashi, A; Kubo, M; Sawanpanyalert, P; Tokunaga, K

    2017-09-01

    Tuberculosis (TB) occurs as a result of complex interactions between the host immune system and pathogen virulence factors. Human leukocyte antigen (HLA) class II molecules play an important role in the host immune system. However, no study has assessed the association between HLA class II genes and susceptibility to TB caused by specific strains. This study investigated the possible association of HLA class II genes with TB caused by modern and ancient Mycobacterium tuberculosis (MTB). The study included 682 patients with TB and 836 control subjects who were typed for HLA-DRB1 and HLA-DQB1 alleles. MTB strains were classified using a large sequence polymorphism typing method. Association analysis was performed using common HLA alleles and haplotypes in different MTB strains. HLA association analysis of patients infected with modern MTB strains showed significant association for HLA-DRB1*09:01 (odds ratio [OR] = 1.82; P-value = 9.88 × 10(-4) ) and HLA-DQB1*03:03 alleles (OR = 1.76; P-value = 1.31 × 10(-3) ) with susceptibility to TB. Haplotype analysis confirmed that these alleles were in strong linkage disequilibrium and did not exert an interactive effect. Thus, the results of this study showed an association between HLA class II genes and susceptibility to TB caused by modern MTB strains, suggesting the importance of strain-specific analysis to determine susceptibility genes associated with TB. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  15. Analysis of HLA-ABC locus-specific transcription in normal tissues.

    PubMed

    García-Ruano, Ana Belén; Méndez, Rosa; Romero, José María; Cabrera, Teresa; Ruiz-Cabello, Francisco; Garrido, Federico

    2010-12-01

    We developed a novel human leukocyte antigen HLA-ABC locus-specific quantitative real-time polymerase chain reaction (PCR) to determine the locus-specific gene expression of HLA-ABC in peripheral blood leukocytes (PBLs, n = 53), colon mucosa (n = 15), and larynx mucosa (n = 15). Laser-assisted tissue microdissection allowed us to study the selected cells without interference from surrounding stroma. We report evidence on the specificity of the technique, describing the HLA-ABC locus-specific gene expression patterns found in the PBLs and two solid tissues studied. PBLs showed a higher gene expression of HLA-B than of HLA-A or HLA-C (p = 4.7 × 10(-10) and p = 1.6 × 10(-6), respectively). In solid tissue, HLA-A and HLA-B gene expressions were similar and HLA-C expression lower. In particular, in larynx mucosa, significant differences were found between HLA-A and HLA-C expressions and between HLA-B and HLA-C expressions (p = 6.5 × 10(-4) and p = 8.1 × 10(-4), respectively). The same differences were observed in colon mucosa, but significance was not reached (p = 0.08 and p = 0.06, respectively). Differences in locus-specific regulation may be related to the control of cytotoxic responses of NK and CD8 positive T cells. Gene expression of HLA-ABC specific locus showed no intra-individual variability, but there was a high inter-individual variability. This may result from differences in the expression of common regulatory factors that control HLA-ABC constitutive expression.

  16. A common rejection module (CRM) for acute rejection across multiple organs identifies novel therapeutics for organ transplantation

    PubMed Central

    Khatri, Purvesh; Roedder, Silke; Kimura, Naoyuki; De Vusser, Katrien; Morgan, Alexander A.; Gong, Yongquan; Fischbein, Michael P.; Robbins, Robert C.; Naesens, Maarten

    2013-01-01

    Using meta-analysis of eight independent transplant datasets (236 graft biopsy samples) from four organs, we identified a common rejection module (CRM) consisting of 11 genes that were significantly overexpressed in acute rejection (AR) across all transplanted organs. The CRM genes could diagnose AR with high specificity and sensitivity in three additional independent cohorts (794 samples). In another two independent cohorts (151 renal transplant biopsies), the CRM genes correlated with the extent of graft injury and predicted future injury to a graft using protocol biopsies. Inferred drug mechanisms from the literature suggested that two FDA-approved drugs (atorvastatin and dasatinib), approved for nontransplant indications, could regulate specific CRM genes and reduce the number of graft-infiltrating cells during AR. We treated mice with HLA-mismatched mouse cardiac transplant with atorvastatin and dasatinib and showed reduction of the CRM genes, significant reduction of graft-infiltrating cells, and extended graft survival. We further validated the beneficial effect of atorvastatin on graft survival by retrospective analysis of electronic medical records of a single-center cohort of 2,515 renal transplant patients followed for up to 22 yr. In conclusion, we identified a CRM in transplantation that provides new opportunities for diagnosis, drug repositioning, and rational drug design. PMID:24127489

  17. A common rejection module (CRM) for acute rejection across multiple organs identifies novel therapeutics for organ transplantation.

    PubMed

    Khatri, Purvesh; Roedder, Silke; Kimura, Naoyuki; De Vusser, Katrien; Morgan, Alexander A; Gong, Yongquan; Fischbein, Michael P; Robbins, Robert C; Naesens, Maarten; Butte, Atul J; Sarwal, Minnie M

    2013-10-21

    Using meta-analysis of eight independent transplant datasets (236 graft biopsy samples) from four organs, we identified a common rejection module (CRM) consisting of 11 genes that were significantly overexpressed in acute rejection (AR) across all transplanted organs. The CRM genes could diagnose AR with high specificity and sensitivity in three additional independent cohorts (794 samples). In another two independent cohorts (151 renal transplant biopsies), the CRM genes correlated with the extent of graft injury and predicted future injury to a graft using protocol biopsies. Inferred drug mechanisms from the literature suggested that two FDA-approved drugs (atorvastatin and dasatinib), approved for nontransplant indications, could regulate specific CRM genes and reduce the number of graft-infiltrating cells during AR. We treated mice with HLA-mismatched mouse cardiac transplant with atorvastatin and dasatinib and showed reduction of the CRM genes, significant reduction of graft-infiltrating cells, and extended graft survival. We further validated the beneficial effect of atorvastatin on graft survival by retrospective analysis of electronic medical records of a single-center cohort of 2,515 renal transplant patients followed for up to 22 yr. In conclusion, we identified a CRM in transplantation that provides new opportunities for diagnosis, drug repositioning, and rational drug design.

  18. Multiple sequence assembly from reads alignable to a common reference genome.

    PubMed

    Peng, Qian; Smith, Andrew D

    2011-01-01

    We describe a set of computational problems motivated by certain analysis tasks in genome resequencing. These are assembly problems for which multiple distinct sequences must be assembled, but where the relative positions of reads to be assembled are already known. This information is obtained from a common reference genome and is characteristic of resequencing experiments. The simplest variant of the problem aims at determining a minimum set of superstrings such that each sequenced read matches at least one superstring. We give an algorithm with time complexity O(N), where N is the sum of the lengths of reads, substantially improving on previous algorithms for solving the same problem. We also examine the problem of finding the smallest number of reads to remove such that the remaining reads are consistent with k superstrings. By exploiting a surprising relationship with the minimum cost flow problem, we show that this problem can be solved in polynomial time when nested reads are excluded. If nested reads are permitted, this problem of removing the minimum number of reads becomes NP-hard. We show that permitting mismatches between reads and their nearest superstrings generally renders these problems NP-hard.

  19. Genetic HLA Study of Kurds in Iraq, Iran and Tbilisi (Caucasus, Georgia): Relatedness and Medical Implications

    PubMed Central

    Muñiz, Ester; Campos, Cristina; Alonso-Rubio, Javier; Gomez-Casado, Eduardo; Salih, Shadallah Fareq; Martin-Villa, Manuel; Al-Qadi, Rawand

    2017-01-01

    Kurds from Iraq (Dohuk and Erbil Area, North Iraq) have been analyzed for HLA genes. Their HLA genetic profile has been compared with that of other Kurd groups from Iran and Tbilisi (Georgia, Caucasus) and also Worldwide populations. A total of 7,746 HLA chromosomes have been used. Genetic distances, NJ dendrograms and correspondence analyses have been carried out. Haplotype HLA-B*52—DRB1*15 is present in all three analyzed Kurd populations. HLA-A*02-B*51-DRB1*11 is present in Iraq and Georgia Kurds. Haplotypes common to Iran and Iraq Kurds are HLA DRB1*11—DQB1*03, HLA DRB1*03—DQB1*02 and others in a lower frequency. Our HLA study conclusions are that Kurds most probably belong to an ancient Mediterranean / Middle East / Caucasian genetic substratum and that present results and those previously obtained by us in Kurds may be useful for Medicine in future Kurd transplantation programs, HLA Epidemiology (HLA linked diseases) and Pharmacogenomics (HLA-associated drug side effects) and also for Anthropology. It is discussed that one of the most ancient Kurd ancestor groups is in Hurrians (2,000 years BC). PMID:28114347

  20. The IMGT/HLA database

    PubMed Central

    Robinson, James; Waller, Matthew J.; Fail, Sylvie C.; McWilliam, Hamish; Lopez, Rodrigo; Parham, Peter; Marsh, Steven G. E.

    2009-01-01

    It is 10 years since the IMGT/HLA database was 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. Many of the genes encode proteins of the immune system and are highly polymorphic. The naming of these HLA genes and alleles, and their quality control is the responsibility of the WHO 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 this data through the website http://www.ebi.ac.uk/imgt/hla/. The first release contained 964 sequences, the most recent release 3300 sequences, with around 450 new sequences been added each year. The tools provided on the website have been updated to allow more complex alignments, which include genomic sequence data, as well as the development of tools for probe and primer design and the inclusion of data from the HLA Dictionary. Regular updates to the website ensure that new and confirmatory sequences are dispersed to the HLA community, and the wider research and clinical communities. PMID:18838392

  1. The Protective Role of HLA-DRB1(∗)13 in Autoimmune Diseases.

    PubMed

    Bettencourt, Andreia; Carvalho, Cláudia; Leal, Bárbara; Brás, Sandra; Lopes, Dina; Martins da Silva, Ana; Santos, Ernestina; Torres, Tiago; Almeida, Isabel; Farinha, Fátima; Barbosa, Paulo; Marinho, António; Selores, Manuela; Correia, João; Vasconcelos, Carlos; Costa, Paulo P; da Silva, Berta Martins

    2015-01-01

    Autoimmune diseases (AIDs) are characterized by a multifactorial aetiology and a complex genetic background, with the MHC region playing a major role. We genotyped for HLA-DRB1 locus 1228 patients with AIDs-213 with Systemic Lupus Erythematosus (SLE), 166 with Psoriasis or Psoriatic Arthritis (Ps + PsA), 153 with Rheumatoid Arthritis (RA), 67 with Systemic Sclerosis (SSc), 536 with Multiple Sclerosis (MS), and 93 with Myasthenia Gravis (MG) and 282 unrelated controls. We confirmed previously established associations of HLA-DRB1(∗)15 (OR = 2.17) and HLA-DRB1(∗)03 (OR = 1.81) alleles with MS, HLA-DRB1(∗)03 with SLE (OR = 2.49), HLA-DRB1(∗)01 (OR = 1.79) and HLA-DRB1(∗)04 (OR = 2.81) with RA, HLA-DRB1(∗)07 with Ps + PsA (OR = 1.79), HLA-DRB1(∗)01 (OR = 2.28) and HLA-DRB1(∗)08 (OR = 3.01) with SSc, and HLA-DRB1(∗)03 with MG (OR = 2.98). We further observed a consistent negative association of HLA-DRB1(∗)13 allele with SLE, Ps + PsA, RA, and SSc (18.3%, 19.3%, 16.3%, and 11.9%, resp., versus 29.8% in controls). HLA-DRB1(∗)13 frequency in the AIDs group was 20.0% (OR = 0.58). Although different alleles were associated with particular AIDs, the same allele, HLA-DRB1(∗)13, was underrepresented in all of the six diseases analysed. This observation suggests that this allele may confer protection for AIDs, particularly for systemic and rheumatic disease. The protective effect of HLA-DRB1(∗)13 could be explained by a more proficient antigen presentation by these molecules, favouring efficient clonal deletion during thymic selection.

  2. Anthrax Lethal Factor as an Immune Target in Humans and Transgenic Mice and the Impact of HLA Polymorphism on CD4+ T Cell Immunity

    PubMed Central

    Ascough, Stephanie; Ingram, Rebecca J.; Chu, Karen K.; Reynolds, Catherine J.; Musson, Julie A.; Doganay, Mehmet; Metan, Gökhan; Ozkul, Yusuf; Baillie, Les; Sriskandan, Shiranee; Moore, Stephen J.; Gallagher, Theresa B.; Dyson, Hugh; Williamson, E. Diane; Robinson, John H.; Maillere, Bernard; Boyton, Rosemary J.; Altmann, Daniel M.

    2014-01-01

    Bacillus anthracis produces a binary toxin composed of protective antigen (PA) and one of two subunits, lethal factor (LF) or edema factor (EF). Most studies have concentrated on induction of toxin-specific antibodies as the correlate of protective immunity, in contrast to which understanding of cellular immunity to these toxins and its impact on infection is limited. We characterized CD4+ T cell immunity to LF in a panel of humanized HLA-DR and DQ transgenic mice and in naturally exposed patients. As the variation in antigen presentation governed by HLA polymorphism has a major impact on protective immunity to specific epitopes, we examined relative binding affinities of LF peptides to purified HLA class II molecules, identifying those regions likely to be of broad applicability to human immune studies through their ability to bind multiple alleles. Transgenics differing only in their expression of human HLA class II alleles showed a marked hierarchy of immunity to LF. Immunogenicity in HLA transgenics was primarily restricted to epitopes from domains II and IV of LF and promiscuous, dominant epitopes, common to all HLA types, were identified in domain II. The relevance of this model was further demonstrated by the fact that a number of the immunodominant epitopes identified in mice were recognized by T cells from humans previously infected with cutaneous anthrax and from vaccinated individuals. The ability of the identified epitopes to confer protective immunity was demonstrated by lethal anthrax challenge of HLA transgenic mice immunized with a peptide subunit vaccine comprising the immunodominant epitopes that we identified. PMID:24788397

  3. Anthrax lethal factor as an immune target in humans and transgenic mice and the impact of HLA polymorphism on CD4+ T cell immunity.

    PubMed

    Ascough, Stephanie; Ingram, Rebecca J; Chu, Karen K; Reynolds, Catherine J; Musson, Julie A; Doganay, Mehmet; Metan, Gökhan; Ozkul, Yusuf; Baillie, Les; Sriskandan, Shiranee; Moore, Stephen J; Gallagher, Theresa B; Dyson, Hugh; Williamson, E Diane; Robinson, John H; Maillere, Bernard; Boyton, Rosemary J; Altmann, Daniel M

    2014-05-01

    Bacillus anthracis produces a binary toxin composed of protective antigen (PA) and one of two subunits, lethal factor (LF) or edema factor (EF). Most studies have concentrated on induction of toxin-specific antibodies as the correlate of protective immunity, in contrast to which understanding of cellular immunity to these toxins and its impact on infection is limited. We characterized CD4+ T cell immunity to LF in a panel of humanized HLA-DR and DQ transgenic mice and in naturally exposed patients. As the variation in antigen presentation governed by HLA polymorphism has a major impact on protective immunity to specific epitopes, we examined relative binding affinities of LF peptides to purified HLA class II molecules, identifying those regions likely to be of broad applicability to human immune studies through their ability to bind multiple alleles. Transgenics differing only in their expression of human HLA class II alleles showed a marked hierarchy of immunity to LF. Immunogenicity in HLA transgenics was primarily restricted to epitopes from domains II and IV of LF and promiscuous, dominant epitopes, common to all HLA types, were identified in domain II. The relevance of this model was further demonstrated by the fact that a number of the immunodominant epitopes identified in mice were recognized by T cells from humans previously infected with cutaneous anthrax and from vaccinated individuals. The ability of the identified epitopes to confer protective immunity was demonstrated by lethal anthrax challenge of HLA transgenic mice immunized with a peptide subunit vaccine comprising the immunodominant epitopes that we identified.

  4. HLA antigens and Berger's disease.

    PubMed

    Bignon, J D; Houssin, A; Soulillou, J P; Denis, J; Guimbretiere, J; Guenel, J

    1980-07-01

    We have studied the frequencies of HLA-A, -B antigens in 73 Berger's disease patients, plus HLA-DR antigens in 35 of them, and compared the percentages of antigens frequencies with those of a local and national panel. This study does not confirm the positive associations with HLA-Bw35 or HLA-B12 which have been previously reported. The HLA-DR typing only showed increased frequency of blanks in the patients (P smaller than 0.01, but no significant corr.P). Patients with Berger's disease and renal failure have a higher (but still not significant) HLA-Bw35 frequency than those without renal failure. The reasons for the discrepancy between our group and others are analysed.

  5. Tumour necrosis factor microsatellites and HLA-DRB1*, HLA-DQA1*, and HLA-DQB1* alleles in Peruvian patients with rheumatoid arthritis

    PubMed Central

    Castro, F; Acevedo, E; Ciusani, E; Angulo, J; Wollheim, F; Sandberg-Wollheim, M

    2001-01-01

    OBJECTIVE—To study the association between rheumatoid arthritis (RA) and HLA and tumour necrosis factor (TNF) polymorphism in Peruvian mestizo patients in comparison with ethnically similar controls.
METHODS—Seventy nine patients with RA and 65 ethnically matched healthy controls were genotyped for HLA-DRB1, HLA-DQA1, HLA-DQB1, and TNFα and TNFβ alleles using PCR amplification. Clinical severity was assessed as mild, moderate, or severe in 35 of the patients.
RESULTS—TNFα6 showed the strongest association with disease susceptibility. The TNFα6 allele was more common in patients than in controls (p<0.0076) and the proportion of patients with at least one copy of this allele was greater (p<0.015, relative risk 2.35). Among the HLA-DRB1* alleles with the shared epitope sequence, only the DRB1*1402 allele was significantly increased in patients compared with controls (p<0.0311), as was the proportion of patients with at least one copy of this allele (p<0.0232, relative risk 2.74). In contrast, the overall frequency of alleles with the shared epitope was not different in patients and controls. The haplotype HLA-DRB1*1402-DQB1*0301-DQA1*0401 was significantly more common in patients. TNFα6 was more common in patients whether or not they had this haplotype. None of the 11 patients lacking the TNFα6 allele had severe disease.
CONCLUSIONS—This study shows for the first time that TNF gene polymorphism is associated with susceptibility to RA in a non-white population. TNFα6 and HLA-DRB1*1402 independently conferred significantly increased risk in Peruvian mestizo patients.

 PMID:11454644

  6. HLA-DR phenotypes in Spanish coeliac children: their contribution to the understanding of the genetics of the disease.

    PubMed Central

    Mearin, M L; Biemond, I; Peña, A S; Polanco, I; Vazquez, C; Schreuder, G T; de Vries, R R; van Rood, J J

    1983-01-01

    The DR-locus controlled B-cell antigens were studied in 163 unrelated Spanish coeliac children and 68 families of this group, nine of them with more than one coeliac patient, to obtain more information about the association between these antigens and coeliac disease. The results show that the most common coeliac phenotypes are DR3/DR7, DR7/DR5, DR3/other DR, and DR3/DR3. The family study confirmed the segregation of the disease with the above mentioned phenotypes. In eight of the nine multiple case families, all coeliac children shared both HLA-DR antigens. These findings make it unlikely that a single dominant gene linked to HLA-DR controls the susceptibility to coeliac disease. The phenotypes in the patients were not distributed according to the Hardy-Weinberg equilibrium. Thus, a model based on one recessive susceptibility gene linked to HLA-DR is not probable either. The complexity of the genetics of coeliac disease and some of the features shared with the HLA-DR pattern in juvenile insulin-dependent diabetes are discussed. PMID:6602084

  7. HLA-DRB and HLA-DQB Allele and Haplotype Frequencies in Iranian Patients with Recurrent Aphthous Stomatitis.

    PubMed

    Najafi, Shamsolmoulouk; Mohammadzadeh, Mahsa; Zare Bidoki, Alireza; Meighani, Ghasem; Aslani, Saeed; Mahmoudi, Mahdi; Rezaei, Nima

    Recurrent aphthous stomatitis (RAS) is known as the most common chronic disease of the oral cavity, which affects a range of 5-25% of the population. RAS appears to be associated with some human leukocyte antigen (HLA) class II alleles and haplotypes. This study attempts to survey the distribution of HLA-DRB and -DQB alleles among Iranian RAS patients and healthy controls. In order to evaluate the association of HLA-DR and DQ alleles and haplotypes, 54 patients with RAS and 100 unrelated healthy subjects as control group were investigated. Our data indicated that DRB1*13:17, DRB1*15:01, and DRB5*01 were significantly more frequent in RAS patients in comparison to controls. However, DRB3:01allele frequency was higher in the controls compared to the patients. The significantly frequent allele in the patients compared with the healthy subjects was HLA-DQB1*03:02. However, both HLA-DQB1*02:01 and HLA-DQB1*03:01 alleles were most frequent in the healthy individuals rather than the patients. The DRB*04/DQB1*03:01 and DRB*01:01/DQB1*02:01 haplotypes were significantly distributed in healthy subjects compared with patients. However, DRB*07:01/DQB1*03:02 haplotype was found to be significantly frequent in patients than controls. In respect of HLA genes, factors are involved in the incidence of RAS; various HLA-DRB and HLA-DQB1 alleles and the related haplotypes are suggested to be the three main RAS susceptibility factors in our population study.

  8. HLA Class I and II alleles, heterozygosity and HLA-KIR interactions are associated with rates of genital HSV shedding and lesions.

    PubMed

    Magaret, A; Dong, L; John, M; Mallal, S A; James, I; Warren, T; Gaudieri, S; Koelle, D M; Wald, A

    2016-12-01

    Variation at HLA and KIR loci is associated with the severity of viral infections. To assess associations of genital HSV-2 infection with human HLA and KIR genetic loci, we measured the frequencies of genital herpes simplex virus (HSV) DNA detection and of genital lesions in HSV-2 seropositive persons. We followed 267 HSV-2 seropositive persons who collected daily genital swabs and recorded lesions for ⩾30 days. All persons were laboratory-documented as HIV-seronegative, and all were Caucasian by self-report. HSV detection rate and lesion frequency were compared by genotype using Poisson regression. Overall, HSV was detected on 19.1% of days and lesions on 11.6% of days. The presence of HLA-A*01 was directly associated with HSV detection frequency, whereas the presence of HLA-C*12 was inversely associated with HSV detection frequency. The presence of HLA-A*01 was directly associated with lesion rate, while HLA-A*26, -C*01 and -DQB1*0106 were associated with decreased lesions. We observed an interaction between the absence of both 2DS4del and HLA-Bw4 and higher lesion rate. Heterozygosity of HLA was also associated with reduced lesion frequency. Immune control of genital HSV infection relies on multiple interacting immunogenetic elements, including epistatic interactions between HLA and KIR.

  9. Antigen presentation of the immunodominant T-cell epitope of the major mugwort pollen allergen, Art v 1, is associated with the expression of HLA-DRB1 *01.

    PubMed

    Jahn-Schmid, Beatrice; Fischer, Gottfried F; Bohle, Barbara; Faé, Ingrid; Gadermaier, Gabriele; Dedic, Azra; Ferreira, Fatima; Ebner, Christof

    2005-02-01

    Mugwort pollen allergens are the main cause of pollinosis in late summer in Europe. Ninety-five percent of patients allergic to mugwort are sensitized to the major allergen Art v 1. In contrast to other common pollen allergens that contain multiple T-cell epitopes, Art v 1 contains only 1 immunodominant T-cell epitope (Art v 1 25-36 ). To characterize the minimal epitope of Art v 1 25-36 and to investigate a possible association of Art v 1 reactivity with HLA class II phenotypes. Art v 1-specific T-cell lines and clones were established from 51 patients with clinically defined mugwort pollen allergy and IgE specific for Art v 1. To define minimal epitopes and binding sites within Art v 1 25-36 , truncated and single-substitution analog peptides were used for T-cell stimulation. To study HLA restriction, monoclonal anti-HLA antibodies and antigen-presenting cells with defined HLA-DRB and -DQB1 alleles were used. HLA typing of patients with allergy was performed by hybridization with sequence-specific oligonucleotides, PCR, and nucleotide sequencing. In 96% of the patients, a cellular response to Art v 1 25-36 was obtained, and a core region of 5 to 10 amino acids containing 3 to 5 amino acids essential for T-cell reactivity was defined. The frequency of HLA-DRB1 * 01 in patients recognizing Art v 1 25-36 was significantly increased as compared with healthy controls (69% vs 21%; odds ratio, 8.45; P < 10 -6 ), and HLA-DRB1 * 01 was identified as the main restriction element for the presentation of the immunodominant epitope. Allergy to Art v 1 is characterized by a uniform T-cell response. The disease is apparently associated with the HLA-DR1 phenotype. Therefore, mugwort pollinosis is an ideal candidate for a peptide-based immunotherapy.

  10. HLA-DR polymorphisms influence in vivo responses to staphylococcal toxic shock syndrome toxin-1 in a transgenic mouse model.

    PubMed

    Krogman, A; Tilahun, A; David, C S; Chowdhary, V R; Alexander, M P; Rajagopalan, G

    2017-01-01

    Toxic shock syndrome toxin-1 (TSST-1) is a potent superantigen produced by Staphylococcus aureus. In addition to menstrual and nonmenstrual toxic shock syndromes, TSST-1 is also implicated in the immunopathogenesis of pneumonia, infective endocarditis, neonatal exanthematous disease, and atopic dermatitis among others. Superantigens first bind to major histocompatibility complex (MHC) class II molecules and then activate a large proportion of T cells by cross-linking their T cell receptor. As binding to MHC class II molecules is a critical step in the robust activation of the immune system by TSST-1 and other superantigens, polymorphic variations between different HLA-DR alleles could potentially influence the magnitude of immune activation and immunopathology caused by TSST-1. As TSST-1 is highly toxic to humans and given that multiple variations of alleles of HLA-DR and HLA-DQ are expressed in each individual, it is difficult to determine how HLA-DR polymorphisms quantitatively and qualitatively impact immune activation caused by TSST-1 in humans. However, such investigations can be conducted on transgenic mice lacking all endogenous MHC class II molecules and expressing specific HLA class II alleles. Therefore, transgenic mice expressing different HLA-DRB1 alleles (HLA-DRB1*15:01, HLA-DRB1*15:02, HLA-DRB1*03:01, HLA-DRB1*04:01), and sharing HLA-A1*01:01 chain, were systemically challenged with purified TSST-1 and multiple immune parameters were assessed. Among the HLA-DR alleles, mice expressing HLA-DRB1*15:01 allele elicited a significantly higher serum cytokine/chemokine response; greater splenic T cell expansion and most severe organ pathology. Our study highlights the potential utility of human leukocyte antigen (HLA) transgenic mice in understanding the impact of HLA polymorphisms on the outcomes of diseases caused by TSST-1 and other superantigens. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  11. HLA-B7–Restricted Islet Epitopes Are Differentially Recognized in Type 1 Diabetic Children and Adults and Form Weak Peptide-HLA Complexes

    PubMed Central

    Scotto, Matthieu; Afonso, Georgia; Østerbye, Thomas; Larger, Etienne; Luce, Sandrine; Raverdy, Cécile; Novelli, Giulia; Bruno, Graziella; Gonfroy-Leymarie, Céline; Launay, Odile; Lemonnier, François A.; Buus, Søren; Carel, Jean-Claude; Boitard, Christian; Mallone, Roberto

    2012-01-01

    The cartography of β-cell epitopes targeted by CD8+ T cells in type 1 diabetic (T1D) patients remains largely confined to the common HLA-A2 restriction. We aimed to identify β-cell epitopes restricted by the HLA-B7 (B*07:02) molecule, which is associated with mild T1D protection. Using DNA immunization on HLA-B7–transgenic mice and prediction algorithms, we identified GAD and preproinsulin candidate epitopes. Interferon-γ (IFN-γ) enzyme-linked immunospot assays on peripheral blood mononuclear cells showed that most candidates were recognized by new-onset T1D patients, but not by type 2 diabetic and healthy subjects. Some epitopes were highly immunodominant and specific to either T1D children (GAD530–538; 44% T cell–positive patients) or adults (GAD311–320; 38%). All epitopes displayed weak binding affinity and stability for HLA-B7 compared with HLA-A2–restricted ones, a general feature of HLA-B7. Single-cell PCR analysis on β-cell–specific (HLA-B7 tetramer–positive) T cells revealed uniform IFN-γ and transforming growth factor-β (TGF-β) mRNA expression, different from HLA-A2–restricted T cells. We conclude that HLA-B7–restricted islet epitopes display weak HLA-binding profiles, are different in T1D children and adults, and are recognized by IFN-γ+TGF-β+CD8+ T cells. These features may explain the T1D-protective effect of HLA-B7. The novel epitopes identified should find valuable applications for immune staging of HLA-B7+ individuals. PMID:22997432

  12. 40 CFR 75.72 - Determination of NOX mass emissions for common stack and multiple stack configurations.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 40 Protection of Environment 17 2013-07-01 2013-07-01 false Determination of NOX mass emissions... ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) AIR PROGRAMS (CONTINUED) CONTINUOUS EMISSION MONITORING NOX Mass Emissions Provisions § 75.72 Determination of NOX mass emissions for common stack and multiple stack...

  13. 40 CFR 75.72 - Determination of NOX mass emissions for common stack and multiple stack configurations.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 40 Protection of Environment 17 2014-07-01 2014-07-01 false Determination of NOX mass emissions... ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) AIR PROGRAMS (CONTINUED) CONTINUOUS EMISSION MONITORING NOX Mass Emissions Provisions § 75.72 Determination of NOX mass emissions for common stack and multiple stack...

  14. Combining Multiple Performance Measures: Do Common Approaches Undermine Districts' Personnel Evaluation Systems? CALDER Working Paper No. 118

    ERIC Educational Resources Information Center

    Hansen, Michael; Lemke, Mariann; Sorensen, Nicholas

    2014-01-01

    Teacher and principal evaluation systems now emerging in response to federal, state and/or local policy initiatives typically require that a component of teacher evaluation be based on multiple performance metrics, which must be combined to produce summative ratings of teacher effectiveness. Districts have utilized three common approaches to…

  15. HLA typing demands for peptide-based anti-cancer vaccine.

    PubMed

    Nagorsen, Dirk; Thiel, Eckhard

    2008-12-01

    Immunological treatment of cancer has made some very promising advances during the last years. Anti-cancer vaccination using peptides or peptide-pulsed dendritic cells and adoptive transfer of in vitro generated, epitope-specific T cells depend on a well-fitting interaction of HLA molecule and epitope. Accurate HLA-typing is a key factor for successful anti-cancer vaccination. No comprehensive data and no suggestion exist on the HLA-typing in this setting. We performed a systematic review of PubMed analyzing HLA-typing data in cancer vaccination trials over the last 4 years (2004-2007). Then, using the SYFPEITHI database, we calculated the peptide binding prediction of the eight most often used HLA-A*0201 binding epitopes. Finally, high-resolution typing [by sequence-specific primers (SSP)] data of a HLA-A*02 or HLA-A*24 positive population in Berlin, Germany, were analyzed. Forty-five cancer vaccination trials with 764 patients were included. Eighteen studies were performed in the USA, 13 in Europe, 12 in Asia (mainly Japan), and two in Australia. Most common diseases targeted were melanoma, prostate cancer, colorectal cancer, renal cell cancer, and breast cancer. The trials tested protocols using peptide plus adjuvants without DC or protocols using peptide-pulsed DC. In 38 trials (84%) HLA-A2 positive patients were vaccinated, in 11 studies (24%) HLA-A24 positive patients were vaccinated. Nineteen studies with 291 patients (38%) presented the HLA type as four-digit code (high-resolution), 26 studies with 473 patients (62%) presented the HLA-type in a low-resolution code. The method of HLA determination was given in six out of 45 trials (13%). Using the SYFPEITHI database we calculated the peptide binding prediction of the eight most often used HLA-A*0201 binding tumor antigen-derived epitopes for binding to HLA-A*0203. While the epitopes had a binding score of 17-28 for HLA-A*0201, the score for binding to HLA-A*0203 was zero in seven out of eight tested peptides

  16. We Don't Live in a Multiple-Choice World: Inquiry and the Common Core

    ERIC Educational Resources Information Center

    Jaeger, Paige

    2012-01-01

    The Common Core raises the bar for states struggling to decide what should be taught or tested. As low-performing schools strive to improve instruction, the blueprint has been defined. The Common Core defines the curriculum in enough detail and specifies ways to teach that content creatively and innovatively, to produce graduates who are problem…

  17. We Don't Live in a Multiple-Choice World: Inquiry and the Common Core

    ERIC Educational Resources Information Center

    Jaeger, Paige

    2012-01-01

    The Common Core raises the bar for states struggling to decide what should be taught or tested. As low-performing schools strive to improve instruction, the blueprint has been defined. The Common Core defines the curriculum in enough detail and specifies ways to teach that content creatively and innovatively, to produce graduates who are problem…

  18. Modeling Habitat Associations for the Common Loon (Gavia immer) at Multiple Scales in Northeastern North America

    EPA Science Inventory

    The Common Loon (Gavia immer) is considered an emblematic and ecologically important example of aquatic-dependent wildlife in North America. The northern breeding range of Common Loons has contracted over the last century, presumably as a result of habitat degradation from human ...

  19. Modeling Habitat Associations for the Common Loon (Gavia immer) at Multiple Scales in Northeastern North America

    EPA Science Inventory

    The Common Loon (Gavia immer) is considered an emblematic and ecologically important example of aquatic-dependent wildlife in North America. The northern breeding range of Common Loons has contracted over the last century, presumably as a result of habitat degradation from human ...

  20. HLA-B alleles of the Cayapa of Ecuador: new B39 and B15 alleles.

    PubMed

    Garber, T L; Butler, L M; Trachtenberg, E A; Erlich, H A; Rickards, O; De Stefano, G; Watkins, D I

    1995-01-01

    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.

  1. 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.

  2. An Evaluation of the High Level Architecture (HLA) as a Framework for NASA Modeling and Simulation

    NASA Technical Reports Server (NTRS)

    Reid, Michael R.; Powers, Edward I. (Technical Monitor)

    2000-01-01

    The High Level Architecture (HLA) is a current US Department of Defense and an industry (IEEE-1516) standard architecture for modeling and simulations. It provides a framework and set of functional rules and common interfaces for integrating separate and disparate simulators into a larger simulation. The goal of the HLA is to reduce software costs by facilitating the reuse of simulation components and by providing a runtime infrastructure to manage the simulations. In order to evaluate the applicability of the HLA as a technology for NASA space mission simulations, a Simulations Group at Goddard Space Flight Center (GSFC) conducted a study of the HLA and developed a simple prototype HLA-compliant space mission simulator. This paper summarizes the prototyping effort and discusses the potential usefulness of the HLA in the design and planning of future NASA space missions with a focus on risk mitigation and cost reduction.

  3. Structural and Dynamical Insights on HLA-DR2 Complexes That Confer Susceptibility to Multiple Sclerosis in Sardinia: A Molecular Dynamics Simulation Study

    PubMed Central

    Kumar, Amit; Cocco, Eleonora; Atzori, Luigi; Marrosu, Maria Giovanna; Pieroni, Enrico

    2013-01-01

    Sardinia is a major Island in the Mediterranean with a high incidence of multiple sclerosis, a chronic autoimmune inflammatory disease of the central nervous system. Disease susceptibility in Sardinian population has been associated with five alleles of major histocompatibility complex (MHC) class II DRB1 gene. We performed 120 ns of molecular dynamics simulation on one predisposing and one protective alleles, unbound and in complex with the two relevant peptides: Myelin Basic Protein and Epstein Barr Virus derived peptide. In particular we focused on the MHC peptide binding groove dynamics. The predisposing allele was found to form a stable complex with both the peptides, while the protective allele displayed stability only when bound with myelin peptide. The local flexibility of the MHC was probed dividing the binding groove into four compartments covering the well known peptide anchoring pockets. The predisposing allele in the first half cleft exhibits a narrower and more rigid groove conformation in the presence of myelin peptide. The protective allele shows a similar behavior, while in the second half cleft it displays a narrower and more flexible groove conformation in the presence of viral peptide. We further characterized these dynamical differences by evaluating H-bonds, hydrophobic and stacking interaction networks, finding striking similarities with super-type patterns emerging in other autoimmune diseases. The protective allele shows a defined preferential binding to myelin peptide, as confirmed by binding free energy calculations. All together, we believe the presented molecular analysis could help to design experimental assays, supports the molecular mimicry hypothesis and suggests that propensity to multiple sclerosis in Sardinia could be partly linked to distinct peptide-MHC interaction and binding characteristics of the antigen presentation mechanism. PMID:23555757

  4. POPULATION MODELS FOR ASSESSING RISKS OF MULTIPLE STRESSORS TO THE COMMON LOON

    EPA Science Inventory

    As part of a demonstration project focusing on the Common Loon (Gavia immer), the U.S. Environmental Protection Agency's National Health and Environmental Effects Research Laboratory is using a matrix population modeling framework to integrate demographic information for extrapol...

  5. POPULATION MODELS FOR ASSESSING RISKS OF MULTIPLE STRESSORS TO THE COMMON LOON

    EPA Science Inventory

    As part of a demonstration project focusing on the Common Loon (Gavia immer), the U.S. Environmental Protection Agency's National Health and Environmental Effects Research Laboratory is using a matrix population modeling framework to integrate demographic information for extrapol...

  6. Association Between HLA Type and Skin Cancer in Kidney Transplant Recipients.

    PubMed

    Cegielska, A; Dębska-Ślizień, A; Moszkowska, G; Imko-Walczuk, B; Rutkowski, B

    2016-06-01

    Organ transplant recipients (OTRs) are more susceptible to various diseases, among them cancers. Nonmelanoma skin cancers (NMSC) represent the most common malignancies in OTRs in Europe. Due to the significantly higher morbidity, aggressive and rapid progression, and poor prognosis of NMSC in the OTR population, these patients require a special oncological approach. Intensive attention should therefore be paid to factors predisposing OTRs to the development of cancer. The aim of this study was to establish the role of genetic factors in the pathogenesis of skin cancer in kidney transplant recipients (KTRs). This single-center study was performed in 39 KTRs with posttransplant NMSC. The frequency of particular types of HLA Class I (HLA-A and HLA-B) and Class II (HLA-DR) in each group were compared to establish the association between the HLA type and risk of skin cancer after renal transplantation. HLA-DR15 were more commonly detected in patients with MNSC than in the control group of KTRs (P = .014) There was also a positive correlation between HLA-B18 and skin squamous cell carcinoma. The antigen was more often recorded in KTRs with squamous cell carcinoma than in KTRs without NMSC (P = .03) and in the general population (P = .002). Patients who are positive for HLA-BR15 and HLA-B18 should be under special dermatologic surveillance due to the potentially high risk of skin cancer. Copyright © 2016 Elsevier Inc. All rights reserved.

  7. Multiple personality disorder and borderline personality disorder. Distinct entities or variations on a common theme?

    PubMed

    Lauer, J; Black, D W; Keen, P

    1993-06-01

    We report data from a comparison of 14 subjects with multiple personality disorder (MPD) and 13 subjects with borderline personality disorder (BPD). There were few significant differences between the groups. The authors discuss the concept of MPD as an epiphenomenon of BPD, and argue their fundamental similarity.

  8. In silico analysis of HLA associations with drug-induced liver injury: use of a HLA-genotyped DNA archive from healthy volunteers.

    PubMed

    Alfirevic, Ana; Gonzalez-Galarza, Faviel; Bell, Catherine; Martinsson, Klara; Platt, Vivien; Bretland, Giovanna; Evely, Jane; Lichtenfels, Maike; Cederbrant, Karin; French, Neil; Naisbitt, Dean; Park, B Kevin; Jones, Andrew R; Pirmohamed, Munir

    2012-06-25

    Drug-induced liver injury (DILI) is one of the most common adverse reactions leading to product withdrawal post-marketing. Recently, genome-wide association studies have identified a number of human leukocyte antigen (HLA) alleles associated with DILI; however, the cellular and chemical mechanisms are not fully understood. To study these mechanisms, we established an HLA-typed cell archive from 400 healthy volunteers. In addition, we utilized HLA genotype data from more than four million individuals from publicly accessible repositories such as the Allele Frequency Net Database, Major Histocompatibility Complex Database and Immune Epitope Database to study the HLA alleles associated with DILI. We utilized novel in silico strategies to examine HLA haplotype relationships among the alleles associated with DILI by using bioinformatics tools such as NetMHCpan, PyPop, GraphViz, PHYLIP and TreeView. We demonstrated that many of the alleles that have been associated with liver injury induced by structurally diverse drugs (flucloxacillin, co-amoxiclav, ximelagatran, lapatinib, lumiracoxib) reside on common HLA haplotypes, which were present in populations of diverse ethnicity. Our bioinformatic analysis indicates that there may be a connection between the different HLA alleles associated with DILI caused by therapeutically and structurally different drugs, possibly through peptide binding of one of the HLA alleles that defines the causal haplotype. Further functional work, together with next-generation sequencing techniques, will be needed to define the causal alleles associated with DILI.

  9. In silico analysis of HLA associations with drug-induced liver injury: use of a HLA-genotyped DNA archive from healthy volunteers

    PubMed Central

    2012-01-01

    Background Drug-induced liver injury (DILI) is one of the most common adverse reactions leading to product withdrawal post-marketing. Recently, genome-wide association studies have identified a number of human leukocyte antigen (HLA) alleles associated with DILI; however, the cellular and chemical mechanisms are not fully understood. Methods To study these mechanisms, we established an HLA-typed cell archive from 400 healthy volunteers. In addition, we utilized HLA genotype data from more than four million individuals from publicly accessible repositories such as the Allele Frequency Net Database, Major Histocompatibility Complex Database and Immune Epitope Database to study the HLA alleles associated with DILI. We utilized novel in silico strategies to examine HLA haplotype relationships among the alleles associated with DILI by using bioinformatics tools such as NetMHCpan, PyPop, GraphViz, PHYLIP and TreeView. Results We demonstrated that many of the alleles that have been associated with liver injury induced by structurally diverse drugs (flucloxacillin, co-amoxiclav, ximelagatran, lapatinib, lumiracoxib) reside on common HLA haplotypes, which were present in populations of diverse ethnicity. Conclusions Our bioinformatic analysis indicates that there may be a connection between the different HLA alleles associated with DILI caused by therapeutically and structurally different drugs, possibly through peptide binding of one of the HLA alleles that defines the causal haplotype. Further functional work, together with next-generation sequencing techniques, will be needed to define the causal alleles associated with DILI. PMID:22732016

  10. Recommendations for HLA-B*15:02 and HLA-A*31:01 genetic testing to reduce the risk of carbamazepine-induced hypersensitivity reactions.

    PubMed

    Amstutz, Ursula; Shear, Neil H; Rieder, Michael J; Hwang, Soomi; Fung, Vincent; Nakamura, Hidefumi; Connolly, Mary B; Ito, Shinya; Carleton, Bruce C

    2014-04-01

    To systematically review evidence on genetic risk factors for carbamazepine (CBZ)-induced hypersensitivity reactions (HSRs) and provide practice recommendations addressing the key questions: (1) Should genetic testing for HLA-B*15:02 and HLA-A*31:01 be performed in patients with an indication for CBZ therapy to reduce the occurrence of CBZ-induced HSRs? (2) Are there subgroups of patients who may benefit more from genetic testing for HLA-B*15:02 or HLA-A*31:01 compared to others? (3) How should patients with an indication for CBZ therapy be managed based on their genetic test results? A systematic literature search was performed for HLA-B*15:02 and HLA-A*31:01 and their association with CBZ-induced HSRs. Evidence was critically appraised and clinical practice recommendations were developed based on expert group consensus. Patients carrying HLA-B*15:02 are at strongly increased risk for CBZ-induced Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) in populations where HLA-B*15:02 is common, but not CBZ-induced hypersensitivity syndrome (HSS) or maculopapular exanthema (MPE). HLA-B*15:02-positive patients with CBZ-SJS/TEN have been reported from Asian countries only, including China, Thailand, Malaysia, and India. HLA-B*15:02 is rare among Caucasians or Japanese; no HLA-B*15:02-positive patients with CBZ-SJS/TEN have been reported so far in these groups. HLA-A*31:01-positive patients are at increased risk for CBZ-induced HSS and MPE, and possibly SJS/TEN and acute generalized exanthematous pustulosis (AGEP). This association has been shown in Caucasian, Japanese, Korean, Chinese, and patients of mixed origin; however, HLA-A*31:01 is common in most ethnic groups. Not all patients carrying either risk variant develop an HSR, resulting in a relatively low positive predictive value of the genetic tests. This review provides the latest update on genetic markers for CBZ HSRs, clinical practice recommendations as a basis for informed decision making regarding

  11. Non-HLA type 1 diabetes genes modulate disease risk together with HLA-DQ and islet autoantibodies

    PubMed Central

    Maziarz, M; Hagopian, W; Palmer, JP; Sanjeevi, CB; Kockum, I; Breslow, N; Lernmark, Å

    2015-01-01

    The possible interrelations between HLA-DQ, non-HLA single nucleotide polymorphisms (SNPs) and islet autoantibodies were investigated at clinical onset in 1-34 year old type 1 diabetes (T1D) patients (n=305) and controls (n=203). Among the non-HLA SNPs reported by the Type 1 Diabetes Genetics Consortium, 24% were supported in this Swedish replication set including that the increased risk of minor PTPN22 allele and high risk HLA was modified by GAD65 autoantibodies. The association between T1D and the minor AA+AC genotype in ERBB3 gene was stronger among IA-2 autoantibody-positive patients (comparison p=0.047). The association between T1D and the common insulin (AA) genotype was stronger among insulin autoantibody (IAA)-positive patients (comparison p=0.008). In contrast, the association between T1D and unidentified 26471 gene was stronger among IAA-negative (comparison p=0.049) and IA-2 autoantibody-negative (comparison p=0.052) patients. Finally, the association between IL2RA and T1D was stronger among IAA-positive than among IAA-negative patients (comparison p=0.028). These results suggest that the increased risk of T1D by non-HLA genes is often modified by both islet autoantibodies and HLA-DQ. The interactions between non-HLA genes, islet autoantibodies and HLA-DQ should be taken into account in T1D prediction studies as well as in prevention trials aimed at inducing immunological tolerance to islet autoantigens. PMID:26513234

  12. Common colorectal cancer risk alleles contribute to the multiple colorectal adenoma phenotype, but do not influence colonic polyposis in FAP.

    PubMed

    Cheng, Timothy H T; Gorman, Maggie; Martin, Lynn; Barclay, Ella; Casey, Graham; Saunders, Brian; Thomas, Huw; Clark, Sue; Tomlinson, Ian

    2015-02-01

    The presence of multiple (5-100) colorectal adenomas suggests an inherited predisposition, but the genetic aetiology of this phenotype is undetermined if patients test negative for Mendelian polyposis syndromes such as familial adenomatous polyposis (FAP) and MUTYH-associated polyposis (MAP). We investigated whether 18 common colorectal cancer (CRC) predisposition single-nucleotide polymorphisms (SNPs) could help to explain some cases with multiple adenomas who phenocopied FAP or MAP, but had no pathogenic APC or MUTYH variant. No multiple adenoma case had an outlying number of CRC SNP risk alleles, but multiple adenoma patients did have a significantly higher number of risk alleles than population controls (P=5.7 × 10(-7)). The association was stronger in those with ≥10 adenomas. The CRC SNPs accounted for 4.3% of the variation in multiple adenoma risk, with three SNPs (rs6983267, rs10795668, rs3802842) explaining 3.0% of the variation. In FAP patients, the CRC risk score did not differ significantly from the controls, as we expected given the overwhelming effect of pathogenic germline APC variants on the phenotype of these cases. More unexpectedly, we found no evidence that the CRC SNPs act as modifier genes for the number of colorectal adenomas in FAP patients. In conclusion, common colorectal tumour risk alleles contribute to the development of multiple adenomas in patients without pathogenic germline APC or MUTYH variants. This phenotype may have 'polygenic' or monogenic origins. The risk of CRC in relatives of multiple adenoma cases is probably much lower for cases with polygenic disease, and this should be taken into account when counselling such patients.

  13. HLA-A*0201, HLA-A*1101, and HLA-B*0702 transgenic mice recognize numerous poxvirus determinants from a wide variety of viral gene products.

    PubMed

    Pasquetto, Valerie; Bui, Huynh-Hoa; Giannino, Rielle; Banh, Cindy; Mirza, Fareed; Sidney, John; Oseroff, Carla; Tscharke, David C; Irvine, Kari; Bennink, Jack R; Peters, Bjoern; Southwood, Scott; Cerundolo, Vincenzo; Grey, Howard; Yewdell, Jonathan W; Sette, Alessandro

    2005-10-15

    In virus models explored in detail in mice, CTL typically focus on a few immunodominant determinants. In this study we use a multipronged approach to understand the diversity of CTL responses to vaccinia virus, a prototypic poxvirus with a genome approximately 20-fold larger than that of the model RNA viruses typically studied in mice. Based on predictive computational algorithms for peptide binding to HLA supertypes, we synthesized a panel of 2889 peptides to begin to create an immunomic map of human CTL responses to poxviruses. Using this panel in conjunction with CTLs from vaccinia virus-infected HLA transgenic mice, we identified 14 HLA-A*0201-, 4 HLA-A*1101-, and 3 HLA-B*0702-restricted CD8(+) T cell determinants distributed over 20 distinct proteins. These peptides were capable of binding one or multiple A2, A3, and B7 supertype molecules with affinities typical of viral determinants. Surprisingly, many of the viral proteins recognized are predicted to be late gene products, in addition to the early intermediate gene products expected. Nearly all of the determinants identified have identical counterparts encoded by modified vaccinia virus Ankara as well as variola virus, the agent of smallpox. These findings have implications for the design of new smallpox vaccines and the understanding of immune responses to large DNA viruses in general.

  14. Multiple mutations in a specific gene in a small geographic area: A common phenomenon

    SciTech Connect

    Zlotogora, J.; Bach, G.; Gieselmann, V.

    1996-01-01

    We read with interest the article from Allamand et al., which demonstrates in a genetic isolate the presence of at least six different haplotypes in the limb-girdle muscular dystrophy type 2A chromosome. Several hypotheses were proposed by the authors to explain this finding, but, after the identification of calpain, the gene involved in the disorder, multiple mutations were proved to be at the origin of this observation. The authors proposed that both the presence of multiple distinct calpain mutations within the Reunion Island pedigrees and the relatively low frequency of the disease in the isolate may be explained by a digenic inheritance of the disorder. Their hypothesis postulates that, although calpain mutations may be frequent in all populations, the disease manifestations are controlled by another frequently mutated nuclear or mitochondrial gene in the Reunion isolate. 8 refs.

  15. A practical discussion to avoid common pitfalls when constructing multiple choice questions items

    PubMed Central

    Al-Faris, Eiad A.; Alorainy, Ibrahim A.; Abdel-Hameed, Ahmad A.; Al-Rukban, Mohammed O.

    2010-01-01

    This paper is an attempt to produce a guide for improving the quality of Multiple Choice Questions (MCQs) used in undergraduate and postgraduate assessment. Multiple Choice Questions type is the most frequently used type of assessment worldwide. Well constructed, context rich MCQs have a high reliability per hour of testing. Avoidance of technical items flaws is essential to improve the validity evidence of MCQs. Technical item flaws are essentially of two types (i) related to testwiseness, (ii) related to irrelevant difficulty. A list of such flaws is presented together with discussion of each flaw and examples to facilitate learning of this paper and to make it learner friendly. This paper was designed to be interactive with self-assessment exercises followed by the key answer with explanations. PMID:21359033

  16. Statistical inference from multiple iTRAQ experiments without using common reference standards.

    PubMed

    Herbrich, Shelley M; Cole, Robert N; West, Keith P; Schulze, Kerry; Yager, James D; Groopman, John D; Christian, Parul; Wu, Lee; O'Meally, Robert N; May, Damon H; McIntosh, Martin W; Ruczinski, Ingo

    2013-02-01

    Isobaric tags for relative and absolute quantitation (iTRAQ) is a prominent mass spectrometry technology for protein identification and quantification that is capable of analyzing multiple samples in a single experiment. Frequently, iTRAQ experiments are carried out using an aliquot from a pool of all samples, or "masterpool", in one of the channels as a reference sample standard to estimate protein relative abundances in the biological samples and to combine abundance estimates from multiple experiments. In this manuscript, we show that using a masterpool is counterproductive. We obtain more precise estimates of protein relative abundance by using the available biological data instead of the masterpool and do not need to occupy a channel that could otherwise be used for another biological sample. In addition, we introduce a simple statistical method to associate proteomic data from multiple iTRAQ experiments with a numeric response and show that this approach is more powerful than the conventionally employed masterpool-based approach. We illustrate our methods using data from four replicate iTRAQ experiments on aliquots of the same pool of plasma samples and from a 406-sample project designed to identify plasma proteins that covary with nutrient concentrations in chronically undernourished children from South Asia.

  17. Statistical Inference from Multiple iTRAQ Experiments without Using Common Reference Standards

    PubMed Central

    Herbrich, Shelley M.; Cole, Robert N.; West, Keith P.; Schulze, Kerry; Yager, James D.; Groopman, John D.; Christian, Parul; Wu, Lee; O’Meally, Robert N.; May, Damon H.; McIntosh, Martin W.; Ruczinski, Ingo

    2014-01-01

    Isobaric tags for relative and absolute quantitation (iTRAQ) is a prominent mass spectrometry technology for protein identification and quantification that is capable of analyzing multiple samples in a single experiment. Frequently, iTRAQ experiments are carried out using an aliquot from a pool of all samples, or “masterpool”, in one of the channels as a reference sample standard to estimate protein relative abundances in the biological samples and to combine abundance estimates from multiple experiments. In this manuscript, we show that using a masterpool is counterproductive. We obtain more precise estimates of protein relative abundance by using the available biological data instead of the masterpool and do not need to occupy a channel that could otherwise be used for another biological sample. In addition, we introduce a simple statistical method to associate proteomic data from multiple iTRAQ experiments with a numeric response and show that this approach is more powerful than the conventionally employed masterpool-based approach. We illustrate our methods using data from four replicate iTRAQ experiments on aliquots of the same pool of plasma samples and from a 406-sample project designed to identify plasma proteins that covary with nutrient concentrations in chronically undernourished children from South Asia. PMID:23270375

  18. Multiple environmental stress tests show no common phenotypes shared among contemporary epidemic strains of Salmonella enterica.

    PubMed

    Kang, Min-Su; Besser, Thomas E; Hancock, Dale D; Call, Douglas R

    2007-05-01

    Phenotypic traits of coexisting epidemic and nonepidemic strains of Salmonella enterica serovars Typhimurium and Newport were compared. Different stress conditions were relatively more or less favorable for the epidemic strains. Transcriptional analysis identified specific upregulated genes during defined stress conditions, but there were no common traits shared by epidemic serovars.

  19. Hierarchical Multiple Regression in Counseling Research: Common Problems and Possible Remedies.

    ERIC Educational Resources Information Center

    Petrocelli, John V.

    2003-01-01

    A brief content analysis was conducted on the use of hierarchical regression in counseling research published in the "Journal of Counseling Psychology" and the "Journal of Counseling & Development" during the years 1997-2001. Common problems are cited and possible remedies are described. (Contains 43 references and 3 tables.) (Author)

  20. The effect of HLA homozygosity on rubella vaccine-induced humoral and cell-mediated immune responses

    PubMed Central

    Kennedy, Richard B.; Ovsyannikova, Inna G.; Vierkant, Robert A.; Jacobson, Robert M.; Poland, Gregory A.

    2009-01-01

    Human Leukocyte Antigen (HLA) genes play a critical role in host immunity including vaccine responses. HLA molecules present antigenic peptides to T cells and provide inhibitory signals to NK cells, and polymorphisms within HLA genes allows for binding and presentation of a diverse array of self and foreign peptides. Heterozygosity across HLA alleles has been found to play a positive role in host defense for a variety of infections. Homozygosity within one or more HLA loci may restrict this epitope repertoire and limit T cell responses to infection or vaccination. Here we report that homozygosity within the HLA DPB1 locus is associated with increased levels of rubella-specific IgG, an effect driven by a common allele DPB1*0401. We also show that homozygosity within different HLA class I and class II loci is correlated with variations (but not necessarily decreases) in IL-2, IL-5, and IL-10 secretion following rubella virus stimulation. PMID:19896518

  1. Association of HLA-A, -B, and -DRB1 with pulmonary tuberculosis in western Javanese Indonesia.

    PubMed

    Yuliwulandari, Rika; Sachrowardi, Qomariyah; Nakajima, Humiaki; Kashiwase, Koichi; Hirayasu, Kouyuki; Mabuchi, Akihiko; Sofro, Abdul Salam Mudzakir; Tokunaga, Katsushi

    2010-07-01

    Genetic studies of pulmonary tuberculosis (PTB), including those of human leukocyte antigen (HLA) genes, have been reported in several populations. Some studies also have reported these genes to have a stronger role in severe tuberculosis. We investigated HLA class I and II alleles and haplotypes to ascertain their role in susceptibility and resistance to new and recurrent PTB in 257 PTB patients (216 new and 41 recurrent PTB patients) and 236 healthy controls in Western Javanese (Indonesia). HLA-B*4006 was associated with new PTB (p = 0.044, p(adj) = ns), whereas HLA-B*1802, HLA-B*4001 and HLA-DRB1*1101 were associated with recurrent PTB (p = 0.013, p(adj) = 0.016; p = 0.015, p(adj) = 0.028; and p = 0.008, p(adj) = 0.027 for new PTB vs recurrent PTB, respectively). Except for HLA-B*4006, those associations remained significant after adjustment for age and gender by logistic regression analysis, although they disappeared after correction for multiple testing. Haplotype HLA-B*1802-DRB1*1202 was associated with susceptibility to recurrent PTB (p = 0.014, odds ratio = 3.8, 95% confidence interval = 1.18-12.27). In contrast, HLA-DRB1*1202 in the absence of HLA-B*1802 showed a significant association with resistance to recurrent PTB (p = 8.2 x 10(-4), odds ratio = 0.32, 95% confidence interval = 0.16-0.64), suggesting that stronger susceptibility effect of HLA-B*1802 masked the protective effect of HLA-DRB1*1202. Further studies using larger number of patients with recurrent PTB will be needed to confirm our findings.

  2. Candidate HLA genes for prediction of co-trimoxazole-induced severe cutaneous reactions.

    PubMed

    Kongpan, Thachanan; Mahasirimongkol, Surakameth; Konyoung, Parinya; Kanjanawart, Sirimas; Chumworathayi, Pansu; Wichukchinda, Nuanjun; Kidkeukarun, Runglak; Preechakul, Suphanlinee; Khunarkornsiri, Usanee; Bamrungram, Warawut; Supharatwattanakun, Butsaban; Mootsikapun, Piroon; Kwangsukstid, Supanida; Denjanta, Sukanda; Vannaprasaht, Suda; Rungapiromnan, Watcharee; Suwankesawong, Wimon; Tassaneeyakul, Wongwiwat; Tassaneeyakul, Wichittra

    2015-08-01

    Co-trimoxazole is a sulfonamide-containing antibiotic that is effective in the treatment of several infections and for prophylaxis of Pneumocystis jiroveci pneumonia. This drug has been reported as a common culprit drug for the Stevens-Johnson syndrome (SJS) and for toxic epidermal necrolysis (TEN). Human leukocyte antigens (HLAs) play a key role in the immunopathogenesis of severe cutaneous reactions induced by several drugs. This study investigated the association between the HLA class I and HLA-DRB1 polymorphisms and co-trimoxazole-induced SJS/TEN in a Thai population. Forty-three patients with co-trimoxazole-induced SJS/TEN and 91 co-trimoxazole-tolerant patients were enrolled in the study. HLA class I and HLA-DRB1 were genotyped using the reverse sequence-specific oligonucleotide probe method. The frequencies of three alleles of HLA, namely HLA-B*15:02, HLA-C*06:02, and HLA-C*08:01, were significantly higher in the co-trimoxazole-induced SJS/TEN group compared with controls. The risks for co-trimoxazole-induced SJS/TEN in patients with the HLA-B*15:02, HLA-C*06:02, or HLA-C*08:01 allele were about 3-11-fold higher when compared with those who did not carry one of these alleles. Individuals who carried the HLA-B*15:02-C*08:01 haplotype had a 14-fold higher risk for co-trimoxazole-induced SJS/TEN. Evidence of associations between co-trimoxazole-induced SJS/TEN and HLA alleles including HLA-B*15:02, HLA-C*06:02, and HLA-C*08:01 were found in the study population. These findings may suggest that apart from the HLA molecules, other molecules involved in the molecular pathogenesis of these severe cutaneous adverse drug reactions may play an important role in the susceptibility of individuals to SJS/TEN caused by co-trimoxazole.

  3. 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.

  4. One stone, two birds: managing multiple common warts on hands and face by local hyperthermia.

    PubMed

    Hu, Lanting; Qi, Ruiqun; Hong, Yuxiao; Huo, Wei; Chen, Hong-Duo; Gao, Xing-Hua

    2015-01-01

    A man developed with multiple warts on his hands and the inner canthus of his left eye. We applied local hyperthermia on a single target lesion on his hand at a surface temperature of 44 °C for 30 minutes on Days 1, 2, 3, 17, and 18. All the lesions treated with or without heat cleared 8 weeks after the last treatment. Treatment of a target lesion resolved all other untreated lesions, a fact suggestive that local hyperthermia could induce activation of specific immunity against human papillomavirus on the lesional skin, which lead to resolution of all the warts. © 2014 Wiley Periodicals, Inc.

  5. The construction of common and specific significance subnetworks of Alzheimer's disease from multiple brain regions.

    PubMed

    Kong, Wei; Mou, Xiaoyang; Zhang, Na; Zeng, Weiming; Li, Shasha; Yang, Yang

    2015-01-01

    Alzheimer's disease (AD) is a progressively and fatally neurodegenerative disorder and leads to irreversibly cognitive and memorial damage in different brain regions. The identification and analysis of the dysregulated pathways and subnetworks among affected brain regions will provide deep insights for the pathogenetic mechanism of AD. In this paper, commonly and specifically significant subnetworks were identified from six AD brain regions. Protein-protein interaction (PPI) data were integrated to add molecular biological information to construct the functional modules of six AD brain regions by Heinz algorithm. Then, the simulated annealing algorithm based on edge weight is applied to predicting and optimizing the maximal scoring networks for common and specific genes, respectively, which can remove the weak interactions and add the prediction of strong interactions to increase the accuracy of the networks. The identified common subnetworks showed that inflammation of the brain nerves is one of the critical factors of AD and calcium imbalance may be a link among several causative factors in AD pathogenesis. In addition, the extracted specific subnetworks for each brain region revealed many biologically functional mechanisms to understand AD pathogenesis.

  6. Biosynthesis of 2-Hydroxyethylphosphonate, an Unexpected Intermediate Common to Multiple Phosphonate Biosynthetic Pathways*S⃞

    PubMed Central

    Shao, Zengyi; Blodgett, Joshua A. V.; Circello, Benjamin T.; Eliot, Andrew C.; Woodyer, Ryan; Li, Gongyong; van der Donk, Wilfred A.; Metcalf, William W.; Zhao, Huimin

    2008-01-01

    Phosphonic acids encompass a common yet chemically diverse class of natural products that often possess potent biological activities. Here we report that, despite the significant structural differences among many of these compounds, their biosynthetic routes contain an unexpected common intermediate, 2-hydroxyethyl-phosphonate, which is synthesized from phosphonoacetaldehyde by a distinct family of metal-dependent alcohol dehydrogenases (ADHs). Although the sequence identity of the ADH family members is relatively low (34–37%), in vitro biochemical characterization of the homologs involved in biosynthesis of the antibiotics fosfomycin, phosphinothricin tripeptide, and dehydrophos (formerly A53868) unequivocally confirms their enzymatic activities. These unique ADHs have exquisite substrate specificity, unusual metal requirements, and an unprecedented monomeric quaternary structure. Further, sequence analysis shows that these ADHs form a monophyletic group along with additional family members encoded by putative phosphonate biosynthetic gene clusters. Thus, the reduction of phosphonoacetaldehyde to hydroxyethyl-phosphonate may represent a common step in the biosynthesis of many phosphonate natural products, a finding that lends insight into the evolution of phosphonate biosynthetic pathways and the chemical structures of new C–P containing secondary metabolites. PMID:18544530

  7. HLA Class I-T Cell Epitopes from trans-Sialidase Proteins Reveal Functionally Distinct Subsets of CD8+ T Cells in Chronic Chagas Disease

    PubMed Central

    Alvarez, María G.; Postan, Miriam; Weatherly, D. Brent; Albareda, María C.; Sidney, John; Sette, Alessandro; Olivera, Carina; Armenti, Alejandro H.

    2008-01-01

    Background Previously, we identified a set of HLA-A020.1-restricted trans-sialidase peptides as targets of CD8+ T cell responses in HLA-A0201+ individuals chronically infected by T. cruzi. Methods and Findings Herein, we report the identification of peptides encoded by the same trans-sialidase gene family that bind alleles representative of the 6 most common class I HLA-supertypes. Based on a combination of bioinformatic predictions and HLA-supertype considerations, a total of 1001 epitopes predicted to bind to HLA A01, A02, A03, A24, B7 and B44 supertypes was selected. Ninety-six supertype-binder epitopes encoded by multiple trans-sialidase genes were tested for the ability to stimulate a recall CD8+ T cell response in the peripheral blood from subjects with chronic T. cruzi infection regardless the HLA haplotype. An overall hierarchy of antigenicity was apparent, with the A02 supertype peptides being the most frequently recognized in the Chagas disease population followed by the A03 and the A24 supertype epitopes. CD8+ T cell responses to promiscuous epitopes revealed that the CD8+ T cell compartment specific for T. cruzi displays a functional profile with T cells secreting interferon-γ alone as the predominant pattern and very low prevalence of single IL-2-secreting or dual IFN-γ/IL-2 secreting T cells denoting a lack of polyfunctional cytokine responses in chronic T. cruzi infection. Conclusions This study identifies a set of T. cruzi peptides that should prove useful for monitoring immune competence and changes in infection and disease status in individuals with chronic Chagas disease. PMID:18846233

  8. Frequency of Class I and II HLA alleles in patients with lung cancer according to chemotherapy response and 5-year survival.

    PubMed

    Araz, Omer; Ucar, Elif Yilmazel; Meral, Mehmet; Yalcin, Aslıhan; Acemoglu, Hamit; Dogan, Hasan; Karaman, Adem; Aydin, Yener; Gorguner, Metin; Akgun, Metin

    2015-07-01

    Lung cancer is the most common cause of cancer death in the world, and the most common type is non-small-cell lung cancer (NSCLC). At present, surgical resection, chemotherapy, and radiation therapy are the main treatments for patients with NSCLC, but unfortunately outcome remains unsatisfactory. This study aimed to determine whether Class I and II histocompatibility leukocyte antigen (HLA) alleles are related with response to chemotherapy and survival of lung cancer. A total of 65 NSCLC patients (56 men and 9 women, mean age 58.4 ± 11 years) were included in the study. Patient groups were compared with a control group of 88 unrelated healthy kidney or bone marrow donors in order to clearly identify susceptible and protective HLA alleles in lung cancer. Target lesions and tumor response were assessed using the Response Evaluation Criteria for Solid Tumors (RECIST) guidelines. Results were classified into two groups: complete-partial response and stable-progressive disease. We found that expression of HLA-A32, HLA-B41, HLA-B57, HLA-DRB1*13, and HLA-DQ5 were more frequent in the complete and partial response groups to chemotherapy than in the control group. The frequency of HLA-A11, HLA-A29, HLA-BW6, HLA-CW3, HLA-DR1*1, and HLA-DRB1*3 were determined to be higher in the stable and progressive disease groups taking chemotherapy than in the control group. Additionally, expressions of HLA-A2 and HLA-B49 were statistically related with 5-year survival. Our results suggested that expressions of HLA-BW6 and HLA-DRB1*13 alleles may be predictable markers for response to chemotherapy in lung cancer patients. © 2014 John Wiley & Sons Ltd.

  9. Donor-specific HLA antibodies and graft function in children after renal transplantation.

    PubMed

    Miettinen, Jenni; Peräsaari, Juha; Lauronen, Jouni; Qvist, Erik; Valta, Helena; Pakarinen, Mikko; Merenmies, Jussi; Jalanko, Hannu

    2012-06-01

    The presence of circulating donor-specific human leukocyte antigen antibodies (HLA-DSA) has been associated with chronic antibody-mediated rejection, leading to progressive graft dysfunction and poor graft survival.The aim of this study was to investigate the incidence and significance of HLA-DSA in paediatric renal transplantation(RTx) patients. A total of 294 post-transplant serum samples from 123 RTx patients were retrospectively analysed for HLA antibodies. Positive samples were further tested for HLADSA by a Luminex Single Antigen bead assay. The antibody findings were correlated to measured glomerular filtration rate(GFR) and clinical outcome. HLA antibodies were detected in half of the routine samples (140/294) taken 1 month to 10 years after RTx, and 40% (62/140) of these were HLA-DSA. Overall, one-third(42/123) of the patients had HLA-DSA, which mostly(65%) reacted against class II antigens. Detection of HLADSA was not associated with poor GFR at the time of sampling, and no exceptional deterioration of GFR after the HLA-DSA detection was noted in individual patients regardless of the antibody level. The presence of HLA-DSA in the first 2 years posttransplantation was not associated with poorer graft function later on. Detection of HLA antibodies is common in children after RTx, and this finding, as such, does not predict any deterioration of graft function.

  10. NATO HLA Certification

    DTIC Science & Technology

    2002-06-01

    les M&S (NMSG), a été implantée au sein de l’organisation de recherche et technologie (RTO). Les activités du NMSG sont organisées selon un plan...le cadre de son plan d’action, le NMSG a décidé la création d’un groupe de travail chargé de comparer différentes possibilités pour implanter ... une capacité de certification de conformité au standard HLA des simulations développées et utilisées par l’OTAN. Ce groupe de travail (le MSG-011

  11. Common but unappreciated sources of error in one, two, and multiple-color pyrometry

    NASA Technical Reports Server (NTRS)

    Spjut, R. Erik

    1988-01-01

    The most common sources of error in optical pyrometry are examined. They can be classified as either noise and uncertainty errors, stray radiation errors, or speed-of-response errors. Through judicious choice of detectors and optical wavelengths the effect of noise errors can be minimized, but one should strive to determine as many of the system properties as possible. Careful consideration of the optical-collection system can minimize stray radiation errors. Careful consideration must also be given to the slowest elements in a pyrometer when measuring rapid phenomena.

  12. Common variable immunodeficiency (CVID): exploring the multiple dimensions of a heterogeneous disease.

    PubMed

    Salzer, Ulrich; Unger, Susanne; Warnatz, Klaus

    2012-02-01

    Common variable immunodeficiency (CVID) represents a large heterogeneous group of antibody deficiency syndromes associated with a plethora of clinical features and as yet largely undefined molecular causes. We are now seeing this heterogeneous group being increasingly defined into single-gene and polygenic disorders after stratification into homogeneous patient subgroups based on improved clinical and immunological criteria, including molecular, functional, immunohistological, and longitudinal and outcome information. In this perspective, we highlight recent developments in CVID, addressing mainly its genetic and immunological dimensions. © 2012 New York Academy of Sciences.

  13. Therapeutic approaches against common structural features of toxic oligomers shared by multiple amyloidogenic proteins.

    PubMed

    Guerrero-Muñoz, Marcos J; Castillo-Carranza, Diana L; Kayed, Rakez

    2014-04-15

    Impaired proteostasis is one of the main features of all amyloid diseases, which are associated with the formation of insoluble aggregates from amyloidogenic proteins. The aggregation process can be caused by overproduction or poor clearance of these proteins. However, numerous reports suggest that amyloid oligomers are the most toxic species, rather than insoluble fibrillar material, in Alzheimer's, Parkinson's, and Prion diseases, among others. Although the exact protein that aggregates varies between amyloid disorders, they all share common structural features that can be used as therapeutic targets. In this review, we focus on therapeutic approaches against shared features of toxic oligomeric structures and future directions. Copyright © 2014 Elsevier Inc. All rights reserved.

  14. Association of HLA-A*02:06 and HLA-DRB1*04:05 with clinical subtypes of juvenile idiopathic arthritis.

    PubMed

    Yanagimachi, Masakatsu; Miyamae, Takako; Naruto, Takuya; Hara, Takuma; Kikuchi, Masako; Hara, Ryoki; Imagawa, Tomoyuki; Mori, Masaaki; Kaneko, Tetsuji; Goto, Hiroaki; Morita, Satoshi; Mizuki, Nobuhisa; Kimura, Akinori; Yokota, Shumpei

    2011-03-01

    Juvenile idiopathic arthritis (JIA) is one of the most common forms of pediatric chronic arthritis. JIA is a clinically heterogeneous disease. Therefore, the genetic background of JIA may also be heterogeneous. The aim of this study was to investigate associations between human leukocyte antigen (HLA) and susceptibility to JIA and/or uveitis, which is one of the most devastating complications of JIA. A total of 106 Japanese articular JIA patients (67 with polyarthritis and 39 with oligoarthritis) and 678 healthy controls were genotyped for HLA-A, -B and -DRB1 by PCR-sequence-specific oligonucleotide probe methodology. HLA-A(*)02:06 was the risk factor for JIA accompanied by uveitis after adjustment for clinical factors (corrected P-value < 0.001, odds ratio (OR) 11.7, 95% confidence interval (CI) 3.2-43.0). On the other hand, HLA-DRB1(*)04:05 was associated with polyarticular JIA (corrected P-value < 0.001, OR 2.9, 95% CI 1.7-4.8). We found an association of HLA-A(*)02:06 with susceptibility to JIA accompanied by uveitis, which might be considered a separate clinical JIA entity. We also found an association between HLA-DRB1(*)04:05 and polyarticular JIA. Thus, clinical subtypes of JIA can be classified by the presence of the specific HLA alleles, HLA-A(*)02:06 and DRB1(*)04:05.

  15. Comparison of allele frequency for HLA-DR and HLA-DQ between patients with ECC and caries-free children.

    PubMed

    Bagherian, A; Nematollahi, H; Afshari, J T; Moheghi, N

    2008-03-01

    Early childhood caries (ECC) is one of the most common diseases of childhood. The etiology of ECC is multifactorial and both genetic and environmental factors play important roles in the pathogenesis of the disease. Genetic variations in the hosts may contribute to changes in the risk for dental caries. Genetic factors such as human leukocyte antigen (HLA) have recently been suggested as a predisposing factor. The aim of this study was to look for an association between HLA-DRB1 and HLA-DQB1 with ECC for developing new strategies for the diagnosis as well as the prevention of the disease. In this study, we extracted the genomic DNAs from whole blood samples of 44 patients with ECC and 35 caries-free children by the salting-out method. We amplified the genomic DNA by PCR-SSP and then HLA-typing was performed for all alleles. The results revealed a significant increase in the frequency of HLA-DRB1*04 in the patient group (P=0.019). The odds ratio for this allele was detected to be 10. The frequency of HLA-DQB1 alleles was not significantly different between the two groups. The above results suggest that HLA-DRB1*04 is associated with the susceptibility to ECC. Thus HLA-DRB1*04 detection as a molecular marker for early diagnosis of ECC may be recommended.

  16. The common marmoset as an indispensable animal model for immunotherapy development in multiple sclerosis.

    PubMed

    Kap, Yolanda S; Jagessar, S Anwar; Dunham, Jordon; 't Hart, Bert A

    2016-08-01

    New drugs often fail in the translation from the rodent experimental autoimmune encephalomyelitis (EAE) model to human multiple sclerosis (MS). Here, we present the marmoset EAE model as an indispensable model for translational research into MS. The genetic heterogeneity of this species and lifelong exposure to chronic latent infections and environmental pathogens create a human-like immune system. Unique to this model is the presence of the pathological hallmark of progressive MS, in particular cortical grey matter lesions. Another great possibility of this model is systemic and longitudinal immune profiling, whereas in humans and mice immune profiling is usually performed in a single compartment (i.e. blood or spleen, respectively). Overall, the marmoset model provides unique opportunities for systemic drug-effect profiling.

  17. Custom-designed AMLCD modules common to multiple platforms from consumer-oriented fabrication facility

    NASA Astrophysics Data System (ADS)

    Niemczyk, James

    2002-08-01

    The APC- LG-LCD relationship continues to expand with new products developed specifically for APC applications and also LG-LCD products developed for the consumer market, but adapted using APC enhancements for applications in the rugged world. Our delivery performance has proven that a superior, cost effective product can only be produced by incorporating product enhancements at the point of AMLCD manufacture. Further adaptations for specific applications can be simplified by utilizing the same part number panel for multiple platform uses. The manufacturing environment must be flexible enough to run multiple part numbers on a weekly basis. As such, manufacturing automation implemented at APC continues to strengthen our position as the world leader in custom AMLCD display modules. These automation initiatives are the direct result of APC learning the LG-LCD manufacturing method and applying these principals to our particular processes. The APC - LG-LCD relationship affords availability guarantees for display modules for a period of 10 years, thereby reducing procurement risk and minimizing costs associated with redesign when using consumer driven panels. This guarantee redefines the game rules for procurement of AMLCD's. We also offer a very quick turn for those customers who prefer to perform a lifetime buy of product. Typically, thousands of panels can be delivered within six months of a production go ahead. The APC -LC-LCD team remains successful due to the many years spent working together to develop and manufacture products that this niche market demands. The mutual respect for the technical and manufacturing operations at APC and LG-LCD continues to foster a relationship that time and again deliver superior, cost effective products to the market.

  18. A Next-Generation Sequencing Strategy for Evaluating the Most Common Genetic Abnormalities in Multiple Myeloma.

    PubMed

    Jiménez, Cristina; Jara-Acevedo, María; Corchete, Luis A; Castillo, David; Ordóñez, Gonzalo R; Sarasquete, María E; Puig, Noemí; Martínez-López, Joaquín; Prieto-Conde, María I; García-Álvarez, María; Chillón, María C; Balanzategui, Ana; Alcoceba, Miguel; Oriol, Albert; Rosiñol, Laura; Palomera, Luis; Teruel, Ana I; Lahuerta, Juan J; Bladé, Joan; Mateos, María V; Orfão, Alberto; San Miguel, Jesús F; González, Marcos; Gutiérrez, Norma C; García-Sanz, Ramón

    2017-01-01

    Identification and characterization of genetic alterations are essential for diagnosis of multiple myeloma and may guide therapeutic decisions. Currently, genomic analysis of myeloma to cover the diverse range of alterations with prognostic impact requires fluorescence in situ hybridization (FISH), single nucleotide polymorphism arrays, and sequencing techniques, which are costly and labor intensive and require large numbers of plasma cells. To overcome these limitations, we designed a targeted-capture next-generation sequencing approach for one-step identification of IGH translocations, V(D)J clonal rearrangements, the IgH isotype, and somatic mutations to rapidly identify risk groups and specific targetable molecular lesions. Forty-eight newly diagnosed myeloma patients were tested with the panel, which included IGH and six genes that are recurrently mutated in myeloma: NRAS, KRAS, HRAS, TP53, MYC, and BRAF. We identified 14 of 17 IGH translocations previously detected by FISH and three confirmed translocations not detected by FISH, with the additional advantage of breakpoint identification, which can be used as a target for evaluating minimal residual disease. IgH subclass and V(D)J rearrangements were identified in 77% and 65% of patients, respectively. Mutation analysis revealed the presence of missense protein-coding alterations in at least one of the evaluating genes in 16 of 48 patients (33%). This method may represent a time- and cost-effective diagnostic method for the molecular characterization of multiple myeloma. Copyright © 2017 American Society for Investigative Pathology and the Association for Molecular Pathology. Published by Elsevier Inc. All rights reserved.

  19. ProteomeCommons.org IO Framework: reading and writing multiple proteomics data formats.

    PubMed

    Falkner, J A; Falkner, J W; Andrews, P C

    2007-01-15

    Effective use of proteomics data, specifically mass spectrometry data, relies on the ability to read and write the many mass spectrometer file formats. Even with mass spectrometer vendor-specific libraries and vendor-neutral file formats, such as mzXML and mzData it can be difficult to extract raw data files in a form suitable for batch processing and basic research. Introduced here are the ProteomeCommons.org Input and Output Framework, abbreviated to IO Framework, which is designed to abstractly represent mass spectrometry data. This project is a public, open-source, free-to-use framework that supports most of the mass spectrometry data formats, including current formats, legacy formats and proprietary formats that require a vendor-specific library in order to operate. The IO Framework includes an on-line tool for non-programmers and a set of libraries that developers may use to convert between various proteomics file formats. The current source-code and documentation for the ProteomeCommons.org IO Framework is freely available at http://www.proteomecommons.org/current/531/

  20. Multiple modalities converge on a common gate to control K2P channel function.

    PubMed

    Bagriantsev, Sviatoslav N; Peyronnet, Rémi; Clark, Kimberly A; Honoré, Eric; Minor, Daniel L

    2011-07-15

    Members of the K(2P) potassium channel family regulate neuronal excitability and are implicated in pain, anaesthetic responses, thermosensation, neuroprotection, and mood. Unlike other potassium channels, K(2P)s are gated by remarkably diverse stimuli that include chemical, thermal, and mechanical modalities. It has remained unclear whether the various gating inputs act through separate or common channel elements. Here, we show that protons, heat, and pressure affect activity of the prototypical, polymodal K(2P), K(2P)2.1 (KCNK2/TREK-1), at a common molecular gate that comprises elements of the pore-forming segments and the N-terminal end of the M4 transmembrane segment. We further demonstrate that the M4 gating element is conserved among K(2P)s and is employed regardless of whether the gating stimuli are inhibitory or activating. Our results define a unique gating mechanism shared by K(2P) family members and suggest that their diverse sensory properties are achieved by coupling different molecular sensors to a conserved core gating apparatus.

  1. Multiple modalities converge on a common gate to control K2P channel function

    PubMed Central

    Bagriantsev, Sviatoslav N; Peyronnet, Rémi; Clark, Kimberly A; Honoré, Eric; Minor, Daniel L

    2011-01-01

    Members of the K2P potassium channel family regulate neuronal excitability and are implicated in pain, anaesthetic responses, thermosensation, neuroprotection, and mood. Unlike other potassium channels, K2Ps are gated by remarkably diverse stimuli that include chemical, thermal, and mechanical modalities. It has remained unclear whether the various gating inputs act through separate or common channel elements. Here, we show that protons, heat, and pressure affect activity of the prototypical, polymodal K2P, K2P2.1 (KCNK2/TREK-1), at a common molecular gate that comprises elements of the pore-forming segments and the N-terminal end of the M4 transmembrane segment. We further demonstrate that the M4 gating element is conserved among K2Ps and is employed regardless of whether the gating stimuli are inhibitory or activating. Our results define a unique gating mechanism shared by K2P family members and suggest that their diverse sensory properties are achieved by coupling different molecular sensors to a conserved core gating apparatus. PMID:21765396

  2. HLA-B27 Test

    MedlinePlus

    ... arthritis , juvenile rheumatoid arthritis (JRA) , or sometimes anterior uveitis . The HLA-B27 test is not a definitive ... form of arthritis that occurs in children. Anterior uveitis is associated with recurring inflammation of the structures ...

  3. Association of HLA genotypes with phenobarbital hypersensitivity in children.

    PubMed

    Manuyakorn, Wiparat; Mahasirimongkol, Surakameth; Likkasittipan, Plernpit; Kamchaisatian, Wasu; Wattanapokayakit, Sukanya; Inunchot, Wimala; Visudtibhan, Anannit; Wichukchinda, Nuanjun; Benjaponpitak, Suwat

    2016-10-01

    Phenobarbital hypersensitivity is one of the common drug hypersensitivity syndromes in children. Clinical symptoms of phenobarbital hypersensitivity vary from maculopapular rashes (MPs) to severe cutaneous adverse drug reactions (SCARs) including drug reactions with eosinophilia and systemic symptoms (DRESS), Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN). Drug hypersensitivity has been demonstrated to be associated with variations in the HLA genotypes. This study was to investigate the association between the variations of HLA genotypes and phenobarbital hypersensitivity in Thai children. The cases were Thai children, between 0 and 18 years of age, who were diagnosed with phenobarbital hypersensitivity, which included SCARs and MPs. The control patients were Thai children of a corresponding age who had taken phenobarbital for at least 12 weeks without any hypersensitivity reaction. Blood samples were collected for HLA genotyping by using a reverse-sequence-specific oligonucleotide (SSO) probes method. The carrier rates of HLA alleles were compared between 47 cases (27 SCARs and 20 MPs) and 54 controls. The carrier rates of HLA-A*01:01 and HLA-B*13:01 were significantly higher in the phenobarbital-induced SCARs than in the tolerant controls (18.5% vs. 1.85%, p = 0.01, odds ratio [OR] 11.66, 95% confidence interval [CI] 1.21-578.19; 37.04% vs. 11.11%, p = 0.009, OR 4.60, 95%CI 1.29-17.98). There was a trend of a higher carrier rate of HLA-C*06:02 in the phenobarbital-induced SCARs when compared with those in the tolerant controls (29.63% vs. 11.11%, p = 0.059, OR 3.31, 95% CI 0.88-13.31). In contrast to the phenobarbital-induced SCARs, only the HLA-A*01:01 carrier rate in the phenobarbital-induced MPs was significantly higher than those in the tolerant controls (20% vs. 1.85%, p = 0.017, OR 12.69, 95% CI 1.15-661.62). An association between phenobarbital hypersensitivity and HLA-A*01:01 and HLA-B*13:01 has been demonstrated in Thai children

  4. Multiple forms of LTP in hippocampal CA3 neurons use a common postsynaptic mechanism.

    PubMed

    Yeckel, M F; Kapur, A; Johnston, D

    1999-07-01

    We investigated long-term potentiation (LTP) at mossy fiber synapses on CA3 pyramidal neurons in the hippocampus. Using Ca2+ imaging techniques, we show here that when postsynaptic Ca2+ was sufficiently buffered so that [Ca2+]i did not rise during synaptic stimulation, the induction of mossy fiber LTP was prevented. In addition, induction of mossy fiber LTP was suppressed by postsynaptic injection of a peptide inhibitor of cAMP-dependent protein kinase. Finally, when ionotropic glutamate receptors were blocked, LTP depended on the postsynaptic release of Ca2+ from internal stores triggered by activation of metabotropic glutamate receptors. These results support the conclusion that mossy fiber LTP and LTP at other hippocampal synapses share a common induction mechanism involving an initial rise in postsynaptic [Ca2+].

  5. Metal uptake and acute toxicity in zebrafish: common mechanisms across multiple metals.

    PubMed

    Alsop, Derek; Wood, Chris M

    2011-10-01

    Zebrafish larvae (Danio rerio) were used to examine the mechanisms of action and acute toxicities of metals. Larvae had similar physiological responses and sensitivities to waterborne metals as adults. While cadmium and zinc have previously been shown to reduce Ca(2+) uptake, copper and nickel also decreased Ca(2+) uptake, suggesting that the epithelial transport of all these metals is through Ca(2+) pathways. However, exposure to cadmium, copper or nickel for up to 48 h had little or no effect on total whole body Ca(2+) levels, indicating that the reduction of Ca(2+) uptake is not the acute toxic mechanism of these metals. Instead, mortalities were effectively related to whole body Na(+), which decreased up to 39% after 48 h exposures to different metals around their respective 96 h LC50s. Decreases in whole body K(+) were also observed, although they were not as pronounced or frequent as Na(+) losses. None of the metals tested inhibited Na(+) uptake in zebrafish (Na(+) uptake was in fact increased with exposure) and the observed losses of Na(+), K(+), Ca(2+) and Mg(2+) were proportional to the ionic gradients between the plasma and water, indicating diffusive ion loss with metal exposure. This study has shown that there is a common pathway for metal uptake and a common mechanism of acute toxicity across groups of metals in zebrafish. The disruption of ion uptake accompanying metal exposure does not appear to be responsible for the acute toxicity of metals, as has been previously suggested, but rather the toxicity is instead due to total ion loss (predominantly Na(+)).

  6. Second-order statistics-based blind equalization of FIR/IIR multiple-input multiple-output channels with common zeros

    NASA Astrophysics Data System (ADS)

    Tugnait, Jitendra K.; Huang, Bin

    1998-10-01

    The problem of blind equalization of MIMO communications channels is considered using the second order statistics of the data. Such models arise when a single receiver data from multiple sources is fractionally sampled, or when an antenna array is used with or without fractional sampling. We focus on direct design of finite-length MMSE blind equalizers. We allow infinite impulse response channels. Our approaches also work when the 'subchannel' transfer functions have common zeros so long as the common zeros are minimum-phase zeros. We only require that the there exist a causal, stable left inverse to the MIMO transfer function and that the leading coefficient matrix of the MIMO channel impulse response have its rank equal to the number of sources. The channel length or model orders need not be known. The sources are recovered up to a unitary mixing matrix and are further 'unmixed' using higher- order statistics of the data. An illustrative simulation example is provided.

  7. Insulin-like growth factor 1: common mediator of multiple enterotrophic hormones and growth factors

    PubMed Central

    Bortvedt, Sarah F.; Lund, P. Kay

    2013-01-01

    Purpose of review To summarize recent evidence that IGF1 mediates growth effects of multiple trophic factors and discuss clinical relevance. Recent findings Recent reviews and original reports indicate benefits of growth hormone (GH) and long-acting glucagon-like peptide 2 (GLP2) analogues in short bowel syndrome and Crohn’s disease. This review highlights evidence that biomarkers of sustained small intestinal growth or mucosal healing and evaluation of intestinal epithelial stem cell biomarkers may improve clinical measures of intestinal growth or response to trophic hormones. Compelling evidence that IGF1 mediates growth effects of GH and GLP2 on intestine or linear growth in preclinical models of resection or Crohn’s disease is presented, along with a concept that these hormones or IGF1 may enhance sustained growth if given early after bowel resection. Evidence that SOCS protein induction by GH or GLP2 in normal or inflamed intestine, may limit IGF1-induced growth, but protect against risk of dysplasia or fibrosis is reviewed. Whether IGF1 receptor mediates IGF1 action and potential roles of insulin receptors are addressed. Summary IGF1 has a central role in mediating trophic hormone action in small intestine. Better understanding of benefits and risks of IGF1, receptors that mediate IGF1 action, and factors that limit undesirable growth are needed. PMID:22241077

  8. Common infectious agents in multiple sclerosis: a case-control study in children.

    PubMed

    Krone, Bernd; Pohl, Daniela; Rostasy, Kevin; Kahler, Elke; Brunner, Edgar; Oeffner, Frank; Grange, John M; Gärtner, Jutta; Hanefeld, Folker

    2008-01-01

    Environmental factors, in particular infections, have been linked with the risk of developing multiple sclerosis (MS). The association of Epstein-Barr virus infection with childhood onset of MS has been recently recognized. As other infections characteristically experienced during childhood have not yet been studied in larger cohorts of paediatric MS, we conducted a study on 152 German children with MS (age at onset <16 years) and matched controls in the hope of gaining evidence for their possible aetiological role in MS. Patterns of antibody responses were determined to a range of infections which, in prior studies principally on adult patients, had revealed possible associations with MS. In this study on children the serology of several infections showed associations with MS. In the exceptional case of Chlamydia pneumoniae there was a significantly higher prevalence of IgM antibody but, more typically, as in the case of influenza A, measles, parainfluenza 2, varicella/zoster viruses and particularly to the herpes simplex virus type 2 (HSV-2) lysate antigen, there were significantly higher concentrations of IgG antibody. Additional investigations, however, make it highly unlikely that a relevant number of children have experienced infections with HSV-2. In general this study supports and emphasizes a complex infectious and immunologic background of MS.

  9. HLA antigens in patients with adrenocortical hyperfunction.

    PubMed

    Lada, G; Gyódi, E; Gláz, E

    1977-01-01

    The HLA antigen frequencies in 100 Caucasian patients with adrenocortical hyperfunction were compared with those found in 352 healthy unrelated subjects. Fourteen antigens on the HLA--A locus, seventeen antigens on the HLA--B locus and three antigens on the HLA--C locus were determined using the standard NIH microlymphocytotoxicity test. The frequency of HLA--A1 antigen in the patient group was 49% as compared with 28% in the controls (pcorr less than 0.01). An increased frequency of HLA--B8 and HLA-BW35 antigens was also found, but the difference was not significant. Increased A1--B8 and A1--BW35 haplotype frequencies were observed. The relationship between the HLA system and various endogenous and exogenous factors eliciting hypercorticism, together with complementary family studies indicate that the HLA system may be a useful genetic marker of the disease susceptibility gene.

  10. KIR2DL3 and the KIR ligand groups HLA-A-Bw4 and HLA-C2 predict the outcome of hepatitis B virus infection.

    PubMed

    Di Bona, D; Aiello, A; Colomba, C; Bilancia, M; Accardi, G; Rubino, R; Giannitrapani, L; Tuttolomondo, A; Cascio, A; Caiaffa, M F; Rizzo, S; Di Lorenzo, G; Candore, G; Duro, G; Macchia, L; Montalto, G; Caruso, C

    2017-09-01

    Killer immunoglobulin-like receptors (KIRs) regulate the activation of natural killer cells through their interaction with human leucocyte antigens (HLA). KIR and HLA loci are highly polymorphic, and certain HLA-KIR combinations have been found to protect against viral infections. In this study, we analysed whether the KIR/HLA repertoire may influence the course of hepatitis B virus (HBV) infection. Fifty-seven subjects with chronic hepatitis B (CHB), 44 subjects with resolved HBV infection and 60 healthy uninfected controls (HC) were genotyped for KIR and their HLA ligands. The frequency of the HLA-A-Bw4 ligand group was higher in CHB (58%) than subjects with resolved infection (23%) (crude OR, 4.67; P<.001) and HC (10%) (crude OR, 12.38; P<.001). Similar results were obtained for the HLA-C2 ligand group, more frequent in CHB (84%), than subjects with resolved infection (70%) (crude OR, 2.24; P<.10) and HC (60%) (crude OR, 3.56; P<.01). Conversely, the frequency of KIR2DL3 was lower in CHB (81%) than in subjects with resolved infection (98%) (crude OR, 0.10; P<.05). These results suggest a detrimental role of HLA-A-Bw4 and HLA-C2 groups, which are associated with the development of CHB, and a protective role of KIR2DL3. A stepwise variable selection procedure, based on multiple logistic regression analysis, identified these three predictive variables as the most relevant, featuring high specificity (90.9%) and positive predictive value (87.5%) for the development of CHB. Our results suggest that a combination of KIR/HLA gene/alleles is able to predict the outcome of HBV infection. © 2017 John Wiley & Sons Ltd.

  11. Planar micro-optic solar concentration using multiple imaging lenses into a common slab waveguide

    NASA Astrophysics Data System (ADS)

    Karp, Jason H.; Ford, Joseph E.

    2009-08-01

    Conventional CPV systems focus sunlight directly onto a PV cell, usually through a non-imaging optic to avoid hot spots. In practice, many systems use a shared tracking platform to mount multiple smaller aperture lenses, each concentrating light into an associated PV cell. Scaling this approach to the limit would result in a thin sheet-like geometry. This would be ideal in terms of minimizing the tracking system payload, especially since such thin sheets can be arranged into louvered strips to minimize wind-force loading. However, simply miniaturizing results in a large number of individual PV cells, each needed to be packaged, aligned, and electrically connected. Here we describe for the first time a different optical system approach to solar concentrators, where a thin lens array is combined with a shared multimode waveguide. The benefits of a thin optical design can therefore be achieved with an optimum spacing of the PV cells. The guiding structure is geometrically similar to luminescent solar concentrators, however, in micro-optic waveguide concentrators sunlight is coupled directly into the waveguide without absorption or wavelength conversion. This opens a new design space for high-efficiency CPV systems with the potential for cost reduction in both optics and tracking mechanics. In this paper, we provide optical design and preliminary experimental results of one implementation specifically intended to be compatible with large-scale roll processing. Here the waveguide is a uniform glass sheet, held between the lens array and a corresponding array of micro-mirrors self-aligned to each lens focus during fabrication.

  12. Recursive forward dynamics for multiple robot arms moving a common task object

    NASA Technical Reports Server (NTRS)

    Rodriguez, G.

    1988-01-01

    Recursive forward dynamics algorithms are developed for an arbitrary number of robot arms moving a commonly held object. The multiarm forward dynamics problem is to find the angular accelerations at the joints and the contact forces that the arms impart to the task object. The problem also involves finding the acceleration of this object. The multiarm forward dynamics solutions provide a thorough physical and mathematical understanding of the way several arms behave in response to a set of applied joint moments. Such an understanding simplifies and guides the subsequent control design and experimentation process. The forward dynamics algorithms also provide the necessary analytical foundation for conducting analysis and simulation studies. The multiarm algorithms are based on the filtering and smoothing approach recently advanced for single-arm dynamics, and they can be built up modularly from the single-arm algorithms. The algorithms compute recursively the joint-angle accelerations, the contact forces, and the task-object accelerations. Algorithms are also developed to evaluate in closed form the linear transformations from the active joint moments to the joint-angle accelerations, to the task-object accelerations., and to the task-object contact forces. A possible computing architecture is presented as a precursor to a more complete investigation of the computational performance of the dynamics algorithms.

  13. Multiple spring migration strategies in a population of Pacific Common Eiders

    USGS Publications Warehouse

    Petersen, M.R.

    2009-01-01

    Spring migration strategies vary within and among species. Examination of this variability extends our understanding of life histories and has implications for conservation. I used satellite transmitters to determine migration strategies and evaluate factors influencing the timing of spring migration of Pacific Common Eiders (Somateria mollissima v-nigrum) that nest along the western Beaufort Sea coast. Adult females were marked at nesting colonies in the summers of 2000, 2001, and 2003, and were followed throughout spring migration the following year. Each year approximately equal proportions of eiders used three distinct migration strategies varying in duration, staging locations (waters near the Chukotka Peninsula, Russia, and the Chukchi and Beaufort seas, Alaska), and arrival dates at the nesting areas. It is unlikely that differences in the timing of movements to stopover sites in the Chukchi and Beaufort seas were a result of responses to changes in weather, particularly wind direction. Ice distribution and melt/movement patterns vary substantially among staging areas and thus may affect risk of starvation and reproductive potential. Long-term (decadal) changes in climate may favor birds using one strategy during "warmer" and another during "colder" years. ?? 2009 by The Cooper Ornithological Society. All rights reserved.

  14. Common-pull, multiple-push, vacuum-activated telescope mirror cell.

    PubMed

    Ruiz, Elfego; Sohn, Erika; Salas, Luis; Luna, Esteban; Araiza-Durán, José A

    2014-11-20

    A new concept for push-pull active optics is presented, where the push-force is provided by means of individual airbag type actuators and a common force in the form of a vacuum is applied to the entire back of the mirror. The vacuum provides the pull-component of the system, in addition to gravity. Vacuum is controlled as a function of the zenithal angle, providing correction for the axial component of the mirror's weight. In this way, the push actuators are only responsible for correcting mirror deformations, as well as for supporting the axial mirror weight at the zenith, allowing for a uniform, full dynamic-range behavior of the system along the telescope's pointing range. This can result in the ability to perform corrections of up to a few microns for low-order aberrations. This mirror support concept was simulated using a finite element model and was tested experimentally at the 2.12 m San Pedro Mártir telescope. Advantages such as stress-free attachments, lighter weight, large actuator area, lower system complexity, and lower required mirror-cell stiffness could make this a method to consider for future large telescopes.

  15. Multiple vaccine and pyridostigmine interactions: effects on EEG and sleep in the common marmoset.

    PubMed

    Williams, K E; Mann, T M; Chamberlain, S; Smith, A; Wilson, S; Griffiths, G D; Bowditch, A P; Scott, E A M; Pearce, P C

    2006-06-01

    Following active service during the 1990/1991 Gulf conflict, a number of UK and US veterans presented with a diverse range of symptoms, collectively known as Gulf Veterans' Illnesses (GVI). The administration of vaccines and/or the pretreatment against possible nerve agent poisoning, pyridostigmine bromide (PB), given to Armed Forces personnel during the Gulf conflict has been implicated as a possible factor in the aetiology of these illnesses. The possibility that long-term health effects may result from the administration of these vaccines (anthrax, pertussis, plague, yellow fever, polio, typhoid, tetanus, hepatitis B, meningococcal meningitis and cholera) and/or PB, have been investigated using a non-human primate model, the common marmoset. This paper reports the results from two aspects of the study, brain electrical activity (EEG, collected during performance of a touchscreen mediated discrimination task) and sleep. There were no marked long-term changes in EEG or sleep patterns that could be attributed to vaccines and/or PB administration. The changes that were detected were predominantly time related and independent of treatment. Where statistical differences were detected between treatments, the magnitudes of the difference were relatively minor and therefore not regarded as having long term biological significance.

  16. Recursive forward dynamics for multiple robot arms moving a common task object

    NASA Technical Reports Server (NTRS)

    Rodriguez, Guillermo

    1989-01-01

    Recursive forward dynamics algorithms are developed and presented for an arbitrary number of robot arms moving a commonly held object. The multiarm forward dynamics problem is to find the angular accelerations at the joints and the contact forces that the arms impart to the task object. The problem also involves finding the acceleration of this object. The multiarm forward dynamics solutions provide a thorough physical and mathematical understanding of the way several arms behave in response to a set of applied joint moments. Such an understanding simplifies and guides the subsequent control design and experimentation process. The forward dynamics algorithms also provide the necessary analytical foundation for conducting analysis and simulation studies. The multiarm algorithms are based on the filtering and smoothing approach recently advanced for single-arm dynamics, and they can be built up modularly from the single-arm algorithms. The algorithms compute recursively the joint angle accelerations, the contact forces, and the task-object accelerations. Algorithms are also developed to evaluate in closed form the linear transformations from the active joint moments to the joint angle accelerations, to the task object accelerations, and to the task-object contact forces. A possible computing architecture is presented as a precursor to a more complete investigation of the computational performance of the dynamics algorithms.

  17. Comparison of HLA allelic imputation programs.

    PubMed

    Karnes, Jason H; Shaffer, Christian M; Bastarache, Lisa; Gaudieri, Silvana; Glazer, Andrew M; Steiner, Heidi E; Mosley, Jonathan D; Mallal, Simon; Denny, Joshua C; Phillips, Elizabeth J; Roden, Dan M

    2017-01-01

    Imputation of human leukocyte antigen (HLA) alleles from SNP-level data is attractive due to importance of HLA alleles in human disease, widespread availability of genome-wide association study (GWAS) data, and expertise required for HLA sequencing. However, comprehensive evaluations of HLA imputations programs are limited. We compared HLA imputation results of HIBAG, SNP2HLA, and HLA*IMP:02 to sequenced HLA alleles in 3,265 samples from BioVU, a de-identified electronic health record database coupled to a DNA biorepository. We performed four-digit HLA sequencing for HLA-A, -B, -C, -DRB1, -DPB1, and -DQB1 using long-read 454 FLX sequencing. All samples were genotyped using both the Illumina HumanExome BeadChip platform and a GWAS platform. Call rates and concordance rates were compared by platform, frequency of allele, and race/ethnicity. Overall concordance rates were similar between programs in European Americans (EA) (0.975 [SNP2HLA]; 0.939 [HLA*IMP:02]; 0.976 [HIBAG]). SNP2HLA provided a significant advantage in terms of call rate and the number of alleles imputed. Concordance rates were lower overall for African Americans (AAs). These observations were consistent when accuracy was compared across HLA loci. All imputation programs performed similarly for low frequency HLA alleles. Higher concordance rates were observed when HLA alleles were imputed from GWAS platforms versus the HumanExome BeadChip, suggesting that high genomic coverage is preferred as input for HLA allelic imputation. These findings provide guidance on the best use of HLA imputation methods and elucidate their limitations.

  18. Comparison of HLA allelic imputation programs

    PubMed Central

    Shaffer, Christian M.; Bastarache, Lisa; Gaudieri, Silvana; Glazer, Andrew M.; Steiner, Heidi E.; Mosley, Jonathan D.; Mallal, Simon; Denny, Joshua C.; Phillips, Elizabeth J.; Roden, Dan M.

    2017-01-01

    Imputation of human leukocyte antigen (HLA) alleles from SNP-level data is attractive due to importance of HLA alleles in human disease, widespread availability of genome-wide association study (GWAS) data, and expertise required for HLA sequencing. However, comprehensive evaluations of HLA imputations programs are limited. We compared HLA imputation results of HIBAG, SNP2HLA, and HLA*IMP:02 to sequenced HLA alleles in 3,265 samples from BioVU, a de-identified electronic health record database coupled to a DNA biorepository. We performed four-digit HLA sequencing for HLA-A, -B, -C, -DRB1, -DPB1, and -DQB1 using long-read 454 FLX sequencing. All samples were genotyped using both the Illumina HumanExome BeadChip platform and a GWAS platform. Call rates and concordance rates were compared by platform, frequency of allele, and race/ethnicity. Overall concordance rates were similar between programs in European Americans (EA) (0.975 [SNP2HLA]; 0.939 [HLA*IMP:02]; 0.976 [HIBAG]). SNP2HLA provided a significant advantage in terms of call rate and the number of alleles imputed. Concordance rates were lower overall for African Americans (AAs). These observations were consistent when accuracy was compared across HLA loci. All imputation programs performed similarly for low frequency HLA alleles. Higher concordance rates were observed when HLA alleles were imputed from GWAS platforms versus the HumanExome BeadChip, suggesting that high genomic coverage is preferred as input for HLA allelic imputation. These findings provide guidance on the best use of HLA imputation methods and elucidate their limitations. PMID:28207879

  19. 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

  20. [Frequency of HLA alleles class I and II in a cohort of northwestern Colombian patients with spondyloarthritis].

    PubMed

    Velásquez, Eliana Patricia; Quintero, Julio César; Aristizábal, Beatriz Helena; Rincón, Olga Lucía; Velásquez, Carlos Jaime; Pinto, Luis Fernando; Márquez, Javier Darío

    2012-01-01

    Spondyloarthritis is a chronic rheumatic disease that affect the axial skeleton and peripheral joints, along with several extra-articular manifestations. The association with HLA-B27 remains one of the strongest known links between these entities and the major histocompatibility complex. However, the global distribution of HLA-B27 varies considerably and furthermore, associations with non-HLA-B27 genes have been described. The frequency of HLA class I and II was determined in a population of patients with spondyloarthritis with respect to detection in the clinical setting and by radiology. A descriptive, observational, cross-sectional, retrospective and prospective study was conducted in 56 patients from northwestern Colombia. Each was diagnosed with spondyloarthritis between 2005 and 2008. In each case, alleles were identified for the loci HLA class I and II (HLA-B; HLADQB1 and HLADRB). The frequency of these alleles in the axial, peripheral, extraarticular and radiological manifestations. The frequency of HLA-B27 was 50% overall, and it was the most frequent allele. The two other alleles were HLA.DRB4*01 at 35.7% and HLA-DQB1*0501 at 28.6%, as detected in each of the clinical and radiological manifestations. A high frequency of HLA-B27 and HLA-DRB4*01 (64.3%) was noted in patients with dactylitis. The alleles HLA-B27, HLA-DRB4*01 and HLA-DQB1*0501 were common in the different subtypes of spondyloarthritis and were frequent in the specific clinical axial, peripheral and extraarticular clinical manifestations, as well as radiological sacroiliitis.

  1. Multiple vaccine and pyridostigmine bromide interactions in the common marmoset Callithrix jacchus: immunological and endocrinological effects.

    PubMed

    Hornby, Rebecca J; Pearce, Peter C; Bowditch, Andrew P; Scott, Leah; Griffiths, Gareth D

    2006-12-05

    Following active service during the 1990/1991 Gulf Conflict, a number of UK and US veterans presented with a diverse range of symptoms, collectively known as Gulf Veterans Illnesses (GVI). The administration of vaccines and/or the pretreatment against possible nerve agent poisoning, pyridostigmine bromide (PB), given to Armed Forces personnel during the Gulf Conflict has been implicated as a possible factor in the aetiology of these illnesses. The possibility that adverse health effects may result from the administration of these vaccines (anthrax, pertussis, plague, yellow fever, polio, typhoid, tetanus, hepatitis B, meningococcal meningitis and cholera) and/or PB, have been investigated over an eighteen month period, in a non-human primate model, the common marmoset. This study reports immunological indices, including leukocyte phenotypes, intracellular cytokines IFN-gamma and IL-4 and antibody responses against vaccine antigens. Using human isotyping reagents previously shown to cross react with marmoset immunoglobulins (ibid) it was shown that marmosets responded strongly against anthrax PA and pertussis and weakly against killed whole cell plague, cholera and typhoid. At the end of the study the immune response to a previously unseen T-cell dependent antigen, keyhole limpet haemocyanin (KLH), was examined in order to determine whether immune function had been compromised by the compounds administered. Statistically equivalent, robust antibody responses were measured against KLH in all treatment groups indicating that the immune system had not been compromised by any of the treatments. In addition, urinary cortisol was measured at key points throughout the study as an index of physiological stress which may have been induced by the treatments. There were no effects of treatment on urinary cortisol secretion. With respect to the other immunological indices measured, there were no statistical differences between the treatment groups during the period of the study.

  2. A common polymorphism in the LDL receptor gene has multiple effects on LDL receptor function.

    PubMed

    Gao, Feng; Ihn, Hansel E; Medina, Marisa W; Krauss, Ronald M

    2013-04-01

    A common synonymous single nucleotide polymorphism in exon 12 of the low-density lipoprotein receptor (LDLR) gene, rs688, has been associated with increased plasma total and LDL cholesterol in several populations. Using immortalized lymphoblastoid cell lines from a healthy study population, we confirmed an earlier report that the minor allele of rs688 is associated with increased exon 12 alternative splicing (P < 0.05) and showed that this triggered nonsense-mediated decay (NMD) of the alternatively spliced LDLR mRNA. However, since synonymous single nucleotide polymorphisms may influence structure and function of the encoded proteins by co-translational effects, we sought to test whether rs688 was also functional in the full-length mRNA. In HepG2 cells expressing LDLR cDNA constructs engineered to contain the major or minor allele of rs688, the latter was associated with a smaller amount of LDLR protein at the cell surface (-21.8 ± 0.6%, P = 0.012), a higher amount in the lysosome fraction (+25.7 ± 0.3%, P = 0.037) and reduced uptake of fluorescently labeled LDL (-24.3 ± 0.7%, P < 0.01). Moreover, in the presence of exogenous proprotein convertase subtilisin/kexin type 9 (PCSK9), a protein that reduces cellular LDL uptake by promoting lysosomal degradation of LDLR, the minor allele resulted in reduced capacity of a PCSK9 monoclonal antibody to increase LDL uptake. These findings are consistent with the hypothesis that rs688, which is located in the β-propeller region of LDLR, has effects on LDLR activity beyond its role in alternative splicing due to impairment of LDLR endosomal recycling and/or PCSK9 binding, processes in which the β-propeller is critically involved.

  3. Multiple diverse circoviruses infect farm animals and are commonly found in human and chimpanzee feces.

    PubMed

    Li, Linlin; Kapoor, Amit; Slikas, Beth; Bamidele, Oderinde Soji; Wang, Chunlin; Shaukat, Shahzad; Masroor, Muhammad Alam; Wilson, Michael L; Ndjango, Jean-Bosco N; Peeters, Martine; Gross-Camp, Nicole D; Muller, Martin N; Hahn, Beatrice H; Wolfe, Nathan D; Triki, Hinda; Bartkus, Joanne; Zaidi, Sohail Zahoor; Delwart, Eric

    2010-02-01

    Circoviruses are known to infect birds and pigs and can cause a wide range of severe symptoms with significant economic impact. Using viral metagenomics, we identified circovirus-like DNA sequences and characterized 15 circular viral DNA genomes in stool samples from humans in Pakistan, Nigeria, Tunisia, and the United States and from wild chimpanzees. Distinct genomic features and phylogenetic analysis indicate that some viral genomes were part of a previously unrecognized genus in the Circoviridae family we tentatively named "Cyclovirus" whose genetic diversity is comparable to that of all the known species in the Circovirus genus. Circoviridae detection in the stools of U.S. adults was limited to porcine circoviruses which were also found in most U.S. pork products. To determine whether the divergent cycloviruses found in non-U.S. human stools were of dietary origin, we genetically compared them to the cycloviruses in muscle tissue samples of commonly eaten farm animals in Pakistan and Nigeria. Limited genetic overlap between cycloviruses in human stool samples and local cow, goat, sheep, camel, and chicken meat samples indicated that the majority of the 25 Cyclovirus species identified might be human viruses. We show that the genetic diversity of small circular DNA viral genomes in various mammals, including humans, is significantly larger than previously recognized, and frequent exposure through meat consumption and contact with animal or human feces provides ample opportunities for cyclovirus transmission. Determining the role of cycloviruses, found in 7 to 17% of non-U.S. human stools and 3 to 55% of non-U.S. meat samples tested, in both human and animal diseases is now facilitated by knowledge of their genomes.

  4. Genome-wide interaction-based association analysis identified multiple new susceptibility Loci for common diseases.

    PubMed

    Liu, Yang; Xu, Haiming; Chen, Suchao; Chen, Xianfeng; Zhang, Zhenguo; Zhu, Zhihong; Qin, Xueying; Hu, Landian; Zhu, Jun; Zhao, Guo-Ping; Kong, Xiangyin

    2011-03-01

    Genome-wide interaction-based association (GWIBA) analysis has the potential to identify novel susceptibility loci. These interaction effects could be missed with the prevailing approaches in genome-wide association studies (GWAS). However, no convincing loci have been discovered exclusively from GWIBA methods, and the intensive computation involved is a major barrier for application. Here, we developed a fast, multi-thread/parallel program named "pair-wise interaction-based association mapping" (PIAM) for exhaustive two-locus searches. With this program, we performed a complete GWIBA analysis on seven diseases with stringent control for false positives, and we validated the results for three of these diseases. We identified one pair-wise interaction between a previously identified locus, C1orf106, and one new locus, TEC, that was specific for Crohn's disease, with a Bonferroni corrected P < 0.05 (P = 0.039). This interaction was replicated with a pair of proxy linked loci (P = 0.013) on an independent dataset. Five other interactions had corrected P < 0.5. We identified the allelic effect of a locus close to SLC7A13 for coronary artery disease. This was replicated with a linked locus on an independent dataset (P = 1.09 × 10⁻⁷). Through a local validation analysis that evaluated association signals, rather than locus-based associations, we found that several other regions showed association/interaction signals with nominal P < 0.05. In conclusion, this study demonstrated that the GWIBA approach was successful for identifying novel loci, and the results provide new insights into the genetic architecture of common diseases. In addition, our PIAM program was capable of handling very large GWAS datasets that are likely to be produced in the future.

  5. Daphnia parasite dynamics across multiple Caullerya epidemics indicate selection against common parasite genotypes.

    PubMed

    González-Tortuero, Enrique; Rusek, Jakub; Turko, Patrick; Petrusek, Adam; Maayan, Inbar; Piálek, Lubomír; Tellenbach, Christoph; Gießler, Sabine; Spaak, Piet; Wolinska, Justyna

    2016-08-01

    Studies of parasite population dynamics in natural systems are crucial for our understanding of host-parasite coevolutionary processes. Some field studies have reported that host genotype frequencies in natural populations change over time according to parasite-driven negative frequency-dependent selection. However, the temporal patterns of parasite genotypes have rarely been investigated. Moreover, parasite-driven negative frequency-dependent selection is contingent on the existence of genetic specificity between hosts and parasites. In the present study, the population dynamics and host-genotype specificity of the ichthyosporean Caullerya mesnili, a common endoparasite of Daphnia water fleas, were analysed based on the observed sequence variation in the first internal transcribed spacer (ITS1) of the ribosomal DNA. The Daphnia population of lake Greifensee (Switzerland) was sampled and subjected to parasite screening and host genotyping during C. mesnili epidemics of four consecutive years. The ITS1 of wild-caught C. mesnili-infected Daphnia was sequenced using the 454 pyrosequencing platform. The relative frequencies of C. mesnili ITS1 sequences differed significantly among years: the most abundant C. mesnili ITS1 sequence decreased and rare sequences increased over the course of the study, a pattern consistent with negative frequency-dependent selection. However, only a weak signal of host-genotype specificity between C. mesnili and Daphnia genotypes was detected. Use of cutting edge genomic techniques will allow further investigation of the underlying micro-evolutionary relationships within the Daphnia-C. mesnili system. Copyright © 2016 The Authors. Published by Elsevier GmbH.. All rights reserved.

  6. HLA-DRB and HLA-DQB loci in the genetic susceptibility to develop glaucoma in Mexicans.

    PubMed

    Gil-Carrasco, F; Vargas-Alarcón, G; Zúñiga, J; Tinajero-Castañeda, O; Hernández-Martinez, B; Hernández-Pacheco, G; Rodríguez-Reyna, T S; Hesiquio, R; Gamboa, R; Granados, J

    1999-09-01

    Glaucoma is a clinically heterogeneous disease with a pathophysiology that may include genetic susceptibility, possibly associated with an immunologic disorder. The aim of this study was to determine whether the DNA polymorphisms located in the HLA-DRB1 and HLA-DQB1 genes show a specific association pattern in Mexican mestizo patients with primary open-angle glaucoma. This was a cross-sectional, case-control, multicenter study. We analyzed the HLA-DRB1 and DQB1 loci of 81 Mexican mestizo nonrelated patients with primary open-angle glaucoma and 98 healthy ethnic matched control subjects. Patients were diagnosed clinically and by visual fields examination. HLA typing was performed by PCR-SSO reverse dot blot. We documented increased frequencies of HLA-DRB1*0301, DRB1*1101, DRB1*0701, DRB1*1402, DQB1*0302, and DQB1*0301; however, none of them were significantly different from normal control subjects. Haplotype analysis showed that the HLA-DRB1*0407-DQB1*0302 haplotype is significantly increased in patients compared with control subjects (P = .0001). The haplotype HLA-DRB1*0407-DQB1*0302 is common among Mexican mestizo (haplotype frequency = 0.102), and it was increased in our patients (haplotype frequency = 0.259, P = .0001). This may reflect an independent association of this haplotype with the disease as the result of linkage disequilibrium or the influence of a neighboring gene. The pathophysiology of this illness is uncertain, and further studies are needed regarding the genetic susceptibility to develop primary open-angle glaucoma.

  7. Partial pathogen protection by tick-bite sensitization and epitope recognition in peptide-immunized HLA DR3 transgenic mice

    PubMed Central

    Shattuck, Wendy M C; Dyer, Megan C; Desrosiers, Joe; Fast, Loren D; Terry, Frances E; Martin, William D; Moise, Leonard; De Groot, Anne S; Mather, Thomas N

    2014-01-01

    Ticks are notorious vectors of disease for humans, and many species of ticks transmit multiple pathogens, sometimes in the same tick bite. Accordingly, a broad-spectrum vaccine that targets vector ticks and pathogen transmission at the tick/host interface, rather than multiple vaccines against every possible tickborne pathogen, could become an important tool for resolving an emerging public health crisis. The concept for such a tick protective vaccine comes from observations of an acquired tick resistance (ATR) that can develop in non-natural hosts of ticks following sensitization to tick salivary components. Mice are commonly used as models to study immune responses to human pathogens but normal mice are natural hosts for many species of ticks and fail to develop ATR. We evaluated HLA DR3 transgenic (tg) “humanized” mice as a potential model of ATR and assessed the possibility of using this animal model for tick protective vaccine discovery studies. Serial tick infestations with pathogen-free Ixodes scapularis ticks were used to tick-bite sensitize HLA DR3 tg mice. Sensitization resulted in a cytokine skew favoring a Th2 bias as well as partial (57%) protection to infection with Lyme disease spirochetes (Borrelia burgdorferi) following infected tick challenge when compared to tick naïve counterparts. I. scapularis salivary gland homogenate (SGH) and a group of immunoinformatic-predicted T cell epitopes identified from the I. scapularis salivary transcriptome were used separately to vaccinate HLA DR3 tg mice, and these mice also were assessed for both pathogen protection and epitope recognition. Reduced pathogen transmission along with a Th2 skew resulted from SGH vaccination, while no significant protection and a possible T regulatory bias was seen in epitope-vaccinated mice. This study provides the first proof-of-concept for using HLA DR tg “humanized” mice for studying the potential tick protective effects of immunoinformatic- or otherwise-derived tick

  8. Partial pathogen protection by tick-bite sensitization and epitope recognition in peptide-immunized HLA DR3 transgenic mice.

    PubMed

    Shattuck, Wendy M C; Dyer, Megan C; Desrosiers, Joe; Fast, Loren D; Terry, Frances E; Martin, William D; Moise, Leonard; De Groot, Anne S; Mather, Thomas N

    2014-01-01

    Ticks are notorious vectors of disease for humans, and many species of ticks transmit multiple pathogens, sometimes in the same tick bite. Accordingly, a broad-spectrum vaccine that targets vector ticks and pathogen transmission at the tick/host interface, rather than multiple vaccines against every possible tickborne pathogen, could become an important tool for resolving an emerging public health crisis. The concept for such a tick protective vaccine comes from observations of an acquired tick resistance (ATR) that can develop in non-natural hosts of ticks following sensitization to tick salivary components. Mice are commonly used as models to study immune responses to human pathogens but normal mice are natural hosts for many species of ticks and fail to develop ATR. We evaluated HLA DR3 transgenic (tg) "humanized" mice as a potential model of ATR and assessed the possibility of using this animal model for tick protective vaccine discovery studies. Serial tick infestations with pathogen-free Ixodes scapularis ticks were used to tick-bite sensitize HLA DR3 tg mice. Sensitization resulted in a cytokine skew favoring a Th2 bias as well as partial (57%) protection to infection with Lyme disease spirochetes (Borrelia burgdorferi) following infected tick challenge when compared to tick naïve counterparts. I. scapularis salivary gland homogenate (SGH) and a group of immunoinformatic-predicted T cell epitopes identified from the I. scapularis salivary transcriptome were used separately to vaccinate HLA DR3 tg mice, and these mice also were assessed for both pathogen protection and epitope recognition. Reduced pathogen transmission along with a Th2 skew resulted from SGH vaccination, while no significant protection and a possible T regulatory bias was seen in epitope-vaccinated mice. This study provides the first proof-of-concept for using HLA DR tg "humanized" mice for studying the potential tick protective effects of immunoinformatic- or otherwise-derived tick salivary

  9. HLA-B*15:21 and carbamazepine-induced Stevens-Johnson syndrome: pooled-data and in silico analysis

    PubMed Central

    Jaruthamsophon, Kanoot; Tipmanee, Varomyalin; Sangiemchoey, Antida; Sukasem, Chonlaphat; Limprasert, Pornprot

    2017-01-01

    HLA-B*15:02 screening before carbamazepine (CBZ) prescription in Asian populations is the recommended practice to prevent CBZ-induced Stevens-Johnson syndrome (CBZ-SJS). However, a number of patients have developed CBZ-SJS even having no HLA-B*15:02. Herein, we present the case of a Thai patient who had a negative HLA-B*15:02 screening result but later developed CBZ-SJS. Further HLA typing revealed HLA-B*15:21/B*13:01. HLA-B*15:21 is a member of the HLA-B75 serotype and is commonly found in Southeast Asian populations. Based on this case, we hypothesised that if all HLA-B*15:02 carriers were prevented from CBZ prescription, another common HLA-B75 serotype marker would show its association with CBZ-SJS. To test this hypothesis, we pooled data from previous association studies in Asian populations, excluded all cases with HLA-B*15:02, and analysed the association significance of HLA-B75 serotype markers. A significant association was found between CBZ-SJS and HLA-B*15:21 and HLA-B*15:11. We also applied an in silico analysis and found that all HLA-B75 serotype molecules shared similar capability in binding the CBZ molecule. In summary, this report provides the first evidence of a positive association between HLA-B*15:21 and CBZ-SJS and the first in silico analysis of CBZ binding sites and details of the molecular behaviour of HLA-B75 molecule to explain its molecular action. PMID:28358139

  10. HLA-B*15:21 and carbamazepine-induced Stevens-Johnson syndrome: pooled-data and in silico analysis

    NASA Astrophysics Data System (ADS)

    Jaruthamsophon, Kanoot; Tipmanee, Varomyalin; Sangiemchoey, Antida; Sukasem, Chonlaphat; Limprasert, Pornprot

    2017-03-01

    HLA-B*15:02 screening before carbamazepine (CBZ) prescription in Asian populations is the recommended practice to prevent CBZ-induced Stevens-Johnson syndrome (CBZ-SJS). However, a number of patients have developed CBZ-SJS even having no HLA-B*15:02. Herein, we present the case of a Thai patient who had a negative HLA-B*15:02 screening result but later developed CBZ-SJS. Further HLA typing revealed HLA-B*15:21/B*13:01. HLA-B*15:21 is a member of the HLA-B75 serotype and is commonly found in Southeast Asian populations. Based on this case, we hypothesised that if all HLA-B*15:02 carriers were prevented from CBZ prescription, another common HLA-B75 serotype marker would show its association with CBZ-SJS. To test this hypothesis, we pooled data from previous association studies in Asian populations, excluded all cases with HLA-B*15:02, and analysed the association significance of HLA-B75 serotype markers. A significant association was found between CBZ-SJS and HLA-B*15:21 and HLA-B*15:11. We also applied an in silico analysis and found that all HLA-B75 serotype molecules shared similar capability in binding the CBZ molecule. In summary, this report provides the first evidence of a positive association between HLA-B*15:21 and CBZ-SJS and the first in silico analysis of CBZ binding sites and details of the molecular behaviour of HLA-B75 molecule to explain its molecular action.

  11. Diffuse-Type Caroli Disease with Characteristic Central Dot Sign Complicated by Multiple Intrahepatic and Common Bile Duct Stones.

    PubMed

    Hwang, Moon Joo; Kim, Tae Nyeun

    2017-07-01

    Caroli disease (CD) is a rare congenital malformation of the liver characterized by non-obstructive, segmental, cystic dilatation of the intrahepatic bile ducts (IHDs). The clinical course is usually asymptomatic for the first 5-20 years, and symptoms may seldom occur throughout the patient's life. Bile stagnation leads to recurrent episodes of cholangitis, stone formation, or liver abscesses, and biliary cirrhosis usually occurs years later. Here we report on a 42-year-old man diagnosed with diffuse-type CD with a characteristic central dot sign, who had multiple intrahepatic and common bile duct (CBD) stones. CBD stones were treated successfully with endoscopic retrograde cholangiopancreatography (ERCP).

  12. EBV-positive primary central nervous system lymphomas in monozygote twins with common variable immunodeficiency and suspected multiple sclerosis.

    PubMed

    Jensen, M K; Koch-Henriksen, N; Johansen, P; Varming, K; Christiansen, C B; Knudsen, F

    1997-12-01

    Common variable immunodeficiency represents the most frequently occurring primary immunodeficiency disorder and is usually detected sporadically in patients with no family history of immunodeficiency. We present the case stories of two monozygote twins, who following a period of decreasing serum immunoglobulins developed primary central nervous system lymphomas. One twin had clinical and paraclinical features mimicking multiple sclerosis. Immunohistochemical investigations on biopsy tissue showed expression of the bcl-2 and p53 gene products, and Epstein-Barr virus (EBV) encoded small RNA's (EBER) indicating latent infection were detected in lymphoma cells using in situ hybridisation techniques. The pathogenetic role of EBV in oncogenesis is discussed.

  13. A novel HLA class II allele, HLA-DRB1*04:01:17, identified in a Chinese volunteer donor for CMDP.

    PubMed

    Feng, Z-H; Yang, Z-X; Ma, W-H; Pang, S-T

    2017-10-05

    A total of 322 HLA-DRB1*04 alleles have been identified until July 2017(1). HLA-DRB1*04 is the most common HLA- DRB1 allele among North Chinese Han populations with the antigen frequency of 11.51% (2). The DRB1*04:05 , DRB1*04:06 and DRB1*04:01 alleles were well represented in Shandong Peninsula population with allele frequencies of 3.70%, 1.79% and 1.39% respectively (3). This article is protected by copyright. All rights reserved.

  14. Myeloma cells resistance to NK cell lysis mainly involves an HLA class I-dependent mechanism.

    PubMed

    Gao, Minjie; Gao, Lu; Yang, Guang; Tao, Yi; Hou, Jun; Xu, Hongwei; Hu, Xiaojing; Han, Ying; Zhang, Qianqiao; Zhan, Fenghuang; Wu, Xiaosong; Shi, Jumei

    2014-07-01

    The anti-multiple myeloma (MM) potential of natural killer (NK) cells has been of rising interest in recent years. However, the molecular mechanism of NK cell cytotoxicity to myeloma cells remains unclear. In the present study, we investigated the expressions of human leukocyte antigen (HLA) class I and HLA-G in patient myeloma cells, and determined their relevance in patient tumor-cell susceptibility to NK cell cytotoxicity. Our results showed that patient myeloma cells (n = 12) were relatively resistant to NK-92 cell lysis, compared with myeloma cell lines (n = 7, P < 0.01). Gene expression profiling and flow cytometry analysis showed that both mRNA and protein of HLA class I were highly expressed in 12 patient myeloma cells. Interestingly, no or low HLA-G surface expression was detected, although multiple HLA-G transcripts were detected in these myeloma cells. NK cell function assay showed that down-regulating HLA class I expression on patient cells by acid treatment significantly increased the susceptibility of MM cells to NK-mediated lysis. Furthermore, we found that the blocking of membrane-bound HLA class I rather than HLA-G using antibodies on myeloma samples markedly increased their susceptibility to NK-mediated killing. These results demonstrated that the resistance of patient MM cells to NK lysis mainly involves an HLA class I-dependent mechanism, suggesting that HLA class I may be involved in protecting MM cells from NK-mediated attack and contribute to their immune escape in vivo.

  15. Protective Effect of HLA-DQB1 Alleles Against Alloimmunization in Patients with Sickle Cell Disease

    PubMed Central

    Tatari-Calderone, Zohreh; Gordish-Dressman, Heather; Fasano, Ross; Riggs, Michael; Fortier, Catherine; Andrew; Campbell, D.; Charron, Dominique; Gordeuk, Victor R.; Luban, Naomi L.C.; Vukmanovic, Stanislav; Tamouza, Ryad

    2015-01-01

    Background Alloimmunization or the development of alloantibodies to Red Blood Cell (RBC) antigens is considered one of the major complications after RBC transfusions in patients with sickle cell disease (SCD) and can lead to both acute and delayed hemolytic reactions. It has been suggested that polymorphisms in HLA genes, may play a role in alloimmunization. We conducted a retrospective study analyzing the influence of HLA-DRB1 and DQB1 genetic diversity on RBC-alloimmunization. Study design Two-hundred four multi-transfused SCD patients with and without RBC-alloimmunization were typed at low/medium resolution by PCR-SSO, using IMGT-HLA Database. HLA-DRB1 and DQB1 allele frequencies were analyzed using logistic regression models, and global p-value was calculated using multiple logistic regression. Results While only trends towards associations between HLA-DR diversity and alloimmunization were observed, analysis of HLA-DQ showed that HLA-DQ2 (p=0.02), -DQ3 (p=0.02) and -DQ5 (p=0.01) alleles were significantly higher in non-alloimmunized patients, likely behaving as protective alleles. In addition, multiple logistic regression analysis showed both HLA-DQ2/6 (p=0.01) and HLA-DQ5/5 (p=0.03) combinations constitute additional predictor of protective status. Conclusion Our data suggest that particular HLA-DQ alleles influence the clinical course of RBC transfusion in patients with SCD, which could pave the way towards predictive strategies. PMID:26476208

  16. Stimulation of HIV-specific T cell clonotypes using allogeneic HLA.

    PubMed

    Almeida, Coral-Ann; van Miert, Paula; O'Driscoll, Kane; Zoet, Yvonne M; Chopra, Abha; Watson, Mark; de Santis, Dianne; Witt, Campbell; John, Mina; Claas, Frans H J; D'Orsogna, Lloyd J

    2017-06-01

    We hypothesized that HIV-specific CD8 T cell clonotypes can be stimulated by allogeneic HLA molecules. Multiple HIV-specific CD8 T cell clones were derived from 12 individuals with chronic HIV infection, specific for 13 different HIV Gag antigens and restricted to 7 different HLA molecules. The generated T cell clones were assayed for alloreactivity against a panel of single HLA class I expressing cell lines (SALs). HIV-specific T cells recognising at least one allogeneic HLA molecule could be identified from 7 of 12 patients tested. Allorecognition was associated with IFNγ cytokine production, CD137 upregulation and cytotoxicity, suggesting high avidity allo-stimulation. Allo-HLA recognition by HIV-specific T cells was specific to the HIV target peptide/HLA restriction and TCR TRBV usage of the T cells. HIV-specific T cells do crossreact against allogeneic HLA molecules in an epitope and TRBV specific manner. Therefore allo-HLA stimulation could be exploited to induce or augment HIV-specific T cell responses. Copyright © 2017 Elsevier Inc. All rights reserved.

  17. Joint effects of HLA, INS, PTPN22 and CTLA4 genes on the risk of type 1 diabetes.

    PubMed

    Bjørnvold, M; Undlien, D E; Joner, G; Dahl-Jørgensen, K; Njølstad, P R; Akselsen, H E; Gervin, K; Rønningen, K S; Stene, L C

    2008-04-01

    HLA, INS, PTPN22 and CTLA4 are considered to be confirmed type 1 diabetes susceptibility genes. HLA, PTPN22 and CTLA4 are known to be involved in immune regulation. Few studies have systematically investigated the joint effect of multiple genetic variants. We evaluated joint effects of the four established genes on the risk of childhood-onset type 1 diabetes. We genotyped 421 nuclear families, 1,331 patients and 1,625 controls for polymorphisms of HLA-DRB1, -DQA1 and -DQB1, the insulin gene (INS, -23 HphI), CTLA4 (JO27_1) and PTPN22 (Arg620Trp). The joint effect of HLA and PTPN22 on type 1 diabetes risk was significantly less than multiplicative in the case-control data, but a multiplicative model could not be rejected in the trio data. All other two-way gene-gene interactions fitted multiplicative models. The high-risk HLA genotype conferred a very high risk of type 1 diabetes (OR 20.6, using the neutral-risk HLA genotype as reference). When including also intermediate-risk HLA genotypes together with risk genotypes at the three non-HLA loci, the joint odds ratio was 61 (using non-risk genotypes at all loci as reference). Most established susceptibility genes seem to act approximately multiplicatively with other loci on the risk of disease except for the joint effect of HLA and PTPN22. The joint effect of multiple susceptibility loci conferred a very high risk of type 1 diabetes, but applies to a very small proportion of the general population. Using multiple susceptibility genotypes compared with HLA genotype alone seemed to influence the prediction of disease only marginally.

  18. 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.

  19. Hierarchical Generalized Linear Models for Multiple Groups of Rare and Common Variants: Jointly Estimating Group and Individual-Variant Effects

    PubMed Central

    Yi, Nengjun; Liu, Nianjun; Zhi, Degui; Li, Jun

    2011-01-01

    Complex diseases and traits are likely influenced by many common and rare genetic variants and environmental factors. Detecting disease susceptibility variants is a challenging task, especially when their frequencies are low and/or their effects are small or moderate. We propose here a comprehensive hierarchical generalized linear model framework for simultaneously analyzing multiple groups of rare and common variants and relevant covariates. The proposed hierarchical generalized linear models introduce a group effect and a genetic score (i.e., a linear combination of main-effect predictors for genetic variants) for each group of variants, and jointly they estimate the group effects and the weights of the genetic scores. This framework includes various previous methods as special cases, and it can effectively deal with both risk and protective variants in a group and can simultaneously estimate the cumulative contribution of multiple variants and their relative importance. Our computational strategy is based on extending the standard procedure for fitting generalized linear models in the statistical software R to the proposed hierarchical models, leading to the development of stable and flexible tools. The methods are illustrated with sequence data in gene ANGPTL4 from the Dallas Heart Study. The performance of the proposed procedures is further assessed via simulation studies. The methods are implemented in a freely available R package BhGLM (http://www.ssg.uab.edu/bhglm/). PMID:22144906

  20. HLA-linked rheumatoid arthritis

    SciTech Connect

    Hasstedt, S.J.; Clegg, D.O.; Ingles, L.; Ward, R.H.

    1994-10-01

    Twenty-eight pedigrees were ascertained through pairs of first-degree relatives diagnosed with rheumatoid arthritis (RA). RA was confirmed in 77 pedigree members including probands; the absence of disease was verified in an additional 261 pedigree members. Pedigree members were serologically typed for HLA. We used likelihood analysis to statistically characterize the HLA-linked RA susceptibility locus. The genetic model assumed tight linkage to HLA. The analysis supported the existence of an HLA-linked RA susceptibility locus, estimated the lifetime penetrance as 41% in male homozygotes and as 48% in female homozygotes. Inheritance was recessive in males and was nearly recessive in females. In addition, the analysis attributed 78% of the variance within genotypes to genetic or environmental effects shared by siblings. The genetic model inferred in this analysis is consistent with previous association, linkage, and familial aggregation studies of RA. The inferred HLA-linked RA susceptibility locus accounts for approximately one-fifth of the RA in the population. Although other genes may account for the remaining familial RA, a large portion of RA cases may occur sporadically. 79 refs., 9 tabs.

  1. HLA-linked rheumatoid arthritis.

    PubMed Central

    Hasstedt, S. J.; Clegg, D. O.; Ingles, L.; Ward, R. H.

    1994-01-01

    Twenty-eight pedigrees were ascertained through pairs of first-degree relatives diagnosed with rheumatoid arthritis (RA). RA was confirmed in 77 pedigree members including probands; the absence of disease was verified in an additional 261 pedigree members. Pedigree members were serologically typed for HLA. We used likelihood analysis to statistically characterize the HLA-linked RA susceptibility locus. The genetic model assumed tight linkage to HLA. The analysis supported the existence of an HLA-linked RA susceptibility locus, estimated the susceptibility allele frequency as 2.16%, and estimated the lifetime penetrance as 41% in male homozygotes and as 48% in female homozygotes. Inheritance was recessive in males and was nearly recessive in females. In addition, the analysis attributed 78% of the variance within genotypes to genetic or environmental effects shared by siblings. The genetic model inferred in this analysis is consistent with previous association, linkage, and familial aggregation studies of RA. The inferred HLA-linked RA susceptibility locus accounts for approximately one-half of familial RA, although it accounts for only approximately one-fifth of the RA in the population. Although other genes may account for the remaining familial RA, a large portion of RA cases may occur sporadically. PMID:7942852

  2. HLA-A gene polymorphisms contribute to osteoporosis susceptibility in postmenopausal Han Chinese women.

    PubMed

    Li, S M; Guo, H; Yang, H J; Lv, M Q; Zhou, D X

    2015-08-28

    Osteoporosis is a common disease characterized by low bone mineral density, deterioration in bone microarchitecture, and increased fracture risk and is more prevalent in postmenopausal women. HLA is a complex gene family; previous studies have shown that it plays an important role in the pathogenesis of osteoporosis among Japanese and Greek populations. Prompted by these findings, this study was designed to explore the associations between HLA-A gene polymorphisms and postmenopausal osteoporosis in the Han Chinese population. The polymerase chain reaction-sequence-based typing method was used for DNA genotyping at the HLA-A locus in 70 patients with postmenopausal osteoporosis and 73 healthy controls. We identified 17 HLA-A alleles in patients with postmenopausal osteoporosis and 20 HLA-A alleles in control subjects. Furthermore, we found that the frequency of the HLA-A* 02:07 allele was significantly higher in patients with postmenopausal osteoporosis than in control subjects (P = 0.023), and the relative risk was 4.065 (95% confidence interval = 1.109-14.893). Our study provides supportive evidence for the contribution of HLA-A gene polymorphisms to the susceptibility to postmenopausal osteoporosis and suggests that HLA-A* 02:07 is likely an important genetic risk factor for postmenopausal osteoporosis in the Han Chinese population.

  3. Novel HLA-A and HLA-B alleles.

    PubMed

    Hurley, C K; Steiner, N; Kosman, C; Mitton, W; Koester, R; Bei, M; Bush, J; McCormack, J; Hahn, A; Henson, V; Hoyer, R; Wade, J A; Hartzman, R J; Ng, J

    1998-07-01

    Nine novel HLA-A and HLA-B alleles are described: A*2609, A*6803, A*6806, B*1539, B*1540, B*2712, B*4103, B*5109, and B*5603. Most appear to have arisen by gene conversion events. B*5603 appears to have arisen by a reciprocal recombination event joining exon 2 of a B*55/ *56 allele with exon 3 of a B*15 allele. Serologically, the antigen encoded by this allele types with broad B22- and Bw6-specific alloantisera. Also unique, the antigen encoded by B*2712 does not react with B27-specific alloantisera but does react with Bw6-specific alloantisera.

  4. HLA molecules in autoimmune diseases.

    PubMed

    Braun, W E

    1992-06-01

    The association of certain autoimmune diseases with HLA molecules is being refined through the use of sequence-specific oligonucleotide probes and amino acid sequencing, together with continuing elucidation of the functional features of HLA molecules derived from the milestone description by Bjorkman of the HLA molecular structure. The association of insulin-dependent diabetes mellitus and HLA began with weak associations of Class I antigens (B8 and B15) and progressed to Class II antigens (DR3 and DR4), then to subtypes of DR4 (Dw4, 10, and 14), and now to DQ molecules including the absence of aspartic acid at position 57 of the DQ beta chain and the presence of arginine at position 52 of the DQ alpha chain. In rheumatoid arthritis (RA) the HLA antigen association remains with certain Class II molecules of the DR series (DR4 and DR1) that share amino acid sequences with a restricted number of other DR antigens seen in RA, as well as a segment of the gp 110 protein of the Epstein-Barr virus. Although ankylosing spondylitis has a strong association with the Class I antigen B27, that association is not explained by any of the B27 subtypes defined by monoclonal antibodies, by the eight variable amino acids in B27 subtypes, or by the two unique amino acids on B27. The remarkable antibody cross-reactivity among lymphocytes bearing B27, a synthetic peptide sequence (63-84) of B27, and the 188-193 sequence of K. pneumoniae nitrogenase has provided strong support for molecular mimicry being an important mechanism in the association of HLA molecules with disease.(ABSTRACT TRUNCATED AT 250 WORDS)

  5. 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

  6. 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.

  7. Findings of Optical Coherence Tomography of Retinal Nerve Fiber Layer in Two Common Types of Multiple Sclerosis.

    PubMed

    Yousefipour, Gholamali; Hashemzahi, Zabihollah; Yasemi, Masood; Jahani, Pegah

    2016-06-01

    Multiple sclerosis (MS) is the most prevalent disease caused by the inflammatory demyelinating process that causes progressive nervous system degeneration over the time. Optical Coherence Tomography (OCT) is a non-invasive optical imaging technology, which can measure the thickness of retinal nerve fiber layer as well as the diameter of the macula. The purpose of the study is evaluation OCT findings in two common types of multiple sclerosis. For doing the cross-sectional study, 63 patients with two prevalent types of multiple sclerosis (35 patients with Relapse Remitting Multiple Sclerosis (RRMS) and 28 patients with Secondary Progressive Multiple Sclerosis (SPMS) were evaluated for 6 months. Exclusion criteria of the study were a history of optic neuritis, suffering from diabetes mellitus, hypertension, ocular disease, and the presence of other neurologic degenerative diseases. Then, the thickness of retinal nerve fiber layer (RNFL), as well as thickness and volume of the macula, were measured in the patients using OCT technology. The disability rate of patients was evaluated according to Expanded Disability Status Scale (EDSS). Finally, data was analyzed by means of SPSS software. Overall, 35 patients with RRMS (with mean age of 32.37+10.01, average disease period of 3.81+3.42 and mean EDSS of 1.84+0.45) and 28 patients with SPMS (with mean age of 39.21+9.33, average disease period of 11.32+5.87 and mean EDSS of 5.12+1.46) were assessed and compared in terms of retinal nerve fiber layer and size and thickness of macula. In all of these sections, the thicknesses were smaller in SPMS patients than patients with RRMS. But, there was a significant difference in total thickness (81.82µm versus 96.03µm with P=0.04) and thickness of temporal sector (54.5 µm versus 69.34 µm with P=0.04) of retinal nerve fiber layer and macular size at the superior sector of external ring (1.48 mm³ versus 1.58 mm³ with P=0.03), and nasal sector of external ring surrounding macula (1

  8. Analysis of TACI mutations in CVID & RESPI patients who have inherited HLA B*44 or HLA*B8.

    PubMed

    Waldrep, Manda L; Zhuang, Yingxin; Schroeder, Harry W

    2009-09-23

    Recent reports have suggested that Common Variable Immunodeficieny (CVID) can present as an autosomal dominant trait dependent on the inheritance of a set of uncommon mutations/alleles of TACI (transmembrane activator and calcium-modulator and cyclophilin ligand interactor) involving exons 3 or 4. Penetrance, however, appears to be incomplete. Among our clinic population, the greatest genetic linkage for CVID is to the major histocompatibility complex (MHC) on chromosome 6. The majority of our patients have inherited HLA *DQ2, *DR7, *DR3(17), *B8, and/or *B44. Of these, HLA*B44 was present in almost half of the patients and was thus the most common susceptibility allele. HLA *B44 was also found to be over-represented among patients who presented to our clinic with adult-onset recurrent sinopulmonary infections (RESPI) and normal serum immunoglobulin levels, a cohort that included first and second degree relatives of patients with CVID. One of the two original reports of the association between TACI and CVID also reported Human Leukocyte Antigen (HLA) haplotypes. Of 13 affected subjects, nine had inherited HLA *B8 and six had inherited HLA B44. This raised the possibility that TACI mutations might synergize with MHC class I alleles to enhance susceptibility to humoral immune deficiency. We identified 63 CVID patients irrespective of HLA status and 13 RESPI patients who had inherited HLA*B44. To evaluate for mutations in the gene for TACI, we PCR amplified and sequenced TACI exons 3 and 4 from these patients. Of the 76 patients, eleven proved heterozygous for a previously reported, silent T->G polymorphism [rs35062843] at proline 97 in exon 3. However, none of the 13 RESPI patients and only one of the 63 CVID patients inherited a TACI allele previously associated with CVID. This patient was heterozygous for the TACI A181E allele (exon 4). She did not carry *DQ2, *DR7, *DR3(17), *B8, or *B44. These findings suggest that TACI mutations are unlikely to play a critical

  9. Jaw muscle spindle afferents coordinate multiple orofacial motoneurons via common premotor neurons in rats: an electrophysiological and anatomical study.

    PubMed

    Zhang, Jingdong; Luo, Pifu; Ro, Jin Y; Xiong, Huangui

    2012-12-13

    Jaw muscle spindle afferents (JMSA) in the mesencephalic trigeminal nucleus (Vme) project to the parvocellular reticular nucleus (PCRt) and dorsomedial spinal trigeminal nucleus (dm-Vsp). A number of premotor neurons that project to the trigeminal motor nucleus (Vmo), facial nucleus (VII) and hypoglossal nucleus (XII) are also located in the PCRt and dm-Vsp. In this study, we examined whether these premotor neurons serve as common relay pool for relaying JMSA to multiple orofacial motoneurons. JMSA inputs to the PCRt and dm-Vsp neurons were verified by recording extracellular responses to electrical stimulation of the caudal Vme or masseter nerve, mechanical stimulation of jaw muscles and jaw opening. After recording, biocytin in recording electrode was inotophorized into recording sites. Biocytin-Iabeled fibers traveled to the Vmo, VII, XII, and the nucleus ambiguus (Amb). Labeled boutons were seen in close apposition with Nissl-stained motoneurons in the Vmo, VII, XII and Amb. In addition, an anterograde tracer (biotinylated dextran amine) was iontophorized into the caudal Vme, and a retrograde tracer (Cholera toxin B subunit) was delivered into either the VII or Xll to identify VII and XII premotor neurons that receive JMSA input. Contacts between labeled Vme neuronal boutons and premotor neurons were observed in the PCRt and adjacent dm-Vsp. Confocal microscopic observations confirmed close contacts between Vme boutons and VII and XII premotor neurons. This study provides evidence that JMSA may coordinate activities of multiple orofacial motor nuclei, including Vmo, VII, XII and Amb in the brainstem via a common premotor neuron pool.

  10. HLA class II genotypes are not associated with age related macular degeneration in a case-control, population-based study

    PubMed Central

    Pappas, Derek; Hollenbach, Jill; Coleman, Anne L.; Gorin, Michael B.; Yu, Fe; Williams, Kevin; Noble, Janelle; Tranah, Gregory J.

    2015-01-01

    Multiple lines of evidence support an immunologic basis and genetic disposition for the development of age-related macular degeneration (AMD). Comprehensive Human Leukocyte Antigens (HLA) class II typing at four loci (DRB1, DQA1, DQB1, and DPB1) was assessed using next generation sequencing methods and tested for association with Age-related Macular Degeneration (AMD) in a case-control study of 456 AMD cases and 499 controls from the population-based Study of Osteoporotic Fractures (SOF) cohort. No statistically significant associations were identified for any of the class II loci and a previously identified association between DRB1*13:01 was not replicated in this dataset. These results reported here suggest that common HLA class II genetic variation does not contribute to AMD disease risk. PMID:25665771

  11. HLA class II genotypes are not associated with age related macular degeneration in a case-control, population-based study.

    PubMed

    Pappas, Derek; Hollenbach, Jill; Coleman, Anne L; Gorin, Michael B; Yu, Fe; Williams, Kevin; Noble, Janelle; Tranah, Gregory J

    2015-03-01

    Multiple lines of evidence support an immunologic basis and genetic disposition for the development of age-related macular degeneration (AMD). Comprehensive human leukocyte antigens (HLA) class II typing at four loci (DRB1, DQA1, DQB1, and DPB1) was assessed using next generation sequencing methods and tested for association with age-related macular degeneration (AMD) in a case-control study of 456 AMD cases and 499 controls from the population-based Study of Osteoporotic Fractures (SOF) cohort. No statistically significant associations were identified for any of the class II loci and a previously identified association between DRB1*13:01 was not replicated in this dataset. These results reported here suggest that common HLA class II genetic variation does not contribute to AMD disease risk. Copyright © 2015 American Society for Histocompatibility and Immunogenetics. Published by Elsevier Inc. All rights reserved.

  12. Evaluation of TNF-α serum level in patients with recalcitrant multiple common warts, treated by lipid garlic extract.

    PubMed

    Kenawy, Soha; Mohammed, Ghada Farouk; Younes, Soha; Elakhras, Atef Ibrahim

    2014-01-01

    No universal consensus about optimal modality for treating the recalcitrant multiple common warts (RMCW). The objective of the study was to evaluate the immunological mechanisms and clinical therapeutic effect of using lipid garlic extract (LGE) in the treatment of RMCW. The study included 50 patients with RMCW. They were randomly assigned into two groups: the first group (25 patients) received LGE, and the second group (25 patients) received saline as a control group. In both groups, treatments were made to single lesions, or largest wart in case of multiple lesions, until complete clearance of lesions or for a maximum of 4 weeks. Blood serum was taken at pre-study and at the fourth week to measure tumor necrosis factor alpha (TNF-α) level. A significant difference was found between the therapeutic responses of RMCW to LGE antigen and saline control group (p < 0.001). In the LGE group, complete response was achieved in 96% of patients presenting with RMCW. There was a statistically nonsignificant increase in TNF-α of LGE group versus saline group. No recurrence was observed in the LGE group. LGE as an immunotherapy is an inexpensive, effective, and safe modality with good cure rates for treatment of RMCWs, when other topical or physical therapies have failed.

  13. Evaluation of IL-12 serum level in patients with recalcitrant multiple common warts, treated by intralesional tuberculin antigen.

    PubMed

    Abd-Elazeim, Fian M A; Mohammed, Ghada F A; Fathy, Amal; Mohamed, Roshdy W

    2014-06-01

    No universal consensus about optimal modality for treating the recalcitrant multiple common warts (RMCW). To evaluate the immunological mechanisms and clinical therapeutic effect of using of intralesional purified protein derivative (PPD) in the treatment of RMCW. The study included 40 patients with RMCW. They were randomly assigned to 2 groups: first group (20 patients) received intralesional PPD antigen, and second group (20 patients) received intralesional saline as a control group. In both groups, injections were made into single lesions, or largest wart in case of multiple lesions, at weekly intervals, until complete clearance or for a maximum of six treatments. Blood serum was taken at pre-study and at week 6 to measure IL-12 level. A significant difference was found between the therapeutic responses of RMCW to PPD antigen and saline control group (p < 0.001). In the PPD group, complete response was achieved in 75% after 5.8 ± 0.7 sessions' patients presenting with RMCW. There was a statistically significant increase in IL-12 of PPD group versus saline group. No recurrence was observed in the PPD group. Intralesional immunotherapy by PPD antigen is an effective and a safe treatment for RMCW in previously immunized patients.

  14. HLA Object Model Data Dictionary System

    DTIC Science & Technology

    2007-11-02

    OMDDS DB Tier 3: Thin Client Tier 2: CGI Tier 1: Data Server Web Browser OMDD DIF Oracle RDBMS HLA OMDDS Design Walk-through 3 KEY External Site Internal...Design Walk-through 4 HLA OMDDS WEB SITE DESIGN Open Navbar Query Utilities AboutBrowse HLA FEDEP DMSO mailto: HLAOMDDS HLA OMDDS Design Walk-through 5...AboutTools ARL DMSO AboutScreenAboutMenu Netscape Microsoft OMDD Briefing (.ppt) OMDD DIF (.doc) HLA OMDDS Design Walk-through 9 BSearchEngine UtilMenu

  15. Influence of HLA genotype on birth weight of patients with Turner syndrome.

    PubMed

    Larizza, D; Martinetti, M; Pizzochero, C; Cuccia, M; Severi, F

    1992-02-01

    Growth failure starting before birth is a common characteristic in Turner syndrome, and its pathogenesis is still not completely explained. Experiments performed in mice and rats to test whether a genetic disparity between mothers and offspring and maternal immunological status have any influence on litter size have demonstrated that allogenic litters are significantly larger in size than genetically compatible ones. Studies in humans have given contrasting results, but some authors have found that heterozygosity at enzyme loci and in blood groups is positively correlated with intrauterine growth. HLA class I and II polymorphisms were defined in 53 patients with Turner syndrome and in their parents, and lymphocytotoxic antibody detection was performed in 36 mothers. These data were related to the patients' birth weight. The frequency of the HLA-B16 allele in patients with a birth weight greater than 10th centile was significantly higher in comparison with those less than 10th centile. HLA antigen sharing was present in 43 couples (81.1%). Mean birth weight was 2934 +/- 472 g in patients without HLA antigen parental sharing and 2721 +/- 529 g in those whose parents shared HLA antigens. The mean birth weight of the 10 patients whose parents do not share HLA antigens was significantly higher than that of the patients with parental HLA-B+ DR sharing (P less than 0.05) and not significantly highe than in those patients with parental HLA sharing at other HLA loci. Patients whose parents shared B+DR antigens also had significantly smaller birth weights than those with B and A+B+DR sharing (P less than 0.025 and P less than 0.025). No significant difference in mean birth weight was found in relation to other parameters, such as mother-child histocompatibility, HLA homozygosity and lymphocytotoxic production in the mothers.

  16. HLA-DPB1 polymorphisms in patients with hyperthyroid Graves' disease and early onset myasthenia gravis.

    PubMed

    Ratanachaiyavong, S; Fleming, D; Janer, M; Demaine, A G; Willcox, N; Newsom-Davis, J; McGregor, A M

    1994-01-01

    Using the technique of in vitro enzymatic DNA amplification and dot blot hybridization with sequence-specific oligonucleotide (SSO) probes, a study of genetic polymorphism of HLA-DPB1 was performed in 83 unrelated patients with Graves' disease (GD), 48 patients with early onset myasthenia gravis (EOMG) and 100 normal British caucasoid subjects who were also tissue typed for HLA-A, B and DR antigens. HLA-DPB1*0401 was the commonest allele in both patient and control groups with gene frequencies of 0.380, 0.333 and 0.445 for GD, EOMG and controls, respectively. No significant independent association was found with any HLA-DPB1 allele. As expected, HLA-DR17 is significantly associated with Graves' disease (pc < 8 x 10(-3), RR = 2.9), while both HLA-B8 and DR17 are significantly associated with EOMG (pc < 2 x 10(-7), RR = 10.3 and pc < 0.02, RR = 3.4, respectively)] HLA-DR2 is also significantly increased in EOMG patients who were negative for HLA-DR17 (pc < 0.02, RR = 6.4). In addition, the co-occurrence of HLA-B8 with DPB1*0402 was significantly commoner in patients with GD (p < 0.021, RR = 6.2) and EOMG (p < 0.0007, RR = 10.8) than in controls, although the HLA-DPB1*0402 by itself showed no significant increase.

  17. Frequency of HLA-DRB1 and HLA-DQB1 Alleles and Haplotype Association in Syrian Population.

    PubMed

    Jazairi, Batoul; Khansaa, Issam; Ikhtiar, Adnan; Murad, Hossam

    2016-01-01

    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.

  18. Evidence to support a contribution of polyreactive antibodies to HLA serum reactivity

    PubMed Central

    Gao, Baoshan; Rong, Chunshu; Porcheray, Fabrice; Moore, Carolina; Girouard, Timothy C.; Saidman, Susan L.; Wong, Waichi; Fu, Yaowen; Zorn, Emmanuel

    2015-01-01

    Background Assessing the serum reactivity to HLA is essential for the evaluation of transplant candidates and the follow-up of allograft recipients. In this study, we look for evidence at the clonal level that polyreactive antibodies cross-reactive to apoptotic cells and multiple autoantigens can also react to HLA and contribute to the overall serum reactivity. Methods We immortalized B cell clones from the blood of two kidney transplant recipients and characterized their reactivity to self-antigens, apoptotic cells as well as native, denatured and cryptic HLA determinants using ELISA, immunofluorescence, flow cytometry and Luminex assays. We also assessed the reactivity of 300 pre-transplant serum specimens to HLA and apoptotic cells. Results We report here 4 distinct B cell clones cross-reactive to self and HLA class I. All 4 clones reacted to numerous HLA class I alleles but did not appear to target canonical “shared” epitopes. In parallel experiments, we observed a strong correlation between IgG reactivity to HLA and apoptotic cells in pre-transplant serum samples collected from 300 kidney transplant recipients. Further analysis revealed that samples with higher reactivity to apoptotic cells displayed significantly higher class I percent PRA compared to samples with low reactivity to apoptotic cells. Conclusions We provide here 1) proof of principle at the clonal level that human polyreactive antibodies can cross-react to HLA, multiple self-antigens and apoptotic cells and 2) supportive evidence that polyreactive antibodies contribute to overall HLA reactivity in the serum of patients awaiting kidney transplant. PMID:26285015

  19. Evidence to Support a Contribution of Polyreactive Antibodies to HLA Serum Reactivity.

    PubMed

    Gao, Baoshan; Rong, Chunshu; Porcheray, Fabrice; Moore, Carolina; Girouard, Timothy C; Saidman, Susan L; Wong, Waichi; Fu, Yaowen; Zorn, Emmanuel

    2016-01-01

    Assessing the serum reactivity to HLA is essential for the evaluation of transplant candidates and the follow-up of allograft recipients. In this study, we look for evidence at the clonal level that polyreactive antibodies cross-reactive to apoptotic cells and multiple autoantigens can also react to HLA and contribute to the overall serum reactivity. We immortalized B cell clones from the blood of 2 kidney transplant recipients and characterized their reactivity to self-antigens, apoptotic cells as well as native, denatured, and cryptic HLA determinants using enzyme-linked immunosorbent assay (ELISA), immunofluorescence, flow cytometry and Luminex assays. We also assessed the reactivity of 300 pretransplant serum specimens to HLA and apoptotic cells. We report here 4 distinct B cell clones cross-reactive to self and HLA class I. All 4 clones reacted to numerous HLA class I alleles but did not appear to target canonical "shared" epitopes. In parallel experiments, we observed a strong correlation between IgG reactivity to HLA and apoptotic cells in pretransplant serum samples collected from 300 kidney transplant recipients. Further analysis revealed that samples with higher reactivity to apoptotic cells displayed significantly higher class I percent panel-reactive antibodies compared to samples with low reactivity to apoptotic cells. We provide here (1) proof of principle at the clonal level that human polyreactive antibodies can cross-react to HLA, multiple self-antigens and apoptotic cells and (2) supportive evidence that polyreactive antibodies contribute to overall HLA reactivity in the serum of patients awaiting kidney transplant.

  20. Identification of a common Wnt-associated genetic signature across multiple cell types in pulmonary arterial hypertension

    PubMed Central

    West, James D.; Austin, Eric D.; Gaskill, Christa; Marriott, Shennea; Baskir, Rubin; Bilousova, Ganna; Jean, Jyh-Chang; Hemnes, Anna R.; Menon, Swapna; Bloodworth, Nathaniel C.; Fessel, Joshua P.; Kropski, Johnathan A.; Irwin, David; Ware, Lorraine B.; Wheeler, Lisa; Hong, Charles C.; Meyrick, Barbara; Loyd, James E.; Bowman, Aaron B.; Ess, Kevin C.; Klemm, Dwight J.; Young, Pampee P.; Merryman, W. David; Kotton, Darrell

    2014-01-01

    Understanding differences in gene expression that increase risk for pulmonary arterial hypertension (PAH) is essential to understanding the molecular basis for disease. Previous studies on patient samples were limited by end-stage disease effects or by use of nonadherent cells, which are not ideal to model vascular cells in vivo. These studies addressed the hypothesis that pathological processes associated with PAH may be identified via a genetic signature common across multiple cell types. Expression array experiments were initially conducted to analyze cell types at different stages of vascular differentiation (mesenchymal stromal and endothelial) derived from PAH patient-specific induced pluripotent stem (iPS) cells. Molecular pathways that were altered in the PAH cell lines were then compared with those in fibroblasts from 21 patients, including those with idiopathic and heritable PAH. Wnt was identified as a target pathway and was validated in vitro using primary patient mesenchymal and endothelial cells. Taken together, our data suggest that the molecular lesions that cause PAH are present in all cell types evaluated, regardless of origin, and that stimulation of the Wnt signaling pathway was a common molecular defect in both heritable and idiopathic PAH. PMID:24871858

  1. Identification of a common Wnt-associated genetic signature across multiple cell types in pulmonary arterial hypertension.

    PubMed

    West, James D; Austin, Eric D; Gaskill, Christa; Marriott, Shennea; Baskir, Rubin; Bilousova, Ganna; Jean, Jyh-Chang; Hemnes, Anna R; Menon, Swapna; Bloodworth, Nathaniel C; Fessel, Joshua P; Kropski, Johnathan A; Irwin, David; Ware, Lorraine B; Wheeler, Lisa; Hong, Charles C; Meyrick, Barbara; Loyd, James E; Bowman, Aaron B; Ess, Kevin C; Klemm, Dwight J; Young, Pampee P; Merryman, W David; Kotton, Darrell; Majka, Susan M

    2014-09-01

    Understanding differences in gene expression that increase risk for pulmonary arterial hypertension (PAH) is essential to understanding the molecular basis for disease. Previous studies on patient samples were limited by end-stage disease effects or by use of nonadherent cells, which are not ideal to model vascular cells in vivo. These studies addressed the hypothesis that pathological processes associated with PAH may be identified via a genetic signature common across multiple cell types. Expression array experiments were initially conducted to analyze cell types at different stages of vascular differentiation (mesenchymal stromal and endothelial) derived from PAH patient-specific induced pluripotent stem (iPS) cells. Molecular pathways that were altered in the PAH cell lines were then compared with those in fibroblasts from 21 patients, including those with idiopathic and heritable PAH. Wnt was identified as a target pathway and was validated in vitro using primary patient mesenchymal and endothelial cells. Taken together, our data suggest that the molecular lesions that cause PAH are present in all cell types evaluated, regardless of origin, and that stimulation of the Wnt signaling pathway was a common molecular defect in both heritable and idiopathic PAH.

  2. HLA-A and HLA-B allele frequencies in a mestizo population from Guadalajara, Mexico, determined by sequence-based typing.

    PubMed

    Leal, C A; Mendoza-Carrera, F; Rivas, F; Rodriguez-Reynoso, S; Portilla-de Buen, E

    2005-12-01

    HLA-A and HLA-B genes were typed by DNA sequencing in a mestizo population from Guadalajara, Jalisco, Mexico. Thirty-seven HLA-A and 51 HLA-B alleles were observed in 103 samples. The common typical Amerindian alleles (>5%) and haplotypes (>or=2.0%) found were A*02010101, *24020101, *310102, B*350101, and *4002, and A*310102-B*4002, A*240201-B*350101, and the typical European alleles were A*010101, *29010101, B*1402, B*180101, and A*020101-B*1402, A*020101-B*510101, and A*3002-B*180101. This reflects the blending of the two main parental populations of mestizos: Amerindian and Iberian. Mexicans were found to be relatively closer to the Portuguese than to Spaniards. This proximity may indicate a larger Portuguese influence in Mexicans than previously considered. Present data contribute to the understanding of the genetic structure in Mexico.

  3. 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. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  4. Estimation and partitioning of polygenic variation captured by common SNPs for Alzheimer's disease, multiple sclerosis and endometriosis.

    PubMed

    Lee, S Hong; Harold, Denise; Nyholt, Dale R; Goddard, Michael E; Zondervan, Krina T; Williams, Julie; Montgomery, Grant W; Wray, Naomi R; Visscher, Peter M

    2013-02-15

    Common diseases such as endometriosis (ED), Alzheimer's disease (AD) and multiple sclerosis (MS) account for a significant proportion of the health care burden in many countries. Genome-wide association studies (GWASs) for these diseases have identified a number of individual genetic variants contributing to the risk of those diseases. However, the effect size for most variants is small and collectively the known variants explain only a small proportion of the estimated heritability. We used a linear mixed model to fit all single nucleotide polymorphisms (SNPs) simultaneously, and estimated genetic variances on the liability scale using SNPs from GWASs in unrelated individuals for these three diseases. For each of the three diseases, case and control samples were not all genotyped in the same laboratory. We demonstrate that a careful analysis can obtain robust estimates, but also that insufficient quality control (QC) of SNPs can lead to spurious results and that too stringent QC is likely to remove real genetic signals. Our estimates show that common SNPs on commercially available genotyping chips capture significant variation contributing to liability for all three diseases. The estimated proportion of total variation tagged by all SNPs was 0.26 (SE 0.04) for ED, 0.24 (SE 0.03) for AD and 0.30 (SE 0.03) for MS. Further, we partitioned the genetic variance explained into five categories by a minor allele frequency (MAF), by chromosomes and gene annotation. We provide strong evidence that a substantial proportion of variation in liability is explained by common SNPs, and thereby give insights into the genetic architecture of the diseases.

  5. HLA Immune Function Genes in Autism

    PubMed Central

    Torres, Anthony R.; Westover, Jonna B.; Rosenspire, Allen J.

    2012-01-01

    The human leukocyte antigen (HLA) genes on chromosome 6 are instrumental in many innate and adaptive immune responses. The HLA genes/haplotypes can also be involved in immune dysfunction and autoimmune diseases. It is now becoming apparent that many of the non-antigen-presenting HLA genes make significant contributions to autoimmune diseases. Interestingly, it has been reported that autism subjects often have associations with HLA genes/haplotypes, suggesting an underlying dysregulation of the immune system mediated by HLA genes. Genetic studies have only succeeded in identifying autism-causing genes in a small number of subjects suggesting that the genome has not been adequately interrogated. Close examination of the HLA region in autism has been relatively ignored, largely due to extraordinary genetic complexity. It is our proposition that genetic polymorphisms in the HLA region, especially in the non-antigen-presenting regions, may be important in the etiology of autism in certain subjects. PMID:22928105

  6. Carfilzomib alters the HLA-presented peptidome of myeloma cells and impairs presentation of peptides with aromatic C-termini.

    PubMed

    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

    2016-04-08

    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.

  7. Burden of genetic risk variants in multiple sclerosis families in the Netherlands.

    PubMed

    Mescheriakova, Julia Y; Broer, Linda; Wahedi, Simin; Uitterlinden, André G; van Duijn, Cornelia M; Hintzen, Rogier Q

    2016-01-01

    Approximately 20% of multiple sclerosis patients have a family history of multiple sclerosis. Studies of multiple sclerosis aggregation in families are inconclusive. To investigate the genetic burden based on currently discovered genetic variants for multiple sclerosis risk in patients from Dutch multiple sclerosis multiplex families versus sporadic multiple sclerosis cases, and to study its influence on clinical phenotype and disease prediction. Our study population consisted of 283 sporadic multiple sclerosis cases, 169 probands from multiplex families and 2028 controls. A weighted genetic risk score based on 102 non-human leukocyte antigen loci and HLA-DRB1*1501 was calculated. The weighted genetic risk score based on all loci was significantly higher in familial than in sporadic cases. The HLA-DRB1*1501 contributed significantly to the difference in genetic burden between the groups. A high weighted genetic risk score was significantly associated with a low age of disease onset in all multiple sclerosis patients, but not in the familial cases separately. The genetic risk score was significantly but modestly better in discriminating familial versus sporadic multiple sclerosis from controls. Familial multiple sclerosis patients are more loaded with the common genetic variants than sporadic cases. The difference is mainly driven by HLA-DRB1*1501. The predictive capacity of genetic loci is poor and unlikely to be useful in clinical settings.

  8. Three new HLA-G alleles and their linkage disequilibria with HLA-A.

    PubMed

    Morales, P; Corell, A; Martínez-Laso, J; Martín-Villa, J M; Varela, P; Paz-Artal, E; Allende, L M; Arnaiz-Villena, A

    1993-01-01

    Three new allelic forms of the HLA-G DNA sequence (HLA-G*II, HLA-G*III, and HLA-G*IV) have been identified. With the HLA-G*I sequence (previously designated HLA 6.0) as a reference, HLA-G*II shows a silent (G-->A) mutation at the third base of codon 57, HLA-G*III bears a non-synonymous (A-->T), but conservative, (Thr-->Ser) substitution at the first base of codon 31, and HLA-G*IV shows two silent substitutions: (A-->T) at the third base of codon 107 and (G-->A) at the third base of codon 57. A rapid method of singling out each allele on genomic DNA has been developed by using polymerase chain reaction amplification followed by restriction endonuclease treatment. Also, more or less strong linkage disequilibria has been found between most HLA-A alleles and either HLA-G*I or *II, both being the most prevalent alleles in the population, with a genotypic frequency of 0.55 and 0.38, respectively; HLA-G*III is very rare and HLA-G*IV has a genotypic frequency of 0.07. An evolutive classification of HLA-A alleles results according to their association with either HLA-G*I or HLA-G*II, which does not correlate with the classical serological cross-reacting groups classification. The finding of a strong and selective A/G linkage disequilibria with most HLA-A alleles, together with the existence of less frequent random A/G associations, may suggest that there exist in different haplotypes true and varied A/G genetic distances (and not a recombinational hotspot). It may be inferred from preliminary data that in primates HLA-A/G haplotypes bearing G*II may have appeared later than those bearing G*I.

  9. HLA antigens in Tlingit Indians with rheumatoid arthritis.

    PubMed

    Nelson, J L; Boyer, G; Templin, D; Lanier, A; Barrington, R; Nisperos, B; Smith, A; Mickelson, E; Hansen, J A

    1992-08-01

    HLA-DR4 has been described in association with rheumatoid arthritis (RA) in multiple populations. We have studied HLA antigens in Alaskan Tlingit Indians. HLA-DR4 was decreased in the RA group (n = 32) compared with controls (n = 62) (6% vs 21% p = 0.07). The predominant DR4 allele observed was DRB1*0403 (Dw13.1). The most striking observation in these studies was a marked predominance of the DRB1*1402 allele encoding Dw16 (DRw14). This allele was present in 91% of RA cases, but was also highly prevalent in controls (80%, OR = 2.4 p = 0.20). DRB1*1402 only was observed in 47% of cases and 31% of controls. The DRB3*0101 (DRw52), and the DQA*0501 and DQB*0301 alleles encoding a subset of DQw3 were associated with DRB1*1402 in cases and in controls. HLA-Bw62 was increased in RA cases (28%) compared with controls (8%) (OR = 4.5, p = 0.01, corrected p = ns).

  10. HLA haplotypes in primary sclerosing cholangitis patients of admixed and non-European ancestry.

    PubMed

    Henriksen, E K K; Viken, M K; Wittig, M; Holm, K; Folseraas, T; Mucha, S; Melum, E; Hov, J R; Lazaridis, K N; Juran, B D; Chazouillères, O; Färkkilä, M; Gotthardt, D N; Invernizzi, P; Carbone, M; Hirschfield, G M; Rushbrook, S M; Goode, E; Ponsioen, C Y; Weersma, R K; Eksteen, B; Yimam, K K; Gordon, S C; Goldberg, D; Yu, L; Bowlus, C L; Franke, A; Lie, B A; Karlsen, T H

    2017-10-01

    Primary sclerosing cholangitis (PSC) is strongly associated with several human leukocyte antigen (HLA) haplotypes. Due to extensive linkage disequilibrium and multiple polymorphic candidate genes in the HLA complex, identifying the alleles responsible for these associations has proven difficult. We aimed to evaluate whether studying populations of admixed or non-European descent could help in defining the causative HLA alleles. When assessing haplotypes carrying HLA-DRB1*13:01 (hypothesized to specifically increase the susceptibility to chronic cholangitis), we observed that every haplotype in the Scandinavian PSC population carried HLA-DQB1*06:03. In contrast, only 65% of HLA-DRB1*13:01 haplotypes in an admixed/non-European PSC population carried this allele, suggesting that further assessments of the PSC-associated haplotype HLA-DRB1*13:01-DQA1*01:03-DQB1*06:03 in admixed or multi-ethnic populations could aid in identifying the causative allele. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  11. Analysis of HLA genes in families with autoimmune diabetes and thyroiditis.

    PubMed

    Levin, Lara; Ban, Yoshiyuki; Concepcion, Erlinda; Davies, Terry F; Greenberg, David A; Tomer, Yaron

    2004-06-01

    Type 1 diabetes (T1D) and autoimmune thyroid disease (AITD) are the most common autoimmune endocrine disorders. The similar pathogenesis of T1D and AITD and their tendency to occur together suggest that their etiology may involve common genetic factors. We hypothesized that the human leukocyte antigen (HLA) locus may contribute in part to the joint susceptibility to T1D and AITD. We therefore analyzed a data set of 40 multiplex families in which T1D and AITD clustered ("T1D-AITD families") for linkage and association with the HLA class II locus. We found evidence for linkage of the HLA region to T1D (maximum logarithm of odds score [MLS] = 7.3), to Hashimoto thyroiditis (HT) (MLS = 1.5), and to both (MLS = 3.8). Transmission disequilibrium test analysis revealed significant association of both T1D and AITD with HLA-DR3; however, only T1D was associated with HLA-DR4. We concluded that the finding of evidence for linkage of HLA with HT is in contrast to the strong evidence against linkage found in previous studies of AITD-only families; therefore, it is possible that the AITD phenotype seen in T1D families has a different genetic etiology than the AITD phenotype in AITD-only families; that HLA-DR3 was the major HLA allele contributing to the joint genetic susceptibility to T1D and AITD, whereas other alleles (e.g., DR4) are phenotype specific; and that because the logarithm of odds score for T1D + HT was lower than for T1D alone, additional non-HLA loci must contribute to the shared genetic susceptibility to T1D and AITD.

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

    NASA Astrophysics Data System (ADS)

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

    2016-01-01

    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.

  13. Conflicting HLA assignment by three different typing methods due to the apparent loss of heterozygosity in the MHC region.

    PubMed

    Linjama, T; Impola, U; Niittyvuopio, R; Kuittinen, O; Kaare, A; Rimpiläinen, J; Volin, L; Peräsaari, J; Jaatinen, T; Lauronen, J; Saarinen, T; Juvonen, E; Partanen, J; Koskela, S

    2016-05-01

    Loss of heterozygosity (LOH) has been reported to cause false human leukocyte antigen (HLA) homozygous typing results in pre-transplant patients suffering from haematological malignancies, who in fact are HLA heterozygous. This poses a challenge for histocompatibility testing, as a stem cell graft from a genuinely HLA homozygous donor to a mistyped patient may lead to acute life-threatening graft-vs-host disease. LOH in the HLA region on chromosome 6 is known to be quite common in solid tumours, helping malignant cells to escape T-cell surveillance, but the incidence in haematological malignancies is less well known and the estimates vary. Here we report LOH in the HLA region of five patients with haematological malignancy. We found considerable differences in sensitivity between the three different HLA typing methods used in our laboratory: SSP was clearly the most sensitive method for detecting the lost haplotype, followed by rSSO, while SBT was the least sensitive technique. A subsequent, retrospective genotyping of 65 HLA homozygous haematological patients by SSP method showed no mistyped LOH cases in our laboratory in the past 10 years. The frequency of HLA homozygosity was found to be similar between haematological patients and control groups. It is important for an HLA laboratory to be aware of the differences in various HLA typing techniques' sensitivity for detecting an under-represented haplotype between HLA typing techniques when genotyping patients with haematological diseases. It is advisable for HLA laboratories to have at least two different methods with different sensitivities in their repertoire to be able to retype samples when a false homozygous result is suspected. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  14. The Escape of Cancer from T Cell-Mediated Immune Surveillance: HLA Class I Loss and Tumor Tissue Architecture

    PubMed Central

    Garrido, Federico; Perea, Francisco; Bernal, Mónica; Sánchez-Palencia, Abel; Aptsiauri, Natalia; Ruiz-Cabello, Francisco

    2017-01-01

    Tumor immune escape is associated with the loss of tumor HLA class I (HLA-I) expression commonly found in malignant cells. Accumulating evidence suggests that the efficacy of immunotherapy depends on the expression levels of HLA class I molecules on tumors cells. It also depends on the molecular mechanism underlying the loss of HLA expression, which could be reversible/“soft” or irreversible/“hard” due to genetic alterations in HLA, β2-microglobulin or IFN genes. Immune selection of HLA-I negative tumor cells harboring structural/irreversible alterations has been demonstrated after immunotherapy in cancer patients and in experimental cancer models. Here, we summarize recent findings indicating that tumor HLA-I loss also correlates with a reduced intra-tumor T cell infiltration and with a specific reorganization of tumor tissue. T cell immune selection of HLA-I negative tumors results in a clear separation between the stroma and the tumor parenchyma with leucocytes, macrophages and other mononuclear cells restrained outside the tumor mass. Better understanding of the structural and functional changes taking place in the tumor microenvironment may help to overcome cancer immune escape and improve the efficacy of different immunotherapeutic strategies. We also underline the urgent need for designing strategies to enhance tumor HLA class I expression that could improve tumor rejection by cytotoxic T-lymphocytes (CTL). PMID:28264447

  15. The Escape of Cancer from T Cell-Mediated Immune Surveillance: HLA Class I Loss and Tumor Tissue Architecture.

    PubMed

    Garrido, Federico; Perea, Francisco; Bernal, Mónica; Sánchez-Palencia, Abel; Aptsiauri, Natalia; Ruiz-Cabello, Francisco

    2017-02-27

    Tumor immune escape is associated with the loss of tumor HLA class I (HLA-I) expression commonly found in malignant cells. Accumulating evidence suggests that the efficacy of immunotherapy depends on the expression levels of HLA class I molecules on tumors cells. It also depends on the molecular mechanism underlying the loss of HLA expression, which could be reversible/"soft" or irreversible/"hard" due to genetic alterations in HLA, β2-microglobulin or IFN genes. Immune selection of HLA-I negative tumor cells harboring structural/irreversible alterations has been demonstrated after immunotherapy in cancer patients and in experimental cancer models. Here, we summarize recent findings indicating that tumor HLA-I loss also correlates with a reduced intra-tumor T cell infiltration and with a specific reorganization of tumor tissue. T cell immune selection of HLA-I negative tumors results in a clear separation between the stroma and the tumor parenchyma with leucocytes, macrophages and other mononuclear cells restrained outside the tumor mass. Better understanding of the structural and functional changes taking place in the tumor microenvironment may help to overcome cancer immune escape and improve the efficacy of different immunotherapeutic strategies. We also underline the urgent need for designing strategies to enhance tumor HLA class I expression that could improve tumor rejection by cytotoxic T-lymphocytes (CTL).

  16. HLA-DRB1*1501 and HLA-DQB1*0301 alleles are positively associated with HPV16 infection-related Kazakh esophageal squamous cell carcinoma in Xinjiang China.

    PubMed

    Hu, Jianming; Li, Ling; Pang, Lijuan; Chen, Yunzhao; Yang, Lan; Liu, Chunxia; Zhao, Jin; Chang, Bing; Qi, Yan; Liang, Weihua; Li, Feng

    2012-11-01

    Multiple determinant factors are involved in the occurrence and progression of esophageal squamous cell carcinoma (ESCC). Human papillomavirus (HPV) and human leukocyte antigen (HLA) polymorphism were identified as important factors. This study examined the associations between the development of Kazakh ESCC and the determinant factors including HLA-DRB1*0901, 1501; DQB1*0301, 0602; high-risk HPV infection in the area of Xinjiang, China. 200 Kazakh patients with ESCC and 150 controls were recruited, and polymerase chain reaction (PCR) was performed to detect HLA-DRB1*0901, 1501 and DQB1*0301,0602 using sequence-specific primers (SSPs). HPV16 was detected in esophageal specimens using PCR. HPV16 infection rate in Kazakh ESCC case group was 41 %, significantly higher than that of control group 14 % (OR = 3.62; 95 % CI, 2.15-6.09; P < 0.001). A positive association between ESCC and HLA-DRB1*1501 (OR = 2.46, P < 0.0125) or HLA-DQB1*0301 (OR = 3.34, P < 0.0125) alleles was observed. Similar tendencies were observed for HLA-DRB1*1501 (OR = 3.095, P < 0.0125) and HLA-DQB1*0301 (OR = 2.410, P < 0.0125) alleles with HPV16-positive ESCC. HLA-DRB1*1501, HLA-DQB1*0301 and DQB1*0602 were significantly associated with ESCC when the age was ≥55 years (P < 0.0125 for all), whereas only HLA-DQB1*0301 was significantly associated with ESCC when the age was <55 years (P < 0.0125). HLA-DRB1*1501 and HLA-DQB1*0301 were significantly associated with an increase in ESCC occurrence in females (P < 0.0125), whereas only HLA-DQB1*0301 was significantly associated with ESCC in males. Moreover, the occurrence of HLA-DQB1*0602 gene in poorly differentiated ESCC group (68.8 %) was slightly higher than that of well-differentiated squamous cell carcinoma group (31.2 %). The difference was not statistically significant (P > 0.0125). The study suggests that HLA-DRB1*1501 and HLA-DQB1*0301 may influence the immune response to specific tumor and HPV-encoded epitopes and affect the risk of Kazakh

  17. Nuclear and Chloroplast Microsatellites Show Multiple Introductions in the Worldwide Invasion History of Common Ragweed, Ambrosia artemisiifolia

    PubMed Central

    Gaudeul, Myriam; Giraud, Tatiana; Kiss, Levente; Shykoff, Jacqui A.

    2011-01-01

    Background Ambrosia artemisiifolia is a North American native that has become one of the most problematic invasive plants in Europe and Asia. We studied its worldwide population genetic structure, using both nuclear and chloroplast microsatellite markers and an unprecedented large population sampling. Our goals were (i) to identify the sources of the invasive populations; (ii) to assess whether all invasive populations were founded by multiple introductions, as previously found in France; (iii) to examine how the introductions have affected the amount and structure of genetic variation in Europe; (iv) to document how the colonization of Europe proceeded; (v) to check whether populations exhibit significant heterozygote deficiencies, as previously observed. Principal Findings We found evidence for multiple introductions of A. artemisiifolia, within regions but also within populations in most parts of its invasive range, leading to high levels of diversity. In Europe, introductions probably stem from two different regions of the native area: populations established in Central Europe appear to have originated from eastern North America, and Eastern European populations from more western North America. This may result from differential commercial exchanges between these geographic regions. Our results indicate that the expansion in Europe mostly occurred through long-distance dispersal, explaining the absence of isolation by distance and the weak influence of geography on the genetic structure in this area in contrast to the native range. Last, we detected significant heterozygote deficiencies in most populations. This may be explained by partial selfing, biparental inbreeding and/or a Wahlund effect and further investigation is warranted. Conclusions This insight into the sources and pathways of common ragweed expansion may help to better understand its invasion success and provides baseline data for future studies on the evolutionary processes involved during range

  18. Nuclear and chloroplast microsatellites show multiple introductions in the worldwide invasion history of common ragweed, Ambrosia artemisiifolia.

    PubMed

    Gaudeul, Myriam; Giraud, Tatiana; Kiss, Levente; Shykoff, Jacqui A

    2011-03-10

    Ambrosia artemisiifolia is a North American native that has become one of the most problematic invasive plants in Europe and Asia. We studied its worldwide population genetic structure, using both nuclear and chloroplast microsatellite markers and an unprecedented large population sampling. Our goals were (i) to identify the sources of the invasive populations; (ii) to assess whether all invasive populations were founded by multiple introductions, as previously found in France; (iii) to examine how the introductions have affected the amount and structure of genetic variation in Europe; (iv) to document how the colonization of Europe proceeded; (v) to check whether populations exhibit significant heterozygote deficiencies, as previously observed. We found evidence for multiple introductions of A. artemisiifolia, within regions but also within populations in most parts of its invasive range, leading to high levels of diversity. In Europe, introductions probably stem from two different regions of the native area: populations established in Central Europe appear to have originated from eastern North America, and Eastern European populations from more western North America. This may result from differential commercial exchanges between these geographic regions. Our results indicate that the expansion in Europe mostly occurred through long-distance dispersal, explaining the absence of isolation by distance and the weak influence of geography on the genetic structure in this area in contrast to the native range. Last, we detected significant heterozygote deficiencies in most populations. This may be explained by partial selfing, biparental inbreeding and/or a Wahlund effect and further investigation is warranted. This insight into the sources and pathways of common ragweed expansion may help to better understand its invasion success and provides baseline data for future studies on the evolutionary processes involved during range expansion in novel environments.

  19. HLA class II antigen presentation by prostate cancer cells.

    PubMed

    Younger, A R; Amria, S; Jeffrey, W A; Mahdy, A E M; Goldstein, O G; Norris, J S; Haque, A

    2008-01-01

    Prostate cancer is the second most commonly diagnosed cancer in men. Recent evidence suggests that reduced expression of target protein antigens and human leukocyte antigen (HLA) molecules is the predominant immune escape mechanism of malignant prostate tumor cells. The purpose of this study was to investigate the prospect of antigen specific immunotherapy against prostate cancer via the HLA class II pathway of immune recognition. Here, we show for the first time that prostate cancer cells express HLA class II proteins that are recognized by CD4+ T cells. Prostate tumor cells transduced with class II molecules efficiently presented tumor-associated antigens/peptides to CD4+ T cells. This data suggests that malignant prostate tumors can be targeted via the HLA class II pathway, and that class II-positive tumors could be employed for direct antigen presentation, and CD4+ T-cell mediated tumor immunotherapy.Prostate Cancer and Prostatic Diseases (2008) 11, 334-341; doi:10.1038/sj.pcan.4501021; published online 16 October 2007.

  20. Depression in multiple sclerosis: The utility of common self-report instruments and development of a disease-specific measure.

    PubMed

    Strober, Lauren B; Arnett, Peter A

    2015-01-01

    The ultimate objective of the present investigation was to improve the detection of depression in multiple sclerosis (MS) by comparing common self-report depression measures to a new, modified measure, which takes into account the contribution that symptoms of MS may have on individuals' reports. There has been a longstanding concern regarding the accurate assessment of depression in MS, particularly with regard to the overlap of MS symptomatology and neurovegetative depression symptoms on self-report questionnaires, which may lead to an overdiagnosis of depression in MS. To address these difficulties, we previously proposed a "trunk and branch" of depression in MS. This model allows for the delineation of what symptoms are most reflective of depression in MS. By identifying these symptoms, it was possible to develop a modified Beck Depression Inventory (BDI) in which only the items found to be most related to depression in MS are included in the new measure, the MS Specific BDI (MS-BDI). We compared this measure to common self-report instruments (Beck Depression Inventory-Second Edition, BDI-II; Beck Depression Inventory-Fast Screen, BDI-FS; Chicago Multiscale Depression Inventory, CMDI). Results suggest that cutoffs of 4 on the BDI-FS and 23 on the CMDI Mood subscale are most useful when screening for depression in MS, with a sensitivity for both of 100%, while a cutoff of 19 on the BDI-II, a cutoff of 22 on the CMDI Evaluative scale, and a cutoff of 8 on the MS-BDI had high specificities, suggesting they can be used as to assist in diagnosing depression in MS.

  1. Distinct and common cerebral activation changes during mental time travel in relapsing-remitting multiple sclerosis patients.

    PubMed

    Ernst, A; Noblet, V; Denkova, E; Blanc, F; De Seze, J; Gounot, D; Manning, L

    2016-03-01

    Mental time travel (MTT) entails the ability to mentally travel into autobiographical memory (AM) and episodic future thinking (EFT). While AM and EFT share common phenomenological and cerebral functional properties, distinctive characteristics have been documented in healthy and clinical populations. No report, to our knowledge, has informed on the functional underpinnings of MTT impairment in multiple sclerosis (MS) patients, hence the aim of this work. We studied 22 relapsing-remitting MS patients and 22 matched controls. Participants underwent an AM/EFT assessment using the Autobiographical Interview (Levine et al. 2002), followed by a functional MRI session. The latter consisted in AM and EFT tasks, distinguishing the construction and elaboration phases of events. The results showed impaired performance for AM and EFT in patients, accompanied by increased cerebral activations mostly located in the frontal regions, which extended to the parietal, lateral temporal and posterior regions during AM/EFT tasks, relative to healthy controls. Enhanced brain activations in MS patients were particularly evident during the EFT task and involved the hippocampus, frontal, external temporal, and cingulate regions. The construction phase required greater fronto-parieto-temporal activations in MS patients relative to both healthy controls, and the elaboration phase. Taking together, our results suggested the occurrence of cerebral activation changes in the context of MTT in MS patients, expressed by distinct and common mechanisms for AM and EFT. This study may provide new insights in terms of cerebral activation changes in brain lesion and their application to clinical settings, considering AM/EFT's central role in everyday life.

  2. HLA class I and II polymorphisms in the Gujjar population from Pakistan.

    PubMed

    Raza, Ali; Firasat, Sadaf; Khaliq, Shagufta; Abid, Aiysha; Shah, Syed Shoaib; Mehdi, Syed Qasim; Mohyuddin, Aisha

    2013-01-01

    HLA polymorphisms at the HLA -A, -B, -C, -DRB and -DQB1 loci were investigated in the Gujjar population from the Punjab province of Pakistan. The Gujjars (n = 97) were genotyped using sequence specific primers for polymerase chain reaction. The allele and haplotype frequencies were calculated and a neighbor-joining (NJ) tree comparing the Gujjar with other populations was constructed. The class I allelic groups with a frequency greater than 10% include A*01, A*02, A*11, A*26 and A*31 at the HLA-A locus, B*08 and B*51 at the HLA-B locus and C*07 and C*14 at the HLA-C locus. Among the 12 allelic groups detected at the DRB1* locus, *03, *13, and *15 were present at frequencies higher than 10% whereas at the DQB1 locus, the allelic groups*06 and *02 accounted for over half of the Gujjar population. HLA-A*31-B*51-DRB1*13 was the most common (8.8%) haplotype in this population. A NJ tree revealed that the Pakistani Gujjar are closely related to the Golla tribe from Andhra Pradesh in India. The two populations are dedicated to the same profession, cattle breeding. HLA analyses of additional Punjab castes would provide valuable information for anthropological, organ transplantation and genetic disease studies.

  3. Multi-Population Classical HLA Type Imputation

    PubMed Central

    Moutsianas, Loukas; Shen, Judong; Cox, Charles; Nelson, Matthew R.; McVean, Gil

    2013-01-01

    Statistical imputation of classical HLA alleles in case-control studies has become established as a valuable tool for identifying and fine-mapping signals of disease association in the MHC. Imputation into diverse populations has, however, remained challenging, mainly because of the additional haplotypic heterogeneity introduced by combining reference panels of different sources. We present an HLA type imputation model, HLA*IMP:02, designed to operate on a multi-population reference panel. HLA*IMP:02 is based on a graphical representation of haplotype structure. We present a probabilistic algorithm to build such models for the HLA region, accommodating genotyping error, haplotypic heterogeneity and the need for maximum accuracy at the HLA loci, generalizing the work of Browning and Browning (2007) and Ron et al. (1998). HLA*IMP:02 achieves an average 4-digit imputation accuracy on diverse European panels of 97% (call rate 97%). On non-European samples, 2-digit performance is over 90% for most loci and ethnicities where data available. HLA*IMP:02 supports imputation of HLA-DPB1 and HLA-DRB3-5, is highly tolerant of missing data in the imputation panel and works on standard genotype data from popular genotyping chips. It is publicly available in source code and as a user-friendly web service framework. PMID:23459081

  4. HLA-A, HLA-B, HLA-DRB1 allele and haplotype frequencies in 6384 umbilical cord blood units and transplantation matching and engraftment statistics in the Zhejiang cord blood bank of China.

    PubMed

    Wang, F; He, J; Chen, S; Qin, F; Dai, B; Zhang, W; Zhu, F M; Lv, H J

    2014-02-01

    Umbilical cord blood (UCB) is a widely accepted source of progenitor cells, and now, many cord blood banks were established. Here, we analysed the HLA-A, HLA-B and HLA-DRB1 allele and haplotype frequencies, HLA matching possibilities for searching potential donors and outcome of UCB transplantations in Zhejiang cord blood bank of China. A total of 6384 UCB units were characterized for 17 HLA-A, 30 HLA-B and 13 HLA-DRB1 alleles at the first field resolution level. Additionally, B*14, B*15 and B*40 were typed to the second field level. A total of 1372 distinct A-B-DRB1 haplotypes were identified. The frequencies of 7 haplotypes were more than 1%, and 439 haplotypes were <0.01%. A*02-B*46-DRB1*09, A*33-B*58-DRB1*03 and A*30-B*13-DRB1*07 were the most common haplotypes, with frequencies of 4.4%, 3.3%, and 2.9%, respectively. Linkage disequilibrium(LD) analysis showed that there were 83 A-B, 106 B-DRB1, 54 A-DRB1 haplotypes with positive LD, in which 51 A-B, 60 B-DRB1, 32 A-DRB1 haplotypes exhibited a significant LD (P < 0.05). In 682 search requests, 12.9%, 40.0% and 42.7% of patients were found to have 6 of 6, 5 of 6 and 4 of 6 HLA-A, HLA-B and HLA-DRB1 matching donors, respectively. A total of 30 UCB units were transplanted to 24 patients (3 patients not evaluated due to early death); 14 of 21 patients (66.7%) engrafted. This study reveals the HLA distribution and its transplantation application in the cord blood bank of Zhejiang province. These data can help to select potential UCB donors for transplantation and used to assess the scale of new cord blood banking endeavours.

  5. Males without apparent alloimmunization could have HLA antibodies that recognize target HLA specificities expressed on cells.

    PubMed

    Nakamura, J; Nakajima, F; Kamada, H; Tadokoro, K; Nagai, T; Satake, M

    2017-05-01

    Human leukocyte antigen (HLA) antibodies, which are involved in the development of transfusion-related side effects such as transfusion-related lung injury, are sometimes found in males without a history of alloimmunization (eg, transplantation and transfusion). Whether HLA antibodies in male donors can interact with their target HLA specificities expressed on cells have not been completely investigated. The HLA antibodies detected in 7 male donors were characterized. Flow cytometry and immunocomplex capture fluorescence analysis were performed to evaluate the ability of these antibodies to bind with target HLA specificities expressed on cells. The association of these antibodies with complement was examined using anti-C1q antibody. Sustainability of HLA antibodies over time was compared in 26 male vs 57 female donors. The antibodies from all 7 donors recognized intact HLA molecules coated onto microbeads. The antibodies in 2 of 7 donors also recognized their target HLA specificities expressed on cells. Furthermore, the antibodies in one of these 2 donors showed HLA specificities that involved complement binding. Twenty-one of 26 initially positive male donors had turned negative for HLA antibody at least 1 year after their initial positive screening, whereas HLA antibody positivity was maintained for a long time in most female donors. Males without apparent alloimmunization could have HLA antibodies that recognize their target HLA specificities on cells and that could potentially modify molecular events in affected cells. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  6. HLA-DM interactions with intermediates in HLA-DR maturation and a role for HLA-DM in stabilizing empty HLA-DR molecules.

    PubMed

    Denzin, L K; Hammond, C; Cresswell, P

    1996-12-01

    Major histocompatibility complex (MHC) class II-positive cell lines which lack HLA-DM expression accumulate class II molecules associated with residual invariant (I) chain fragments (class II-associated invariant chain peptides [CLIP]). In vitro, HLA-DM catalyzes CLIP dissociation from class II-CLIP complexes, promoting binding of antigenic peptides. Here the physical interaction of HLA-DM with HLA-DR molecules was investigated. HLA-DM complexes with class II molecules were detectable transiently in cells, peaking at the time when the class II molecules entered the MHC class II compartment. HLA-DR alpha beta dimers newly released from I chain, and those associated with I chain fragments, were found to associate with HLA-DM in vivo. Mature, peptide-loaded DR molecules also associated at a low level. These same species, but not DR-I chain complexes, were also shown to bind to purified HLA-DM molecules in vitro. HLA-DM interaction was quantitatively superior with DR molecules isolated in association with CLIP. DM-DR complexes generated by incubating HLA-DM with purified DR alpha beta CLIP contained virtually no associated CLIP, suggesting that this superior interaction reflects a prolonged HLA-DM association with empty class II dimers after CLIP dissociation. Incubation of peptide-free alpha beta dimers in the presence of HLA-DM was found to prolong their ability to bind subsequently added antigenic peptides. Stabilization of empty class II molecules may be an important property of HLA-DM in facilitating antigen processing.

  7. The HLA-A*31:01 allele: influence on carbamazepine treatment

    PubMed Central

    Yip, Vincent Lai Ming; Pirmohamed, Munir

    2017-01-01

    Carbamazepine (CBZ) is an effective anticonvulsant that can sometimes cause hypersensitivity reactions that vary in frequency and severity. Strong associations have been reported between specific human leukocyte antigen (HLA) alleles and susceptibility to CBZ hypersensitivity reactions. Screening for HLA-B*15:02 is mandated in patients from South East Asia because of a strong association with Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). HLA-A*31:01 predisposes to multiple phenotypes of CBZ hypersensitivity including maculopapular exanthema, hypersensitivity syndrome, and SJS/TEN in a range of populations including Europeans, Japanese, South Koreans and Han Chinese, although the effect size varies between the different phenotypes and populations. Between 47 Caucasians and 67 Japanese patients would need to be tested for HLA-A*31:01 in order to avoid a single case of CBZ hypersensitivity. A cost-effectiveness study has demonstrated that HLA-A*31:01 screening would be cost-effective. Patient preference assessment has also revealed that patients prefer pharmacogenetic screening and prescription of alternative anticonvulsants compared to current standard of practice without pharmacogenetic testing. For patients who test positive for HLA-A*31:01, alternative treatments are available. When alternatives have failed or are unavailable, HLA-A*31:01 testing can alert clinicians to 1) patients who are at increased risk of CBZ hypersensitivity who can then be targeted for more intensive monitoring and 2) increase diagnostic certainty in cases where hypersensitivity has already occurred, so patients can be advised to avoid structurally related drugs in the future. On the basis of the current evidence, we would favor screening all patients for HLA-A*31:01 and HLA-B*15:02 prior to starting CBZ therapy. PMID:28203102

  8. Selective changes in expression of HLA class I polymorphic determinants in human solid tumors

    SciTech Connect

    Natali, P.G.; Nicotra, M.R.; Bigotti, A.; Venturo, I.; Giacomini, P. ); Marcenaro, L.; Russo, C. )

    1989-09-01

    Analysis of surgical biopsies with monoclonal antibodies (mAbs) to framework determinants of major histocompatibility complex class I antigens has shown that malignant transformation is frequently associated with a marked loss of these cell surface molecules. The present study sought to determine whether more selective losses of major histocompatibility complex class I expression occur. Multiple specimens from 13 different types of primary and metastatic tumors were tested utilizing mAb BB7.2, which recognizes a polymorphic HLA-A2 epitope. In each case, expression of HLA-A,B,C molecules was determined by testing with mAb W6/32 directed to a framework HLA class I determinant. The authors have found that in HLA-A2-positive patients, HLA-A2 products are not detectable or are reduced in their expression in 70-80% of endometrial, colorectal, mammary, and renal tumors; in 40-60% of soft-tissue, skin, ovary, urinary bladder, prostate, and stomach tumors; and in 25-30% of melanomas and lung carcinomas tested. All tumors expressed the framework HLA-A,B.C determinant. The HLA-A2 epitope recognized by mAb BB7.2 is located in a portion of the HLA-A2 molecule postulated to react with the T-cell receptor. The selective loss of an HLA class I polymorphic epitope shown in this study may explain the mechanism by which tumor cells escape both T-cell recognition and natural killer cell surveillance.

  9. A Novel Method for Anti-HLA Antibody Detection Using Personalized Peptide Arrays

    PubMed Central

    Liu, Pan; Souma, Tomokazu; Wei, Andrew Zu-Sern; Xie, Xueying; Luo, Xunrong; Jin, Jing

    2016-01-01

    Background HLA mismatches are the primary cause of alloantibody-mediated rejection (AMR) in organ transplantation. To delineate antigenic and immunogenic potentials among individual HLA mismatches, information regarding antibody specificity at the epitope level, instead of the allelic level, is needed. Methods This study explores a direct screening method for HLA linear epitopes in kidney transplant patients. We custom synthesized a large panel of 15-residue HLA peptides in an array format and measured alloantibody reactivity to these peptides from the sera of post and/or pretransplant patients. Two design concepts for the arrays were followed: a standard array of a fixed panel of peptides or personalized arrays. The standard array contains 420 peptides derived from a predetermined set of HLA-DQ allelic antigens based on templates also used in the single-antigen beads assay. Results The array detected distinct antiserum patterns among transplant subjects and revealed epitope levels of specificity largely in accordance with the single-antigen results. Two personalized arrays that each included donor-derived peptides of HLA-A, -B, -C, -DQ, and -DR sequences were separately designed for 2 transplant subjects. The personalized arrays detected de novo antibodies following transplantation. The new method also showed superior sensitivity to a single-antigen assay in one of the cases whose pathological diagnosis of AMR occurred before single-antigen assay could detect antibodies. Conclusions This pilot study proved the feasibility of using personalized peptide arrays to achieve detection of alloantibodies for linear HLA epitopes associated with distinct donor-recipient mismatches. Single or multiple reactive epitopes may occur on an individual HLA molecule, and donor-specific HLA-DQ-reactivity among 5 kidney transplant subjects revealed patterns of shared epitopes. PMID:27826602

  10. Production and delivery batch scheduling with a common due date and multiple vehicles to minimize total cost

    NASA Astrophysics Data System (ADS)

    Prasetyaningsih, E.; Suprayogi; Samadhi, TMAA; Halim, AH

    2016-02-01

    This paper studies production and delivery batch scheduling problems for a single- supplier-to-a-single-manufacturer case, with multiple capacitated vehicles wherein different holding costs between in-process and completed parts are allowed. In the problem, the parts of a single item are first batched,then the resulting batches are processed on a single machine. All completed batches are transported in a number of deliveries in order to be received at a common due date. The objective is to find the integrated schedule of production and delivery batches so as to satisfy its due date and to minimize the total cost of associated in-process parts inventory, completed parts inventory and delivery. It should be noted that both holding costs constitute a derivation of the so-called actual flow time, and the delivery cost is proportional to the required number of deliveries. The problem can be formulated as an integer non-linier programming and it is solved optimally by Lingo 11.0 software. Numerical experiences show that there are two patterns of batch sizes affected by the ratio of holding costs of in-process and completed parts. It can be used by practitioners to solve the realistic integrated production and delivery batch scheduling problem.

  11. Electrophoretic analysis of HLA-DR2 molecules isolated from HLA-Dw2 and HLA-Dw12 cell lines.

    PubMed

    Takenouchi, T; Kasahara, M; Ogasawara, K; Ikeda, H; Ishikawa, N; Hawkin, S; Wakisaka, A; Aizawa, M

    1985-02-01

    To answer the question of whether or not polymorphism exists among HLA-DR2 molecules derived from cells homozygous for HLA-DR2, but expressing different HLA-D specificities, HLA-DR2 molecules were isolated from HLA-Dw2 and HLA-Dw12 homozygous cells using a monoclonal antibody operationally monospecific for HLA-DR2, and were compared to each other by two-dimensional gel electrophoresis. No electrophoretically discernible polymorphism was found in either the heavy or the light chain subunits of the HLA-DR2 molecules. These findings are in marked contrast with previous observations that each of the HLA-DR4-associated HLA-D clusters expresses an electrophoretically distinct HLA-DR4 light chain.

  12. Detection of HLA-D/DR-related DNA polymorphism in HLA-D homozygous typing cells.

    PubMed Central

    Owerbach, D; Lernmark, A; Rask, L; Peterson, P A; Platz, P; Svejgaard, A

    1983-01-01

    Sequences of different sizes are generated when DNA from homozygous HLA-Dw/DR typing cells are digested with restriction endonuclease and analyzed by hybridization with a HLA-D region class II antigen beta-chain cDNA probe. The patterns of hybridization were highly polymorphic but one endonuclease, BamHI, defined sequences unique to all HLA-Dw/DR specificities 1-8 except HLA-Dw/DR 2 and 6; however, these two specificities were resolved with the enzyme EcoRI. Digestion with other endonucleases such as Pst I results in patterns of restriction fragments that differ between homozygous typing cells of the same HLA-Dw/DR specificity. HLA-D region beta-chain probes permit HLA-D region genotyping at the DNA level and may allow detection of genes controlling the association of HLA specificities with a wide variety of diseases. Images PMID:6304735

  13. The Immunogenetics of Multiple Sclerosis: A Comprehensive Review

    PubMed Central

    Hollenbach, Jill A.; Oksenberg, Jorge R.

    2015-01-01

    Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system and common cause of non-traumatic neurological disability in young adults. The likelihood for an individual to develop MS is strongly influenced by her or his ethnic background and family history of disease, suggesting that genetic susceptibility is a key determinant of risk. Over 100 loci have been firmly associated with susceptibility, whereas the main signal genome-wide maps to the class II region of the human leukocyte antigen (HLA) gene cluster and explains up to 10.5% of the genetic variance underlying risk. HLA-DRB1*15:01 has the strongest effect with an average odds ratio of 3.08. However, complex allelic hierarchical lineages, cis/trans haplotypic effects, and independent protective signals in the class I region of the locus have been described as well. Despite the remarkable molecular dissection of the HLA region in MS, further studies are needed to generate unifying models to account for the role of the MHC in disease pathogenesis. Driven by the discovery of combinatorial associations of Killer-cell Immunoglobulin-like Receptor (KIR) and HLA alleles with infectious, autoimmune diseases, transplantation outcome and pregnancy, multi-locus immunogenomic research is now thriving. Central to immunity and critically important for human health, KIR molecules and their HLA ligands are encoded by complex genetic systems with extraordinarily high levels of sequence and structural variation and complex expression patterns. However, studies to-date of KIR in MS have been few and limited to very low resolution genotyping. Application of modern sequencing methodologies coupled with state of the art bioinformatics and analytical approaches will permit us to fully appreciate the impact of HLA and KIR variation in MS. PMID:26142251

  14. The immunogenetics of multiple sclerosis: A comprehensive review.

    PubMed

    Hollenbach, Jill A; Oksenberg, Jorge R

    2015-11-01

    Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system and common cause of non-traumatic neurological disability in young adults. The likelihood for an individual to develop MS is strongly influenced by her or his ethnic background and family history of disease, suggesting that genetic susceptibility is a key determinant of risk. Over 100 loci have been firmly associated with susceptibility, whereas the main signal genome-wide maps to the class II region of the human leukocyte antigen (HLA) gene cluster and explains up to 10.5% of the genetic variance underlying risk. HLA-DRB1*15:01 has the strongest effect with an average odds ratio of 3.08. However, complex allelic hierarchical lineages, cis/trans haplotypic effects, and independent protective signals in the class I region of the locus have been described as well. Despite the remarkable molecular dissection of the HLA region in MS, further studies are needed to generate unifying models to account for the role of the MHC in disease pathogenesis. Driven by the discovery of combinatorial associations of Killer-cell Immunoglobulin-like Receptor (KIR) and HLA alleles with infectious, autoimmune diseases, transplantation outcome and pregnancy, multi-locus immunogenomic research is now thriving. Central to immunity and critically important for human health, KIR molecules and their HLA ligands are encoded by complex genetic systems with extraordinarily high levels of sequence and structural variation and complex expression patterns. However, studies to-date of KIR in MS have been few and limited to very low resolution genotyping. Application of modern sequencing methodologies coupled with state of the art bioinformatics and analytical approaches will permit us to fully appreciate the impact of HLA and KIR variation in MS. Copyright © 2015 Elsevier Ltd. All rights reserved.

  15. Deciphering HLA-I motifs across HLA peptidomes improves neo-antigen predictions and identifies allostery regulating HLA specificity.

    PubMed

    Bassani-Sternberg, Michal; Chong, Chloé; Guillaume, Philippe; Solleder, Marthe; Pak, HuiSong; Gannon, Philippe O; Kandalaft, Lana E; Coukos, George; Gfeller, David

    2017-08-01

    The precise identification of Human Leukocyte Antigen class I (HLA-I) binding motifs plays a central role in our ability to understand and predict (neo-)antigen presentation in infectious diseases and cancer. Here, by exploiting co-occurrence of HLA-I alleles across ten newly generated as well as forty public HLA peptidomics datasets comprising more than 115,000 unique peptides, we show that we can rapidly and accurately identify many HLA-I binding motifs and map them to their corresponding alleles without any a priori knowledge of HLA-I binding specificity. Our approach recapitulates and refines known motifs for 43 of the most frequent alleles, uncovers new motifs for 9 alleles that up to now had less than five known ligands and provides a scalable framework to incorporate additional HLA peptidomics studies in the future. The refined motifs improve neo-antigen and cancer testis antigen predictions, indicating that unbiased HLA peptidomics data are ideal for in silico predictions of neo-antigens from tumor exome sequencing data. The new motifs further reveal distant modulation of the binding specificity at P2 for some HLA-I alleles by residues in the HLA-I binding site but outside of the B-pocket and we unravel the underlying mechanisms by protein structure analysis, mutagenesis and in vitro binding assays.

  16. Pooled analysis of the HLA-DRB1 by smoking interaction in Parkinson's disease.

    PubMed

    Chuang, Yu-Hsuan; Lee, Pei-Chen; Vlaar, Tim; Mulot, Claire; Loriot, Marie-Anne; Hansen, Johnni; Lill, Christina M; Ritz, Beate; Elbaz, Alexis

    2017-10-05

    Inflammatory response plays an important role in Parkinson's disease (PD). Previous studies have reported an association between human leukocyte antigen (HLA)-DRB1 and the risk of PD. There has also been growing interest in investigating whether inflammation-related genes interact with environmental factors such as smoking to influence PD risk. We performed a pooled analysis of the interaction between HLA-DRB1 and smoking in PD in three population-based case-control studies from Denmark and France. We included 2,056 cases and 2,723 controls from three PD studies (Denmark, France) that obtained information on smoking through interviews. Genotyping of the rs660895 polymorphism in the HLA-DRB1 region was based on saliva or blood DNA samples. To assess interactions, we used logistic regression with product terms between rs660895 and smoking. We performed random-effects meta-analysis of marginal associations and interactions. Both carrying rs660895-G (AG vs. AA: OR= 0.81; GG vs. AA: OR= 0.56; p-trend=0.003) and ever smoking (OR=0.56, p<0.001) were inversely associated with PD. A multiplicative interaction was observed between rs660895 and smoking using codominant, additive (interaction parameter=1.37, p=0.005), and dominant (interaction parameter=1.54, p=0.001) genetic models without any heterogeneity (I(2) =0.0%): the inverse association of rs660895-(AG+GG) with PD seen in never smokers (OR=0.64, p<0.001) disappeared among ever smokers (OR=1.00, p=0.99). Similar interactions were observed when we investigated light and heavy smokers separately. Our study provides the first evidence that smoking modifies the previously reported inverse association of rs660895-G with PD, and suggests that smoking and HLA-DRB1 are involved in common pathways, possibly related to neuroinflammation. This article is protected by copyright. All rights reserved. © 2017 American Neurological Association.

  17. HLA and Delayed Drug-Induced Hypersensitivity.

    PubMed

    Sousa-Pinto, Bernardo; Correia, Cláudia; Gomes, Lídia; Gil-Mata, Sara; Araújo, Luís; Correia, Osvaldo; Delgado, Luís

    2016-01-01

    Delayed drug allergy reactions (DDAR) are potentially fatal. Certain human leukocyte antigen (HLA) alleles have been associated with delayed allergy reactions following the administration of particular drugs. Examples are HLA-B*57:01 (abacavir), HLA-B*15:02/HLA-A*31:01 (carbamazepine), and HLA-B*58:01 (allopurinol). Based on the identification of these associations, it may now be possible to prevent certain allergy reactions that were, until recently, considered unpredictable. In this review, we will focus on the pharmacogenetics of the best-studied associations between specific HLA alleles and delayed allergy reactions and describe the pathogenesis models proposed so far. Finally, we will evaluate the genetic screening strategies available and discuss the clinical relevance of a better understanding of the immunogenetics and mechanisms involved in DDAR.

  18. Upregulation of Soluble HLA-G in Chronic Left Ventricular Systolic Dysfunction

    PubMed Central

    Olesen, Line Lisbeth

    2016-01-01

    Left ventricular systolic dysfunction (LVSD) defined by ejection fraction (EF) <40% is common, serious but treatable, and correct diagnosis is the cornerstone of effective treatment. Biomarkers may help to diagnose LVSD and give insight into the pathophysiology. The immune system is activated in LVSD, and the immunomodulatory molecule human leukocyte antigen-G (HLA-G) may be involved. The primary aim was to measure soluble HLA-G (sHLA-G) in the blood in different stages of LVSD (<30% and 30–40%), in the midrange EF 40–50%, and in preserved EF ≥ 50% and to validate sHLA-G as a LVSD biomarker. The secondary aim was to examine associations between HLA-G gene polymorphisms influencing expression levels and LVSD. The 260 study participants were ≥75 years old, many with risk factors for heart disease or with known heart disease. Soluble HLA-G was significantly and uniformly higher in the groups with EF < 50% (<30, 30–40, and 40–50%) compared to EF > 50% (p < 0.0001). N-terminal fragment-pro-B-type natriuretic peptide (NT-proBNP) and uric acid values were inversely related to EF. According to Receiver Operating Characteristic (ROC) curves NT-proBNP outperformed both sHLA-G and uric acid as biomarkers of LVSD. Soluble HLA-G in blood plasma was elevated in LVSD regardless of EF. A novel finding was that a combined 14 bp ins-del/+3142 SNP HLA-G haplotype was associated with EF < 40%. PMID:27800497

  19. 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

  20. Predicting HLA alleles from high-resolution SNP data in three Southeast Asian populations.

    PubMed

    Pillai, Nisha Esakimuthu; Okada, Yukinori; Saw, Woei-Yuh; Ong, Rick Twee-Hee; Wang, Xu; Tantoso, Erwin; Xu, Wenting; Peterson, Trevor A; Bielawny, Thomas; Ali, Mohammad; Tay, Koon-Yong; Poh, Wan-Ting; Tan, Linda Wei-Lin; Koo, Seok-Hwee; Lim, Wei-Yen; Soong, Richie; Wenk, Markus; Raychaudhuri, Soumya; Little, Peter; Plummer, Francis A; Lee, Edmund J D; Chia, Kee-Seng; Luo, Ma; De Bakker, Paul I W; Teo, Yik-Ying

    2014-08-15

    The major histocompatibility complex (MHC) containing the classical human leukocyte antigen (HLA) Class I and Class II genes is among the most polymorphic and diverse regions in the human genome. Despite the clinical importance of identifying the HLA types, very few databases jointly characterize densely genotyped single nucleotide polymorphisms (SNPs) and HLA alleles in the same samples. To date, the HapMap presents the only public resource that provides a SNP reference panel for predicting HLA alleles, constructed with four collections of individuals of north-western European, northern Han Chinese, cosmopolitan Japanese and Yoruba Nigerian ancestry. Owing to complex patterns of linkage disequilibrium in this region, it is unclear whether the HapMap reference panels can be appropriately utilized for other populations. Here, we describe a public resource for the Singapore Genome Variation Project with: (i) dense genotyping across ∼ 9000 SNPs in the MHC; (ii) four-digit HLA typing for eight Class I and Class II loci, in 96 southern Han Chinese, 89 Southeast Asian Malays and 83 Tamil Indians. This resource provides population estimates of the frequencies of HLA alleles at these eight loci in the three population groups, particularly for HLA-DPA1 and HLA-DPB1 that were not assayed in HapMap. Comparing between population-specific reference panels and a cosmopolitan panel created from all four HapMap populations, we demonstrate that more accurate imputation is obtained with population-specific panels than with the cosmopolitan panel, especially for the Malays and Indians but even when imputing between northern and southern Han Chinese. As with SNP imputation, common HLA alleles were imputed with greater accuracy than low-frequency variants.

  1. Evolutionary analysis of classical HLA class I and II genes suggests that recent positive selection acted on DPB1*04:01 in Japanese population.

    PubMed

    Kawashima, Minae; Ohashi, Jun; Nishida, Nao; Tokunaga, Katsushi

    2012-01-01

    The human leukocyte antigen (HLA) genes exhibit the highest degree of polymorphism in the human genome. This high degree of variation at classical HLA class I and class II loci has been maintained by balancing selection for a long evolutionary time. However, little is known about recent positive selection acting on specific HLA alleles in a local population. To detect the signature of recent positive selection, we genotyped six HLA loci, HLA-A, HLA-B, HLA-C, HLA-DRB1, HLA-DQB1, and HLA-DPB1 in 418 Japanese subjects, and then assessed the haplotype homozygosity (HH) of each HLA allele. There were 120 HLA alleles across the six loci. Among the 80 HLA alleles with frequencies of more than 1%, DPB1*04∶01, which had a frequency of 6.1%, showed exceptionally high HH (0.53). This finding raises the possibility that recent positive selection has acted on DPB1*04∶01. The DPB1*04∶01 allele, which was present in the most common 6-locus HLA haplotype (4.4%), A*33∶03-C*14∶03-B*44∶03-DRB1*13∶02-DQB1*06∶04-DPB1*04∶01, seems to have flowed from the Korean peninsula to the Japanese archipelago in the Yayoi period. A stochastic simulation approach indicated that the strong linkage disequilibrium between DQB1*06∶04 and DPB1*04∶01 observed in Japanese cannot be explained without positive selection favoring DPB1*04∶01. The selection coefficient of DPB1*04∶01 was estimated as 0.041 (95% credible interval 0.021-0.077). Our results suggest that DPB1*04∶01 has recently undergone strong positive selection in Japanese population.

  2. Paucity of HLA-identical unrelated donors for African-Americans with hematologic malignancies: the need for new donor options.

    PubMed

    Dew, Alexander; Collins, Demetria; Artz, Andrew; Rich, Elizabeth; Stock, Wendy; Swanson, Kate; van Besien, Koen

    2008-08-01

    Identification of an HLA identical donor/recipient pair using high-resolution techniques at HLA A, B, C, and DRB1 optimizes survival after adult unrelated hematopoietic stem cell transplant. It has been estimated that roughly 50% of African-Americans have suitable unrelated donors based on serologic typing, but there is little information on the likelihood of identifying an HLA-identical unrelated donor using molecular techniques. From February 2002 to May 2007, we performed 51 unrelated donor searches for African-American patients using the National Marrow Donor Program and found HLA identical unrelated donors for only 3. By contrast, 50 (98%) had at least 1, and often multiple, appropriately matched cord blood units available. Very few African-American recipients have HLA-identical unrelated donors. To allow more African-American patients to proceed to transplant, innovative donor strategies, including adult cord blood transplantation, haploidentical transplant, or the identification of permissive mismatches should be investigated.

  3. Lack of association between HLA-G 14-bp polymorphism and systemic lupus erythematosus in a Han Chinese population.

    PubMed

    Wu, F-X; Wu, L-J; Luo, X-Y; Tang, Z; Yang, M-H; Xie, C-M; Liu, N-T; Zhou, J-G; Guan, J-L; Yuan, G-H

    2009-12-01

    HLA-G is a non-classical HLA-class Ib molecule with multiple immunoregulatory properties. A 14-bp insertion/deletion polymorphism in the HLA-G gene has been suggested to influence the expression of HLA-G and to associate with certain pathological conditions, including autoimmune diseases. We investigated the influence of the 14-bp insertion/deletion polymorphism in the HLA-G gene on disease susceptibility in systemic lupus erythematosus by genotyping this polymorphism in 231 patients with systemic lupus erythematosus and 367 healthy controls and analyzing the levels of soluble HLA-G in a subset of patients with systemic lupus erythematosus and healthy subjects from a Han Chinese population. No statistically significant differences were observed in the frequencies of the 14-bp insertion/deletion HLA-G alleles or genotypes between controls and patients with systemic lupus erythematosus. However, a significant increased expression of soluble HLA-G was noted in patients with systemic lupus erythematosus (mean value = 230.2 U/ml vs 118.3 U/ml in controls, p = 0.0001). Moreover, patients with high levels of soluble HLA-G presented with higher disease activity and had more neurological involvement. Our results do not support the HLA-G 14-bp insertion/deletion polymorphism as a genetic factor influencing systemic lupus erythematosus susceptibility. It is possible that the expression of soluble HLA-G in systemic lupus erythematosus is enhanced as part of a mechanism to try to restore the tolerance process towards auto-antigens and to counteract inflammation. However, the participation of this molecule in the pathological process of the disease also could not be excluded.

  4. First report on the antibody verification of HLA-DR, HLA-DQ and HLA-DP epitopes recorded in the HLA Epitope Registry.

    PubMed

    Duquesnoy, Rene J; Marrari, Marilyn; Tambur, Anat R; Mulder, Arend; Sousa, Luiz Cláudio Demes da Mata; da Silva, Adalberto Socorro; do Monte, Semiramis J H

    2014-11-01

    The International Registry of Antibody-Defined HLA Epitopes (http://www.epregistry.com.br) has been recently established as a tool to understand humoral responses to HLA mismatches. These epitopes can be structurally defined as eplets by three-dimensional molecular modeling and amino acid sequence differences between HLA antigens. A major goal is to identify HLA eplets that have been verified experimentally with informative antibodies. This report addresses class II epitopes encoded by genes in the HLA-D region. Our analysis included reviews of many publications about epitope specificity of class II reactive human and murine monoclonal antibodies and informative alloantibodies from HLA sensitized patients as well as our own antibody testing results. As of July 1, 2014, 24 HLA-DRB1/3/4/5, 15 DQB, 3 DQA and 8 DPB antibody-verified epitopes have been identified and recorded. The Registry is still a work-in-progress and will become a useful resource for HLA professionals interested in histocompatibility testing at the epitope level and investigating antibody responses to HLA mismatches in transplant patients.

  5. [The HLA system and habitual abortion].

    PubMed

    Hajek-Rosenmayr, A

    1990-01-01

    HLA-antigens are extremely polymorphic. A calculation of the polymorphism shows a number of 398.476.343 possible HLA-phenotypes, if HLA-A, -B, -C and -DR antigens are taken into account. The compatibility of HLA-antigens of recipient and donor plays a crucial role in transplantation: HLA-antigens are the traits, which are recognized by the immune system of the recipient in the frame of a rejection of the transplant or by the donor in the frame of a graft-versus-host reaction. Large international statistics show that HLA-incompatibility between recipient and donor leads to short transplant function periods, while compatibility brings about good transplant function. Therefore, matching of HLA-antigens plays an important role in transplantation of solid organs, mainly kidneys (3, 4, 5), and is completely necessary in bone marrow transplantation. Also in pregnancy, HLA-antigens are important: If HLA compatibility between mother and child is high, the risk for habitual abortion is higher than in normal pregnancies (6, 7).

  6. Associations of common variants in genes involved in metabolism and response to exogenous chemicals with risk of multiple myeloma

    PubMed Central

    Gold, Laura S.; De Roos, Anneclaire J.; Brown, Elizabeth E.; Lan, Qing; Milliken, Kevin; Davis, Scott; Chanock, Stephen J.; Zhang, Yawei; Severson, Richard; Zahm, Sheila H.; Zheng, Tongzhang; Rothman, Nat; Baris, Dalsu

    2009-01-01

    Background We examined risk of multiple myeloma (MM) associated with variants in genes involved in metabolism and response to exogenous chemicals [cytochrome P450 enzymes (CYP1B1, CYP2C9), epoxide hydrolase (EPHX1), paraoxonase 1 (PON1), arylhydrocarbon hydroxylase receptor (AHR), and NAD(P)H:quinone oxidoreductase (NQO1)]. Methods This study included 279 MM cases and 782 controls in a pooled analysis of two population-based case control studies. One common variant from each candidate gene was genotyped using DNA from blood or buccal cells. We estimated risk of MM associated with each genotype, controlling for race, gender, study site, and age, using odds ratios (OR) and 95% confidence intervals (CI). Results Evaluations of the CYP1B1 V432L variant (rs1056836) suggested increased risk of MM among persons with the CG and GG genotypes compared to the CC genotype [OR (95% CI) = 1.4 (1.0–2.0)]. Similar results were seen in analyses stratified by race and gender. We did not find any associations between MM and the CYP2C9, EPHX1, NQO1, or PON1 genes. Conclusions CYP1B1 activates chemicals such as polycyclic aromatic hydrocarbons and dioxins to create oxidized, reactive intermediates, and higher gene activity has been shown for the G allele. We conducted the largest analysis to date on MM and these genetic variants and our results provide preliminary evidence that variation in CYP1B1 may influence susceptibility to MM. PMID:19736056

  7. Do antibodies to myelin basic protein isolated from multiple sclerosis cross-react with measles and other common virus antigens?

    PubMed Central

    Bernard, C C; Townsend, E; Randell, V B; Williamson, H G

    1983-01-01

    Immunological activity to various antigens, including brain components, measles and other viruses, has been associated with IgG in multiple sclerosis (MS). One possible explanation for the presence of anti-viral antibodies and antibody to myelin basic protein (MBP) in MS patients is that there are antigenic determinants common to certain viruses and MBP. To assess this possibility, IgG from individual brains and sera from patients with MS, subacute sclerosing panencephalitis (SSPE) and controls was isolated by protein A and MBP-Sepharose affinity chromatography. Antibody to MBP was measured with a solid phase radioimmunoassay and antibody to measles and other viruses by immunofluorescence and/or complement fixation. Anti-MBP activity was detected in brain extracts and sera of all MS patients tested. In contrast to the low levels of antibody to MBP in control brains, high levels of anti-MBP antibodies were found in most of the normal sera. There was no correlation between the presence and levels of serum anti-measles antibodies and the anti-MBP activity. None of the anti-MBP antibodies affinity purified from brain and serum of MS patients reacted with any of the viruses tested, including measles. IgG purified from SSPE patients or from a rabbit hyperimmunized with measles antigen had no reactivity to MBP, despite high levels of anti-measles antibody. It is concluded that there is not direct link between the presence of antibody to MBP and antibody to measles and other viruses in MS patients. PMID:6190599

  8. SNP-based HLA allele tagging, imputation and association with antiepileptic drug-induced cutaneous reactions in Hong Kong Han Chinese.

    PubMed

    Gui, H; Kwok, M; Baum, L; Sham, P C; Kwan, P; Cherny, S S

    2017-04-11

    Human leukocyte antigen (HLA) genes control the regulation of the human immune system and are involved in immune-related diseases. Population surveys on relationships between single nucleotide polymorphisms (SNP) and HLA alleles are essential to conduct genetic association between HLA variants and diseases. Samples were obtained from our in-house database for epilepsy genetics and pharmacogenetics research. Using 184 epilepsy patients with both genome-wide SNP array and HLA-A/B candidate gene sequencing data, we sought tagging SNPs that completely represent sixHLA risk alleles; in addition, a Hong Kong population-specific reference panel was constructed for SNP-based HLA imputation. The performance of our new panel was compared to a recent Han Chinese panel. Finally, genetic associations of HLA variants with mild skin rash were performed on the combined sample of 408 patients. Common SNPs rs2571375 and rs144295468 were found to successfully tag HLA risk alleles A*31:01 and B*13:01, respectively. HLA-B*15:02 can be predicted by rs144012689 with >95% sensitivity and specificity. The imputation reference panel for the Hong Kong population had comparable performance to the Han Chinese panel due to the large sample size for common HLA alleles, though it retained discordance for imputing rare alleles. No significant genetic associations were found between HLA genetic variants and mild skin rash induced by aromatic antiepileptic drugs. This study provides new information on the genetic structure of HLA regions in the Hong Kong population by identifying tagging SNPs and serving as a reference panel. Moreover, our comprehensive genetic analyses revealed no significant association between HLA alleles and mild skin rash in Hong Kong Han Chinese.The Pharmacogenomics Journal advance online publication, 11 April 2017; doi:10.1038/tpj.2017.11.

  9. HLA-G UTR haplotype conservation in the Malian population: association with soluble HLA-G.

    PubMed

    Carlini, Federico; Traore, Karim; Cherouat, Nissem; Roubertoux, Pierre; Buhler, Stéphane; Cortey, Martì; Simon, Sophie; Doumbo, Ogobara; Chiaroni, Jacques; Picard, Christophe; Di Cristofaro, Julie

    2013-01-01

    The HLA-G molecule plays an important role in immunomodulation. In a previous study carried out on a southern French population our team showed that HLA-G haplotypes, defined by SNPs in the coding region and specific SNPs located in 5'URR and 3'UTR regulatory regions, are associated with differential soluble HLA-G expression (sHLA-G). Furthermore, the structure of these HLA-G haplotypes appears to be conserved in geographically distant populations. The aim of our study is to confirm these expectations in a sub-Saharan African population and to explore additional factors, such as HLA-A alleles, that might influence sHLA-G expression. DNA and plasma samples were collected from 229 Malians; HLA-G and HLA-A genotyping were respectively performed by the Snap Shot® method and by Luminex™ technology. sHLA-G dosage was performed using an ELISA kit. HLA-G and HLA-A allelic and haplotypic frequencies were estimated using an EM algorithm from the Gene[Rate] program. Associations between genetic and non genetic parameters with sHLA-G were performed using a non-parametric test with GRAPH PAD Prism 5. Our results reveal a good conservation of the HLA-G UTR haplotype structure in populations with different origins and demographic histories. These UTR haplotypes appear to be involved in different sHLA-G expression patterns. Specifically, the UTR-2 haplotype was associated with low sHLA-G levels, displaying a dominant negative effect. Furthermore, an allelic effect of both HLA-G and HLA-A, as well as non genetic parameters, such as age and gender possibly linked to osteogenesis and sexual hormones, also seem to be involved in the modulation of sHLA-G. These data suggest that further investigation in larger cohorts and in populations from various ethnical backgrounds is necessary not only to detect new functional polymorphism in HLA-G regulatory regions, but also to reveal the extent of biological phenomena that influence sHLA-G secretion and this might therefore have an impact

  10. Generation of MANAbodies specific to HLA-restricted epitopes encoded by somatically mutated genes.

    PubMed

    Skora, Andrew D; Douglass, Jacqueline; Hwang, Michael S; Tam, Ada J; Blosser, Richard L; Gabelli, Sandra B; Cao, Jianhong; Diaz, Luis A; Papadopoulos, Nickolas; Kinzler, Kenneth W; Vogelstein, Bert; Zhou, Shibin

    2015-08-11

    Mutant epitopes encoded by cancer genes are virtually always located in the interior of cells, making them invisible to conventional antibodies. We here describe an approach to identify single-chain variable fragments (scFvs) specific for mutant peptides presented on the cell surface by HLA molecules. We demonstrate that these scFvs can be successfully converted to full-length antibodies, termed MANAbodies, targeting "Mutation-Associated Neo-Antigens" bound to HLA. A phage display library representing a highly diverse array of single-chain variable fragment sequences was first designed and constructed. A competitive selection protocol was then used to identify clones specific for mutant peptides bound to predefined HLA types. In this way, we obtained two scFvs, one specific for a peptide encoded by a common KRAS mutant and the other by a common epidermal growth factor receptor (EGFR) mutant. The scFvs bound to these peptides only when the peptides were complexed with HLA-A2 (KRAS peptide) or HLA-A3 (EGFR peptide). We converted one scFv to a full-length antibody (MANAbody) and demonstrate that the MANAbody specifically reacts with mutant peptide-HLA complex even when the peptide differs by only one amino acid from the normal, WT form.

  11. Identification and distribution of three serologically undetected alleles of HLA-DR by oligonucleotide x DNA typing analysis

    SciTech Connect

    Tiercy, J.M.; Gorski, J.; Jeannet, M.; Mach, B.

    1988-01-01

    Recent progress in the molecular biology of human major histocompatibility complex class II genes (HLA-DP, -DQ, -DR) have shown that the genetic complexity and allelic polymorphism are greater than expected. In the case of HLA-DR, three DR ..beta..-chain loci have been identified and linked, two of which (DR ..beta..I and DR ..beta..III, now assigned names HLA-DR1B and HLA-DR3B) are functional. The authors have shown that the HLA micropolymorphism detected at the DNA sequence level can easily be analyzed by hybridization with allele-specific oligonucleotides (HLA oligotyping). In the case of the HLA DRw52 supertypic specificity, which includes the DR3, DR5, DRw6, and DRw8 haplotypes, three alleles, referred to as DRw52a, DRw52b, and DRw52c, have recently been identified at the HLA-DR3B locus by DNA sequencing. Hybridization with locus- and allele-specific oligonucleotide probes (designated 52a, 52b, and 52c) has been performed on DNA from normal individuals forming a panel of 82 haplotypes to establish the distribution of these three alleles. Individuals of the DR3 haplotype had either the DRw52a or DRw52b allele, and individuals of extended haplotype HLA-A1,B8,DR3 had only the DRw52a allele. DR5 individuals all had the DRw52b allele, while individuals of DRw6 haplotype had the DRw52a, -52b, or -52c allele. None of these three alleles are found in DRw8 individuals. Analysis of this micropolymorphism, undetectable by common typing procedures, is therefore now operational for more accurate HLA matching for transplantation and for improving correlations between HLA and disease susceptibility.

  12. Discordant Impact of HLA on Viral Replicative Capacity and Disease Progression in Pediatric and Adult HIV Infection

    PubMed Central

    Adland, Emily; Paioni, Paolo; Thobakgale, Christina; Laker, Leana; Mori, Luisa; Muenchhoff, Maximilian; Csala, Anna; Clapson, Margaret; Flynn, Jacquie; Novelli, Vas; Hurst, Jacob; Naidoo, Vanessa; Shapiro, Roger; Huang, Kuan-Hsiang Gary; Frater, John; Prendergast, Andrew; Prado, Julia G.; Ndung’u, Thumbi; Walker, Bruce D.; Carrington, Mary; Jooste, Pieter; Goulder, Philip J. R.

    2015-01-01

    HLA class I polymorphism has a major influence on adult HIV disease progression. An important mechanism mediating this effect is the impact on viral replicative capacity (VRC) of the escape mutations selected in response to HLA-restricted CD8+ T-cell responses. Factors that contribute to slow progression in pediatric HIV infection are less well understood. We here investigate the relationship between VRC and disease progression in pediatric infection, and the effect of HLA on VRC and on disease outcome in adult and pediatric infection. Studying a South African cohort of >350 ART-naïve, HIV-infected children and their mothers, we first observed that pediatric disease progression is significantly correlated with VRC. As expected, VRCs in mother-child pairs were strongly correlated (p = 0.004). The impact of the protective HLA alleles, HLA-B*57, HLA-B*58:01 and HLA-B*81:01, resulted in significantly lower VRCs in adults (p<0.0001), but not in children. Similarly, in adults, but not in children, VRCs were significantly higher in subjects expressing the disease-susceptible alleles HLA-B*18:01/45:01/58:02 (p = 0.007). Irrespective of the subject, VRCs were strongly correlated with the number of Gag CD8+ T-cell escape mutants driven by HLA-B*57/58:01/81:01 present in each virus (p = 0.0002). In contrast to the impact of VRC common to progression in adults and children, the HLA effects on disease outcome, that are substantial in adults, are small and statistically insignificant in infected children. These data further highlight the important role that VRC plays both in adult and pediatric progression, and demonstrate that HLA-independent factors, yet to be fully defined, are predominantly responsible for pediatric non-progression. PMID:26076345

  13. Counteraction of HLA-C-Mediated Immune Control of HIV-1 by Nef▿ †

    PubMed Central

    Specht, Anke; Telenti, Amalio; Martinez, Raquel; Fellay, Jacques; Bailes, Elizabeth; Evans, David T.; Carrington, Mary; Hahn, Beatrice H.; Goldstein, David B.; Kirchhoff, Frank

    2010-01-01

    A host genetic variant (−35C/T) correlates with increased human leukocyte antigen C (HLA-C) expression and improved control of HIV-1. HLA-C-mediated immunity may be particularly protective because HIV-1 is unable to remove HLA-C from the cell surface, whereas it can avoid HLA-A- and HLA-B-mediated immunity by Nef-mediated down-modulation. However, some individuals with the protective −35CC genotype exhibit high viral loads. Here, we investigated whether the ability of HIV-1 to replicate efficiently in the “protective” high-HLA-C-expression host environment correlates with specific functional properties of Nef. We found that high set point viral loads (sVLs) were not associated with the emergence of Nef variants that had acquired the ability to down-modulate HLA-C or were more effective in removing HLA-A and HLA-B from the cell surface. However, in individuals with the protective −35CC genotype we found a significant association between sVLs and the efficiency of Nef-mediated enhancement of virion infectivity and modulation of CD4, CD28, and the major histocompatibility complex class II (MHC-II)-associated invariant chain (Ii), while this was not observed in subjects with the −35TT genotype. Since the latter Nef functions all influence the stimulation of CD4+ T helper cells by antigen-presenting cells, they may cooperate to affect both the activation status of infected T cells and the generation of an antiviral cytotoxic T-lymphocyte (CTL) response. In comparison, different levels of viremia in individuals with the common −35TT genotype were not associated with differences in Nef function but with differences in HLA-C mRNA expression levels. Thus, while high HLA-C expression may generally facilitate control of HIV-1, Nef may counteract HLA-C-mediated immune control in some individuals indirectly, by manipulating T-cell function and MHC-II antigen presentation. PMID:20463068

  14. The correlation of HLA allele frequencies and HLA antibodies in sensitized kidney transplantation candidates.

    PubMed

    Fu, Q; Wang, C; Zeng, W; Liu, L

    2012-01-01

    The clinical importance of the HLA system is as a transplant antigen. However, correlations between the development and strength of the immune response and HLA genes or specific foreign antigens are not clear. The objectives of this study were to detect HLA-A, -B, and -DRB1 allele frequencies and HLA antibodies in sensitized patients, and to investigate the correlation between the HLA alleles and HLA sensitization. This study included 383 sensitized patients and 1000 unsensitized patients awaiting kidney transplantation from 2001-2010. HLA -A, -B, and -DRB1 typing was performed using sequence-specific primer-polymerase chain reactions (SSP-PCR). Arlequin statistical analysis software was used to calculate the HLA allele frequencies among the 2 groups. The anti-HLA-specific antibodies of sensitized patients were identified and analyzed using enzyme-linked immunosorbent assay (ELISA). The numbers of identified HLA -A, -B, and -DRB1 alleles were 20, 43, and 14, respectively. The 5 most frequent HLA alleles in the 2 groups were not different: A-02, 11, 24, 33, 26; B-46, 60, 13, 75, 58; and DR-9, 15, 12, 4, 14. Among the sensitized group, the most frequent HLA-specific antibodies were as follows: A-2, 24, 68, 23, 32; B-27, 56, 57, 7, 60; and DR-7, 4, 9, 13, 17. There was little correlation between HLA sensitization and HLA alleles of oneself. High frequency alleles and the specificity of high-frequency HLA antibodies were not consistent. Copyright © 2012 Elsevier Inc. All rights reserved.

  15. Norwegian Sami differs significantly from other Norwegians according to their HLA profile.

    PubMed

    Harbo, H F; Riccio, M E; Lorentzen, A R; Utsi, E; Myhr, K-M; Mellgren, S I; Flåm, S T; Thorsby, E; Sanchez-Mazas, A; Lie, B A

    2010-03-01

    This study reports extensive genomic data for both human leukocyte antigen (HLA) class I and II loci in Norwegian Sami, a native population living in the northwest of Europe. The Sami have a distinct culture and their own languages, which belong to the Uralic linguistic family. Norwegian Sami (n = 200) were typed at the DNA level for the HLA-A, -C, -B, -DRB1 and -DQB1 loci, and compared with a non-Sami Norwegian population (n = 576). The two populations exhibited some common genetic features but also differed significantly at all HLA loci. The most significantly deviating allele frequencies were an increase of HLA-A*03, -B*27, -DRB1*08 and -DQB1*04 and a decrease of HLA-A*01, C*01, -DRB1*04 and -DQB1*02 among Sami compared with non-Sami Norwegians. The Sami showed no deviation from Hardy-Weinberg equilibrium. The hypothesis of selective neutrality was rejected at all loci except for the A- and C- loci for the Sami. HLA haplotype frequencies also differed between the two populations. The most common extended HLA haplotypes were A*02-B*27-C*01-DR*08-DQB1*04 in the Sami and A*01-B*08-C*07-DR*03-DQB1*02 in the other Norwegians. Genetic distance analyses indicated that the Norwegian Sami were highly differentiated from other Europeans and were most closely related to Finns whose language also belongs to the Uralic linguistic family. In conclusion, the Norwegian Sami and the non-Sami Norwegians were significantly different at all HLA loci. Our results can be explained by the fact that the two populations have different origins and that the Sami population has remained smaller and more isolated than its neighbors.

  16. Co-expression of ILT4/HLA-G in human non-small cell lung cancer correlates with poor prognosis and ILT4-HLA-G interaction activates ERK signaling.

    PubMed

    Zhang, Yanwen; Zhao, Jianqiang; Qiu, Lijun; Zhang, Pei; Li, Juan; Yang, Dong; Wei, Xiaojuan; Han, Yali; Nie, Siyue; Sun, Yuping

    2016-08-01

    Non-small cell lung cancer (NSCLC) is the most common malignant tumor in the world, of which prognosis is generally poor due to insufficient mechanistic understanding. To explore the molecular pathogenesis of NSCLC, the co-expression of immunoglobulin-like transcript 4 (ILT4) and its ligand human leukocyte antigen G (HLA-G) in NSCLC tissues and cells were investigated. Here, we detected the expression of ILT4 and HLA-G in 81 tumor specimens from primary NSCLC patients, and we found that co-expression of ILT4/HLA-G was significantly associated with regional lymph node involvement, advanced stages, and the overall survival of patients. In NSCLC cell lines, HLA-G expression increased/decreased accordingly when ILT4 was up-/down-regulated, and ILT4 expression increased in a concentration-dependent manner via the stimulation of HLA-G fusion protein. Interestingly, HLA-G fusion protein could also up-regulate the phospho-ERK1/2 expression, which means the activation of extracellular signal-regulated kinase (ERK) signaling. All in all, our results indicate that the ILT4-HLA-G interaction might play an important role in NSCLC progression. Identification of ILT4 and HLA-G expression may provide an indicator to predict prognosis and guide prevention and treatment of NSCLC.

  17. HLA-DQA1 and HLA-DQB1 allele diversity and its extended haplotypes in Madeira Island (Portugal).

    PubMed

    Spínola, H; Lemos, A; Couto, A R; Parreira, B; Soares, M; Dutra, I; Bruges-Armas, J; Brehm, A

    2017-02-01

    This study shows, for the first time, high-resolution allele frequencies of HLA-DQA1 loci in Madeira Island (Portugal) and allows us to better understand and refine present knowledge on DQB1 variation, with the identification of several alleles not previously reported in this population. Estimates on haplotype profile, involving HLA-A, HLA-B, HLA-DRB1, HLA-DQA1 and HLA-DQB1, are also reported. © 2016 John Wiley & Sons Ltd.

  18. Influence of stellar multiplicity on planet formation. II. Planets are less common in multiple-star systems with separations smaller than 1500 AU

    SciTech Connect

    Wang, Ji; Fischer, Debra A.; Xie, Ji-Wei; Ciardi, David R.

    2014-08-20

    Almost half of the stellar systems in the solar neighborhood are made up of multiple stars. In multiple-star systems, planet formation is under the dynamical influence of stellar companions, and the planet occurrence rate is expected to be different from that of single stars. There have been numerous studies on the planet occurrence rate of single star systems. However, to fully understand planet formation, the planet occurrence rate in multiple-star systems needs to be addressed. In this work, we infer the planet occurrence rate in multiple-star systems by measuring the stellar multiplicity rate for planet host stars. For a subsample of 56 Kepler planet host stars, we use adaptive optics (AO) imaging and the radial velocity (RV) technique to search for stellar companions. The combination of these two techniques results in high search completeness for stellar companions. We detect 59 visual stellar companions to 25 planet host stars with AO data. Three stellar companions are within 2'' and 27 within 6''. We also detect two possible stellar companions (KOI 5 and KOI 69) showing long-term RV acceleration. After correcting for a bias against planet detection in multiple-star systems due to flux contamination, we find that planet formation is suppressed in multiple-star systems with separations smaller than 1500 AU. Specifically, we find that compared to single star systems, planets in multiple-star systems occur 4.5 ± 3.2, 2.6 ± 1.0, and 1.7 ± 0.5 times less frequently when a stellar companion is present at a distance of 10, 100, and 1000 AU, respectively. This conclusion applies only to circumstellar planets; the planet occurrence rate for circumbinary planets requires further investigation.

  19. The dilemma of DQ HLA-antibodies.

    PubMed

    Al Attas, Rabab; Al Abduladheem, Dalal; Shawhatti, Adel A; Lopez, Ricardo; Liacini, Abdelhamid; AlZahrani, Saber; Akkari, Khalid; Hasan, Nasreen; Alabadi, Abdulnaser

    2015-05-01

    Accurate identification of antibody reactivity against HLA-DQ antigens was difficult by using the old serological assays because of the strong linkage disequilibrium between HLA-DR and HLA-DQ (the usual inheritance of a certain HLA-DR molecule that ties together with the same DQ molecule within a racial group). The accurate and precise identifications of anti-HLA-antibodies of DQ specificities were made possible with the introduction of multiplex-bead arrays (Luminex), using single antigen bead (SAB) assay. The SAB assay is also considered today to be the most sensitive and specific method for alloimmunization assessment even for the low titer anti-HLA-antibodies. However, it is becoming clear that the detection of the HLA antibodies by SAB is not absolutely perfect due to the variation in densities, conformations and orientations of the antigen coated beads. Unlike HLA-DR, the HLA-DQ antigens are made of two polymorphic chains, both (alpha and beta chains) can contribute to the process of immunization individually or jointly. Routine SAB testing approach, which assigns the specificities based on beta chains and ignores the contribution of the DQα chains, can lead to erroneous DQ-antibody assignments. Therefore, it is important to recognize both the peculiarity of the HLA-DQ antigens as well as the nature of the assay format used in order to reach the correct antibody assignments. Erroneous donor specific antibodies (DSA) assignment may lead to denial of an otherwise immunologically compatible organ transplant, or exposing transplant recipients to unnecessary investigations or immunosuppression. The following two patients presented with HLA-antibodies against DQ antigens (anti-DQ-Abs) highlight these two scenarios. Copyright © 2015 American Society for Histocompatibility and Immunogenetics. Published by Elsevier Inc. All rights reserved.

  20. Ancestral association between HLA and HFE H63D and C282Y gene mutations from northwest Colombia

    PubMed Central

    Rodriguez, Libia M; Giraldo, Mabel C; Velasquez, Laura I; Alvarez, Cristiam M; Garcia, Luis F; Jimenez-Del-Rio, Marlene; Velez-Pardo, Carlos

    2015-01-01

    A significant association between HFE gene mutations and the HLA-A*03-B*07 and HLA-A*29-B*44 haplotypes has been reported in the Spanish population. It has been proposed that these mutations are probably connected with Celtic and North African ancestry, respectively. We aimed to find the possible ancestral association between HLA alleles and haplotypes associated with the HFE gene (C282Y and H63D) mutations in 214 subjects from Antioquia, Colombia. These were 18 individuals with presumed hereditary hemochromatosis (“HH”) and 196 controls. The HLA-B*07 allele was in linkage disequilibrium (LD) with C282Y, while HLA-A*23, A*29, HLA-B*44, and B*49 were in LD with H63D. Altogether, our results show that, although the H63D mutation is more common in the Antioquia population, it is not associated with any particular HLA haplotype, whereas the C282Y mutation is associated with HLA-A*03-B*07, this supporting a northern Spaniard ancestry. PMID:25983618

  1. Burden of Common Multiple-Morbidity Constellations on Out-of-Pocket Medical Expenditures among Older Adults

    ERIC Educational Resources Information Center

    Schoenberg, Nancy E.; Kim, Hyungsoo; Edwards, William; Fleming, Steven T.

    2007-01-01

    Purpose: On average, adults aged 60 years or older have 2.2 chronic diseases, contributing to the over 60 million Americans with multiple morbidities. We aimed to understand the financial implications of the most frequent multiple morbidities among older adults. Design and Methods: We analyzed Health and Retirement Study data, determining…

  2. Burden of Common Multiple-Morbidity Constellations on Out-of-Pocket Medical Expenditures among Older Adults

    ERIC Educational Resources Information Center

    Schoenberg, Nancy E.; Kim, Hyungsoo; Edwards, William; Fleming, Steven T.

    2007-01-01

    Purpose: On average, adults aged 60 years or older have 2.2 chronic diseases, contributing to the over 60 million Americans with multiple morbidities. We aimed to understand the financial implications of the most frequent multiple morbidities among older adults. Design and Methods: We analyzed Health and Retirement Study data, determining…

  3. Relevance of HLA-G, HLA-E and IL-10 expression in lip carcinogenesis.

    PubMed

    Gonçalves, Andréia Souza; Oliveira, Jéssica Petini; Oliveira, Carolina Ferrari Piloni; Silva, Tarcília Aparecida; Mendonça, Elismauro Francisco; Wastowski, Isabela Jubé; Batista, Aline Carvalho

    2016-09-01

    HLA-G, HLA-E and IL-10 are molecules which can provide tumor immunosuppression as well as the capacity of evasion to the immune system host. This study set out to evaluate HLA-G, HLA-E and IL-10 expression in lip squamous cell carcinoma (LSCC) and in a potentially malignant disorder (actinic cheilitis - AC), correlating the expression of these proteins with the degree of epithelial dysplasia. Immunohistochemistry was undertaken to identify HLA-G, HLA-E and IL-10 in samples from patients with LSCC (n=20), AC (n=30) and healthy lip mucosa (control) (n=10). A semiquantitative scoring system was used for analysis. Differences between the groups were evaluated using the Pearson Chi-Squared test. The percentage of LSCC samples showing high immunoreactivity (IRS>2) for HLA-G, HLA-E and IL-10 (neoplastic/epithelial cells) and HLA-E (stroma/connective tissue) was significantly higher that of the control (P<0.05). A tendency for a progressive increase in the proteins analyzed was observed from the control to AC and to LSCC. The degree of dysplasia in the AC samples was not significantly associated with the proteins evaluated (P>0.05). The high expression of HLA-G, HLA-E and IL-10 in AC and LSCC reflects the capacity that these pathologies have for evasion and progression.

  4. Natalizumab-related anaphylactoid reactions in MS patients are associated with HLA class II alleles

    PubMed Central

    de la Hera, Belén; Urcelay, Elena; Brassat, David; Chan, Andrew; Vidal-Jordana, Angela; Salmen, Anke; Villar, Luisa Maria; Álvarez-Cermeño, José Carlos; Izquierdo, Guillermo; Fernández, Oscar; Oliver, Begoña; Saiz, Albert; Ara, Jose Ramón; Vigo, Ana G.; Arroyo, Rafael; Meca, Virginia; Malhotra, Sunny; Fissolo, Nicolás; Horga, Alejandro; Montalban, Xavier

    2014-01-01

    Objectives: We aimed to investigate potential associations between human leukocyte antigen (HLA) class I and class II alleles and the development of anaphylactic/anaphylactoid reactions in patients with multiple sclerosis (MS) treated with natalizumab. Methods: HLA class I and II genotyping was performed in patients with MS who experienced anaphylactic/anaphylactoid reactions and in patients who did not develop infusion-related allergic reactions following natalizumab administration. Results: A total of 119 patients with MS from 3 different cohorts were included in the study: 54 with natalizumab-related anaphylactic/anaphylactoid reactions and 65 without allergic reactions. HLA-DRB1*13 and HLA-DRB1*14 alleles were significantly increased in patients who developed anaphylactic/anaphylactoid reactions (pM-H = 3 × 10−7; odds ratio [OR]M-H = 8.96, 95% confidence interval [CI] = 3.40–23.64), with a positive predictive value (PPV) of 82%. In contrast, the HLA-DRB1*15 allele was significantly more represented in patients who did not develop anaphylactic/anaphylactoid reactions to natalizumab (pM-H = 6 × 10−4; ORM-H = 0.2, 95% CI = 0.08–0.50), with a PPV of 81%. Conclusions: HLA-DRB1 genotyping before natalizumab treatment may help neurologists to identify patients with MS at risk for developing serious systemic hypersensitivity reactions associated with natalizumab administration. PMID:25520955

  5. Relation of HLA class I and II supertypes with spontaneous clearance of hepatitis C virus.

    PubMed

    Kuniholm, M H; Anastos, K; Kovacs, A; Gao, X; Marti, D; Sette, A; Greenblatt, R M; Peters, M; Cohen, M H; Minkoff, H; Gange, S J; Thio, C L; Young, M A; Xue, X; Carrington, M; Strickler, H D

    2013-01-01

    Human leukocyte antigen (HLA) genotype has been associated with the probability of spontaneous clearance of hepatitis C virus (HCV). However, no prior studies have examined whether this relationship may be further characterized by grouping HLA alleles according to their supertypes, defined by their binding capacities. There is debate regarding the most appropriate method to define supertypes. Therefore, previously reported HLA supertypes (46 class I and 25 class II) were assessed for their relation with HCV clearance in a population of 758 HCV-seropositive women. Two HLA class II supertypes were significant in multivariable models that included: (i) supertypes with significant or borderline associations with HCV clearance after adjustment for multiple tests, and (ii) individual HLA alleles not part of these supertypes, but associated with HCV clearance in our prior study in this population. Specifically, supertype DRB3 (prevalence ratio (PR)=0.4; P=0.004) was associated with HCV persistence, whereas DR8 (PR=1.8; P=0.01) was associated with HCV clearance. Two individual alleles (B*57:01 and C*01:02) associated with HCV clearance in our prior study became nonsignificant in analysis that included supertypes, whereas B*57:03 (PR=1.9; P=0.008) and DRB1*07:01 (PR=1.7; P=0.005) retained their significance. These data provide epidemiologic support for the significance of HLA supertypes in relation to HCV clearance.

  6. Classification of mutations at the HLA-A locus by use of the polymerase chain reaction

    SciTech Connect

    Joseph, G.; Grist, S.; Firgaira, F.; Turner, D.; Morley, A. )

    1993-01-01

    The authors investigated whether the polymerase chain reaction (PCR) could be used to determine the mechanism of mutation in lymphocyte clones mutated at the HLA-A locus. Three polymorphisms, at Factor XIIIA, D6S109, and intron 3 of the HLA-A gene, were used to study a series of clones previously characterized by Southern blotting (SB) at multiple loci on chromosome 6. For detection of loss of heterozygosity, the results of PCR and SB were concordant in 140 of 141 clones when polymorphism in the Factor XIIIA region was studied and in 144 of 145 clones when polymorphism in the HLA-A gene was studied. For classification of the mechanism of mutation, PCR and SB gave the same result in 88 of 92 clones (96%) when a combination of the HLA-A and Factor XIIIA polymorphisms was used and in 46 of 47 clones (98%) when a combination of the HLA-A and D6S109 polymorphisms was used. The results indicate that PCR provides a simple and reliable method for categorizing mutations at the HLA-A locus as arising from mitotic recombination, deletion, or from presumptive minor changes within the gene. Rare events such as gene conversion, nondisjunction, or large deletions extending to the telomere will be misclassified. However, such events are rare for mutations at this locus. 9 refs., 2 figs., 5 tabs.

  7. Association between HLA-DQ genotypes and haplotypes vs Helicobacter pylori infection in an Indonesian population.

    PubMed

    Zhao, Yang; Wang, Jingwen; Tanaka, Tsutomu; Hosono, Akihiro; Ando, Ryosuke; Soeripto, Soeripto; Ediati Triningsih, F X; Triono, Tegu; Sumoharjo, Suwignyo; Astuti, E Y Wenny; Gunawan, Stephanus; Tokudome, Shinkan

    2012-01-01

    Helicobacter pylori is an important gastrointestinal pathogen related to the development of not only atrophic gastritis and peptic ulcer, but also gastric cancer. Human leukocyte antigens (HLA) may play particular roles in host immune responses to bacterial antigens. This study aimed to investigate the association between HLA-DQA1 and DQB1 genotypes and haplotypes vs H. pylori infection in an Indonesian population. We selected 294 healthy participants in Mataram, Lombok Island, Indonesia. H. pylori infection was determined by urea breath test (UBT). We analyzed HLA-DQA1 and DQB1 genotypes by PCR-RFLP and constructed haplotypes of HLA-DQA1 and DQB1 genes. Multiple comparisons were conducted according to the Bonferroni method. The H. pylori infection rate was 11.2% in this Indonesian population. The DQB1*0401 genotype was noted to be associated with a high risk of H. pylori infection, compared with the DQB1*0301 genotype. None of the HLA-DQA1 or DQB1 haplotypes were related to the risk of H. pylori infection. The study suggests that HLADQB1 genes play important roles in H. pylori infection, but there was no statistically significant association between HLA-DQA1 or DQB1 haplotypes and H.pylori infection in our Lombok Indonesian population.

  8. Cytomegalovirus Infection in Ireland: Seroprevalence, HLA Class I Alleles, and Implications.

    PubMed

    Hassan, Jaythoon; O'Neill, Derek; Honari, Bahman; De Gascun, Cillian; Connell, Jeff; Keogan, Mary; Hickey, David

    2016-02-01

    .2%, and 30.8%, respectively. The presence of the most common inherited haplotype in the Irish population, HLA-A1, B8 was significantly associated with CMV seronegativity (OR = 1.278, P < 0.001, CI [1.049, 1.556]).CMV seroprevalence is lower in Ireland compared with other countries. The high frequency of HLA-A1 in the Irish population may, in part, have a role in the reduced susceptibility to CMV infection.

  9. Obstructive sleep apnoea syndrome and HLA in the North of Portugal.

    PubMed

    Silva, Luís; Lopes, João; Ramalheira, João; Cunha, Daniela; Carvalho, Cláudia; Bettencourt, Andreia; Bras, Sandra; Costa, Sandra; Silva, M Berta; Martins-da-Silva, António

    2015-10-01

    Introduccion. El sindrome de apnea obstructiva del sueño (SAOS) es una enfermedad frecuente, compleja y poligenica, con diversas etiologias que interaccionan originando un fenotipo unico. El SAOS puede ocurrir a cualquier edad del individuo y se presume la existencia de agregacion familiar. Han sido descritos diversos factores de predisposicion, como la edad, el sexo y la obesidad. La relacion entre los polimorfismos del antigeno leucocitario humano (HLA) y trastornos del sueño esta confirmada, tanto en poblaciones europeas como no europeas. No obstante, las relaciones descritas entre los alelos HLA y SAOS no han sido coherentes y carecen de valor informativo para la clasificacion del trastorno del sueño. Objetivo. Explorar la asociacion genetica del HLA con el SAOS en una poblacion del norte de Portugal y evaluar el papel de la obesidad en el contexto del HLA en el SAOS. Pacientes y metodos. Se estudio una cohorte de 131 pacientes con SAOS. Los pacientes fueron atendidos en una clinica del sueño ambulatoria donde se valoraron los antecedentes clinicos, se les practico una polisomnografia nocturna, una prueba de latencia multiple del sueño (si lo exigio el diagnostico diferencial), analiticas y estudios demograficos. A efectos comparativos, se utilizo una poblacion de control de 223 personas sanas. Se efectuo el genotipado del HLA-DRB1 con la reaccion en cadena de la polimerasa mediante cebadores de secuencia especifica. Resultados. En esta cohorte, el alelo HLA-DRB1*03 fue identificado como un factor de predisposicion para el SAOS (24% del SAOS frente a 15% de la poblacion de control; p = 0,025; odds ratio = 1,861; intervalo de confianza al 95% = 1,081-3,205). No hubo diferencias significativas en lo referente a otros alelos HLA-DBR1*. Conclusion. El HLA-DRB1*03 es un factor de predisposicion para el SAOS en la poblacion portuguesa.

  10. [HLA and myasthenia. Subdivision in 3 categories].

    PubMed

    Elchidiac, A; Lepage, V; Berrih, S; Colombani, J; Degos, L

    1985-01-01

    Genetic susceptibility (HLA types), clinical and pathological findings, amount of acetylcholine receptor antibodies and T lymphocyte subpopulations were studied in 63 patients with Myasthenia Gravis (MG). The frequency of HLA-DR5 was increased among patients (0.50 versus 0.23 in controls, pc less than 0.01, relative risk 3.3) and that of HLA-DR3 previously described as associated with MG was slightly increased (0.31 versus 0.20 in controls). The relative frequencies of two T cell subpopulations (T4 helper and T8 suppressor/cytotoxic lymphocytes) were normal in HLA-DR5 positive patients while the ratio T4/T8 was increased in other MG patients, who were HLA-DR3 (p less than 0.005). The high rate was due to an increase in the absolute number of T4 lymphocytes (p less than 0.001). HLA-DR3 patients were mostly women with early onset of a severe form of the disease, marked by the presence of thymic follicular lymphoid hyperplasia. A third genetic susceptibility to this disease was recently described in patients treated with D-penicillamine, the antigenic frequency of HLA-Bw35, DR1 is significantly increased. These 3 types of association between HLA and myasthenia gravis can be related to three different physiopathological mechanisms: the first two are probably linked to individual immunity (inductor/suppressor disequilibrium), in the third association, the mechanism is immunopharmacological.

  11. Monocytic HLA DR antigens in schizophrenic patients.

    PubMed

    Krause, Daniela; Wagner, Jenny; Matz, Judith; Weidinger, Elif; Obermeier, Michael; Riedel, Michael; Gruber, Rudolf; Schwarz, Markus; Mueller, Norbert

    2012-01-01

    A genetic association of specific human leukocyte antigens (HLA) DR genes and schizophrenia has recently been shown. These HLA play a fundamental role in the control of immune responses. Furthermore infectious agents have been proposed to be involved in the pathogenesis of schizophrenia. In this study we investigated the rate of HLA DR positive monocytes in schizophrenic patients compared to controls with a special focus on the adaption to in vitro stimulation with toll-like receptor ligands. Patients with schizophrenia and matched controls were included. For each individual, we evaluated the rate of HLA DR positive monocytes (either incubated at 37 °C or after stimulation with lipopolysaccharide or Poly I:C). We found a significantly higher percentage of schizophrenic patients with elevated HLA DR positive cells (p=0.045) as compared to controls. The adjustment rate from baseline levels of monocytic HLA DR positive cells to stimulation with Poly I:C was significantly lower in schizophrenic patients (p=0.038). The increased monocytic HLA DR in schizophrenic patients and the maladjustment of their monocytic HLA DR levels to an infectious stimulus might be a sign for a disturbed monocytic immune balance in schizophrenic individuals.

  12. Predicted indirectly recognizable HLA epitopes presented by HLA-DR correlate with the de novo development of donor-specific HLA IgG antibodies after kidney transplantation.

    PubMed

    Otten, Henny G; Calis, Jorg J A; Keşmir, Can; van Zuilen, Arjan D; Spierings, Eric

    2013-03-01

    HLA class-I mismatches selectively induce antibody formation after kidney transplantation. The de novo development of donor-specific IgG HLA class-I antibodies may be dependent on the HLA class-II background of the patient by presenting T-helper epitopes within the recognized HLA class-I antigens. The correlation between antibody production against mismatched donor human leukocyte antigens (HLA) class I and the number of HLA class II-restricted predicted indirectly recognizable HLA epitopes (PIRCHE-II) in the respective HLA class-I mismatches was investigated. To this end, we analyzed sera taken after nephrectomy from a cohort of 21 non-immunized individuals that received a renal transplant. Fourty-nine HLA class-I mismatches were found which all contained immunogenic eplets according to HLAMatchmaker. Donor specific HLA antibody responses were detected against 38 HLA class-I mismatches after nephrectomy. These mismatches were found to contain a larger number of PIRCHE-II when compared to mismatches which did not induce donor specific HLA antibodies. Most PIRCHE-II (68%) were not part of an eplet as defined by HLAMatchmaker. Our data suggest that presentation of donor-derived HLA class-I peptides by recipient HLA class-II molecules plays a significant role in de novo development of donor-specific IgG HLA antibodies. Copyright © 2012 American Society for Histocompatibility and Immunogenetics. Published by Elsevier Inc. All rights reserved.

  13. Uncovering the peptide-binding specificities of HLA-C: a general strategy to determine the specificity of any MHC class I molecule.

    PubMed

    Rasmussen, Michael; Harndahl, Mikkel; Stryhn, Anette; Boucherma, Rachid; Nielsen, Lise Lotte; Lemonnier, François A; Nielsen, Morten; Buus, Søren

    2014-11-15

    MHC class I molecules (HLA-I in humans) present peptides derived from endogenous proteins to CTLs. Whereas the peptide-binding specificities of HLA-A and -B molecules have been studied extensively, little is known about HLA-C specificities. Combining a positional scanning combinatorial peptide library approach with a peptide-HLA-I dissociation assay, in this study we present a general strategy to determine the peptide-binding specificity of any MHC class I molecule. We applied this novel strategy to 17 of the most common HLA-C molecules, and for 16 of these we successfully generated matrices representing their peptide-binding motifs. The motifs prominently shared a conserved C-terminal primary anchor with hydrophobic amino acid residues, as well as one or more diverse primary and auxiliary anchors at P1, P2, P3, and/or P7. Matrices were used to generate a large panel of HLA-C-specific peptide-binding data and update our pan-specific NetMHCpan predictor, whose predictive performance was considerably improved with respect to peptide binding to HLA-C. The updated predictor was used to assess the specificities of HLA-C molecules, which were found to cover a more limited sequence space than HLA-A and -B molecules. Assessing the functional significance of these new tools, HLA-C*07:01 transgenic mice were immunized with stable HLA-C*07:01 binders; six of six tested stable peptide binders were immunogenic. Finally, we generated HLA-C tetramers and labeled human CD8(+) T cells and NK cells. These new resources should support future research on the biology of HLA-C molecules. The data are deposited at the Immune Epitope Database, and the updated NetMHCpan predictor is available at the Center for Biological Sequence Analysis and the Immune Epitope Database. Copyright © 2014 by The American Association of Immunologists, Inc.

  14. NK cell tolerance of self-specific activating receptor KIR2DS1 in individuals with cognate HLA-C2 ligand

    PubMed Central

    Pittari, Gianfranco; Liu, Xiao-Rong; Selvakumar, Annamalai; Zhao, Zeguo; Merino-Plaza, Ernesto; Huse, Morgan; Chewning, Joseph H.; Hsu, Katharine C.; Dupont, Bo

    2013-01-01

    NK cells are regulated by inhibiting and activating cell surface receptors. Most inhibitory receptors recognize MHC-class I antigens, and protect healthy cells from NK cell-mediated auto-aggression. However, certain activating receptors, including the human killer cell Ig-like receptor (KIR) 2DS1, also recognize MHC-class I. This raises the question of how NK cells expressing such activating receptors are tolerized to host tissues. We investigated whether the presence of HLA-C2, the cognate ligand for 2DS1, induces tolerance in 2DS1-expressing NK cells. Anti-HLA-C2 activity could be detected in vitro in some 2DS1 positive NK clones irrespective of presence or absence of HLA-C2 ligand in the donor. The frequency of anti-HLA-C2 reactivity was high in donors homozygous for HLA-C1. Surprisingly, there was no significant difference in frequency of anti-HLA-C2 cytotoxicity in donors heterozygous for HLA-C2 and donors without HLA-C2 ligand. However, donors homozygous for HLA-C2 had significantly reduced frequency of anti-HLA-C2 reactive clones as compared to all other donors. 2DS1 positive clones that express inhibitory KIR for self-HLA class I were commonly non-cytotoxic, and anti-HLA-C2 cytotoxicity was nearly exclusively restricted to 2DS1 single positive clones lacking inhibitory KIR. 2DS1 single positive NK clones with anti-HLA-C2 reactivity were also present post-transplantation in HLA-C2 positive recipients of hematopoietic stem cell transplants from 2DS1 positive donors. These results demonstrate that many NK cells with anti-HLA-C2 reactivity are present in HLA-C1 homozygous and heterozygous donors with 2DS1. In contrast, 2DS1 positive clones from HLA-C2 homozygous donors are frequently tolerant to HLA-C2. PMID:23554313

  15. Analysis of KIR gene frequencies and HLA class I genotypes in prostate cancer and control group.

    PubMed

    Portela, P; Jobim, L F; Salim, P H; Koff, W J; Wilson, T J; Jobim, M R; Schwartsmann, G; Roesler, R; Jobim, M

    2012-10-01

    Prostate cancer is the second most common cancer in men, with a significant increase in incidence and mortality in men over 50 years of age. Natural killer cells (NK) are part of the innate immune system recognizing class I HLA molecules on target cells through their membrane receptors, called killer cell immunoglobulin-like receptors (KIR). The aim of our study is to evaluate the association between the KIR genes and HLA alleles in patients with prostate cancer and healthy controls. Two hundred patients with prostate cancer and 185 healthy controls were typed for HLA class I and KIR genes by PCR-SSP. When both groups were compared, no significant differences were found for HLA-C group 1 and group 2, HLA-Bw4, HLA-A3 and A11. No difference was seen either in KIR frequency between patients with prostate cancer and controls. In conclusion, our data suggest no potential role for the KIR gene system in prostate cancer.

  16. Human leukocyte antigen (HLA) class I and II alleles in Turkish patients with rheumatic heart disease.

    PubMed

    Gündogdu, Fuat; Islamoglu, Yahya; Pirim, Ibrahim; Gurlertop, Yekta; Dogan, Hasan; Arslan, Sakir; Sevimli, Serdar; Aksakal, Enbiya; Senocak, Huseyin

    2007-05-01

    Rheumatic heart disease (RHD) is often preceded by rheumatic fever (RF). The disease is a multisystem inflammatory condition that develops as a sequel to untreated throat infection by group A beta-hemolytic streptococci. Several studies have suggested that genetic susceptibility to RHD may be linked to human leukocyte antigen (HLA) class II alleles. The study aim was to investigate the association between RHD and the antigens HLA-A, -B, -C, -DR and -DQ profile in RHD patients in eastern Turkey. A case-control study was conducted which included 85 unrelated patients with RHD, and 85 control subjects. The diagnosis was supported by echocardiography and histories of RHD of those patients who underwent valve replacement. The association of class I and class II HLA antigens was examined in RHD and control subjects using a sequence-specific primer (SSP) method. The phenotypes HLA-B51, -Cw*4 and -DRB1*01 were encountered in significantly lower frequencies in patients with RHD compared to the control population (p <0.05, p <0.05, p <0.05, respectively). There was also a significant increase in antigen frequency of HLA-DQB1*08 in RHD patients compared to controls (p <0.005). Among the studied population, the results suggested that susceptibility to RHD was HLA-related, with HLA-DQB1*08 most likely influencing the occurrence of the condition. HLA-B51, -Cw*4 and -DRB1*01 appeared to be more common in control subjects.

  17. HLA-A*31: 01 and HLA-B*15:02 association with Stevens-Johnson syndrome and toxic epidermal necrolysis to carbamazepine in a multiethnic Malaysian population.

    PubMed

    Khor, Amy Hui-Ping; Lim, Kheng-Seang; Tan, Chong-Tin; Kwan, Zhenli; Tan, Wooi-Chiang; Wu, David Bin-Chia; Ng, Ching-Ching

    2017-07-01

    The majority of the carbamazepine-induced Stevens-Johnson syndrome and toxic epidermal necrolysis CBZ-SJS/TEN are associated with HLA-B*15:02 in Asian populations where this allele is common. In contrast, the association with HLA-A*31:01 is only reported in Japanese and Europeans. This study aimed to further investigate the association with HLA-A*31:01 besides HLA-B*15:02 in a multiethnic Malaysian population. Twenty-eight CBZ-SJS/TEN cases and 227 CBZ-tolerant controls were recruited. Association was tested by comparing carrier frequencies of the alleles between cases and controls. Significant associations were detected between HLA-B*15:02 and CBZ-SJS/TEN in independent ethnic groups: Malays [P=2.00×10; odds ratio (OR): 49.0; 95% confidence interval (CI): 9.36-256.81], Chinese (P=0.0047; OR: 14.3; 95% CI: 2.38-86.03) and Indians (P=0.04; OR: 13.8; 95% CI: 1.51-124.99). Combined analysis of all ethnic groups showed a significant association with OR Cochran-Mantel-Haenszel (ORCMH) of 26.6 (95% CI: 12.80-55.25; PCMH=2.31×10). In Indians, HLA-A*31:01 was found to be associated significantly with CBZ-SJS/TEN (P=0.023; OR: 10.4; 95% CI: 1.64-65.79) and combined analyses of both variants, HLA-A*31:01 and HLA-B*15:02, increased the strength of the association (P=0.0068; OR: 14.3; 95% CI: 2.20-92.9). Besides HLA-B*15:02, our study found a new association between HLA-A*31:01 and CBZ-SJS/TEN in Indians.

  18. HLA-Cw*1214 allele arisen via recombination between HLA-Cw*070201 and HLA-Cw*120201.

    PubMed

    Lebedeva, T V; Ohashi, M; Huang, A; Vasconcellos, S; Alosco, S M; Kempenich, J; Yu, N

    2004-12-01

    Allelic polymorphism of the major histocompatibility complex arises mostly from gene conversion. Intralocus gene conversion usually involves limited fragments of DNA, whereas recombination involving large fragments of DNA is considered to be a rare event. During routine sequencing-based typing of donors for the National Marrow Donor Program, a new HLA-C allele was identified in a Caucasian donor. The allele, HLA-Cw*1214, proved to be the product of recombination between HLA-Cw*070201 and HLA-Cw*120201. Exons 1, 2, the 3' end of exon 3 and exon 4 (with one mismatch) belong to HLA-Cw*120201, whereas part of exon 3 belongs to HLA-Cw*070201. Sequencing with primers based in exon 2 and exon 3 showed that intron 2 of the new allele also belonged completely to HLA-Cw*1202. The recombination event apparently occurred within exon 3 with the first point of recombination somewhere between codons 92 and 134 and the second one between codons 157 and 181.

  19. HLA Footprints for Multipurpose Science

    NASA Astrophysics Data System (ADS)

    Greene, G.; Lubow, S.; Donaldson, T.; Gillies, K.; Budavari, T.; Szalay, A.

    2010-12-01

    Footprints from the science observations of the Hubble Space Telescope are defined by a set of hierarchical geometric regions of instrument coverage; exposures, combined observations, high level science products, and mosaics. In the growing global community of networked applications, the science end-user has several use cases for visualizing and accessing footprint data including scientific proposal preparation, research and analysis of generated science products, and interoperability between archives for correlation of coverage. The Hubble Legacy Archive (HLA) at Space Telescope Science Institute, in coordination with ESO-ECF and CADC, has developed a web based science user interface built on a VO service oriented architecture system to enable varying levels of astronomical community access to science products derived from the HST archive. In this ADASS poster paper we describe new features and technologies for the HLA footprint component web browser visualization tool and the underlying footprint services utilized by the HST Astronomers Proposal Tool (APT) in compliance with an IVOA standard data access protocol. The service infrastructure is based on a high performance spherical geometric model developed by Johns Hopkins University (JHU) and database search algorithms co-developed by STScI and JHU.

  20. The IPD-IMGT/HLA Database - New developments in reporting HLA variation.

    PubMed

    Robinson, James; Soormally, Anup R; Hayhurst, James D; Marsh, Steven G E

    2016-03-01

    IPD-IMGT/HLA is a constituent of the Immuno Polymorphism Database (IPD), which was developed to provide a centralised system for the study of polymorphism in genes of the immune system. The IPD project works with specialist groups of nomenclature committees who provide and curate individual sections before they are submitted to IPD for online publication. The primary database within the IPD project is the IPD-IMGT/HLA Database, which provides a locus-specific database for the hyper-polymorphic allele sequences of the genes in the HLA system, also known as the human Major Histocompatibility Complex. The IPD-IMGT/HLA Database was first released over 17 years ago, building on the work of the WHO Nomenclature Committee for Factors of the HLA system that was initiated in 1968. The IPD-IMGT/HLA Database enhanced this work by providing the HLA community with an online, searchable repository of highly curated HLA sequences. Many of the genes encode proteins of the immune system and are hyper polymorphic, with some genes currently having over 4000 known allelic variants. Through the work of the HLA Informatics Group and in collaboration with the European Bioinformatics Institute we are able to provide public access to this data through the website, http://www.ebi.ac.uk/ipd/imgt/hla.

  1. HLA expression and HLA type associations in relation to EBV status in Hispanic Hodgkin lymphoma patients

    PubMed Central

    Fletcher, Luke B.; Veenstra, Rianne N.; Loo, Eric Y.; Hwang, Amie E.; Siddiqi, Imran N.; Visser, Lydia; Hepkema, Bouke G.; Nolte, Ilja M.; van den Berg, Anke; Cozen, Wendy; Diepstra, Arjan

    2017-01-01

    A proportion of classical Hodgkin lymphomas harbor the Epstein Barr virus (EBV). We previously demonstrated that associations between Human Leukocyte Antigen (HLA) alleles and susceptibility to EBV+ classical Hodgkin lymphoma differ between European and Chinese populations. Data on Hispanic populations is missing. Here we examined the association between HLA type, tumor cell HLA expression and other characteristics in Hispanic Hodgkin lymphoma patients. Hispanic Hodgkin lymphoma patients diagnosed at the Los Angeles County-University of Southern California Medical Center from 2000–2012 were included (n = 65). Formalin-fixed paraffin-embedded tumor tissue was analyzed for EBV by in situ hybridization and for HLA class I and class II expression by immunohistochemistry. HLA typing was performed by HLA-A specific quantitative PCR of genomic DNA from tissue. Thirty patients (46%) had EBV+ tumors. Expression of HLA class I (p = 0.0006) was significantly associated with EBV+ tumor status in Hispanic patients, similar to Europeans and Chinese. A positive association between HLA class II expression and EBV+ tumor status, as present in large studies in Europeans, was not found (p = 0.06). The prevalences of the specific European HLA-A*01 risk and European HLA-A*02 protective types were not significantly associated with EBV+ tumors among these Hispanic patients, however numbers were too low to draw firm conclusions. The HLA-A*02:07 allele, that is associated with EBV+ Hodgkin lymphoma in Chinese, was absent. In conclusion, the association between EBV positivity in tumor cells and HLA class I expression appears to be consistent across different populations. Larger studies in Hispanics are needed to evaluate HLA allele susceptibility associations. PMID:28334025

  2. Expression of HLA-ABC, HLA-DR and intercellular adhesion molecule-1 in oesophageal carcinoma.

    PubMed Central

    Rockett, J C; Darnton, S J; Crocker, J; Matthews, H R; Morris, A G

    1995-01-01

    AIM--To examine the expression of HLA-ABC and HLA-DR major histocompatibility (MHC) antigens and intercellular adhesion molecule (ICAM)-1 in normal, inflamed, metaplastic, and neoplastic oesophageal tissue and in freshly disaggregated tumours. METHODS--Sequential sections of frozen tissue and cytospins of freshly disaggregated tumour were stained using the ABC peroxidase system and monoclonal antibodies specific for HLA-ABC, HLA-DR and ICAM-1. RESULTS--Normal oesophageal tissue showed positive staining for HLA-ABC in the basal layers of the oesophageal squamous epithelium and on the epithelial cells of the submucosal oesophageal glands. HLA-DR and ICAM-1 were not detected in either of these cell types. In 20 of 37 (54%) carcinomas HLA-ABC was expressed weakly, with heterogeneous expression in nine (24%). Two tumours showed strong expression of HLA-ABC, but 15 of 37 (41%) were negative. HLA-DR and ICAM-1 were expressed weakly in six of 37 (16%) carcinomas without correlation with each other or with the expression of HLA-ABC. CONCLUSIONS--HLA-ABC is absent from a high proportion of oesophageal carcinomas (41%) and is otherwise variably and weakly expressed with strong expression in only a small fraction (3%). In other carcinomas there is a higher level of HLA-ABC expression. This discrepancy may partly explain the aggressive nature of oesophageal carcinomas. HLA-DR and ICAM-1 are not normally expressed on those cells from which oesophageal carcinomas are thought to arise. The limited expression found here could suggest a partial or inhibited immune response against oesophageal carcinoma. In vivo repressive factors may be involved. Images PMID:7665697

  3. HLA expression and HLA type associations in relation to EBV status in Hispanic Hodgkin lymphoma patients.

    PubMed

    Fletcher, Luke B; Veenstra, Rianne N; Loo, Eric Y; Hwang, Amie E; Siddiqi, Imran N; Visser, Lydia; Hepkema, Bouke G; Nolte, Ilja M; van den Berg, Anke; Cozen, Wendy; Diepstra, Arjan

    2017-01-01

    A proportion of classical Hodgkin lymphomas harbor the Epstein Barr virus (EBV). We previously demonstrated that associations between Human Leukocyte Antigen (HLA) alleles and susceptibility to EBV+ classical Hodgkin lymphoma differ between European and Chinese populations. Data on Hispanic populations is missing. Here we examined the association between HLA type, tumor cell HLA expression and other characteristics in Hispanic Hodgkin lymphoma patients. Hispanic Hodgkin lymphoma patients diagnosed at the Los Angeles County-University of Southern California Medical Center from 2000-2012 were included (n = 65). Formalin-fixed paraffin-embedded tumor tissue was analyzed for EBV by in situ hybridization and for HLA class I and class II expression by immunohistochemistry. HLA typing was performed by HLA-A specific quantitative PCR of genomic DNA from tissue. Thirty patients (46%) had EBV+ tumors. Expression of HLA class I (p = 0.0006) was significantly associated with EBV+ tumor status in Hispanic patients, similar to Europeans and Chinese. A positive association between HLA class II expression and EBV+ tumor status, as present in large studies in Europeans, was not found (p = 0.06). The prevalences of the specific European HLA-A*01 risk and European HLA-A*02 protective types were not significantly associated with EBV+ tumors among these Hispanic patients, however numbers were too low to draw firm conclusions. The HLA-A*02:07 allele, that is associated with EBV+ Hodgkin lymphoma in Chinese, was absent. In conclusion, the association between EBV positivity in tumor cells and HLA class I expression appears to be consistent across different populations. Larger studies in Hispanics are needed to evaluate HLA allele susceptibility associations.

  4. An HLA-B7-specific antibody in an HLA-B*07 positive patient explained by a nonexpressed allele (HLA-B*07:181N).

    PubMed

    Wenda, S; Faé, I; Fischer, G F

    2017-07-01

    Antibody identification by a bead array assay in a kidney patient revealed several HLA-specific antibodies including one directed against the HLA-B7 antigen. Low-resolution typing of the patient indicated the presence of an HLA-B*07 allele. To rule out an HLA-specific autoantibody the HLA-typing of the patient was further refined by nucleotide sequencing on a next-generation sequencing platform and eventually showed an HLA-B*39:01:01:03 and HLA-B*07:181N genotype. Thereby the allospecific nature of the antibody was proven. The HLA-B7-specific antibody could be explained by an immunization during the first kidney-transplantation in 1996 with an HLA-B*07 positive donor. When assessing the plausibility of antibodies, the presence of nonexpressed alleles should be taken into consideration. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  5. [HL-A antigens in dust allergy in children].

    PubMed

    Seignalet, J; Levallois, C; Lapinski, H; Jean, R

    1976-12-01

    The distribution of 29 HLA antigens has been compared in 60 unrelated children presenting a dust allergy and in 300 healthy controls. We observed an increased frequency for HLA-Aw19 and HLA-B5 in patients. Yet, the differences are not very significant and there is probably no association between one HLA gene and the dust allergy.

  6. Generation of HLA-Universal iPSC-Derived Megakaryocytes and Platelets for Survival Under Refractoriness Conditions

    PubMed Central

    Börger, Ann-Kathrin; Eicke, Dorothee; Wolf, Christina; Gras, Christiane; Aufderbeck, Susanne; Schulze, Kai; Engels, Lena; Eiz-Vesper, Britta; Schambach, Axel; Guzman, Carlos A; Lachmann, Nico; Moritz, Thomas; Martin, Ulrich; Blasczyk, Rainer; Figueiredo, Constança

    2016-01-01

    Platelet (PLT) transfusion is indispensable to maintain homeostasis in thrombocytopenic patients. However, PLT transfusion refractoriness is a common life-threatening condition observed in multitransfused patients. The most frequent immune cause for PLT transfusion refractoriness is the presence of alloantibodies specific for human leukocyte antigen (HLA) class I epitopes. Here, we have silenced the expression of HLA class I to generate a stable HLA-universal induced pluripotent stem cell (iPSC) line that can be used as a renewable cell source for the generation of low immunogenic cell products. The expression of HLA class I was silenced by up to 82% and remained stable during iPSC cultivation. In this study, we have focused on the generation of megakaryocytes (MK) and PLTs from a HLA-universal iPSC source under feeder- and xeno-free conditions. On d 19, differentiation rates of MKs and PLTs with means of 58% and 76% were observed, respectively. HLA-universal iPSC-derived MKs showed polyploidy with DNA contents higher than 4n and formed proPLTs. Importantly, differentiated MKs remained silenced for HLA class I expression. HLA-universal MKs produced functional PLTs. Notably, iPSC-derived HLA-universal MKs were capable to escape antibody-mediated complement- and cellular-dependent cytotoxicity. Furthermore, HLA-universal MKs were able to produce PLTs after in vivo transfusion in a mouse model indicating that they might be used as an alternative to PLT transfusion. Thus, in vitro produced low immunogenic MKs and PLTs may become an alternative to PLT donation in PLT-based therapies and an important component in the management of severe alloimmunized patients. PMID:27262025

  7. HLA Class I and Class II Alleles and Haplotypes Confirm the Berber Origin of the Present Day Tunisian Population

    PubMed Central

    Hajjej, Abdelhafidh; Almawi, Wassim Y.; Hattab, Lasmar; El-Gaaied, Amel; Hmida, Slama

    2015-01-01

    In view of its distinct geographical location and relatively small area, Tunisia witnessed the presence of many civilizations and ethnic groups throughout history, thereby questioning the origin of present-day Tunisian population. We investigated HLA class I and class II gene profiles in Tunisians, and compared this profile with those of Mediterranean and Sub-Sahara African populations. A total of 376 unrelated Tunisian individuals of both genders were genotyped for HLA class I (A, B) and class II (DRB1, DQB1), using reverse dot-blot hybridization (PCR-SSO) method. Statistical analysis was performed using Arlequin software. Phylogenetic trees were constructed by DISPAN software, and correspondence analysis was carried out by VISTA software. One hundred fifty-three HLA alleles were identified in the studied sample, which comprised 41, 50, 40 and 22 alleles at HLA-A,-B,-DRB1 and -DQB1 loci, respectively. The most frequent alleles were HLA-A*02:01 (16.76%), HLA-B*44:02/03 (17.82%), HLA-DRB1*07:01 (19.02%), and HLA-DQB1*03:01 (17.95%). Four-locus haplotype analysis identified HLA-A*02:01-B*50:01-DRB1*07:01-DQB1*02:02 (2.2%) as the common haplotype in Tunisians. Compared to other nearby populations, Tunisians appear to be genetically related to Western Mediterranean population, in particular North Africans and Berbers. In conclusion, HLA genotype results indicate that Tunisians are related to present-day North Africans, Berbers and to Iberians, but not to Eastern Arabs (Palestinians, Jordanians and Lebanese). This suggests that the genetic contribution of Arab invasion of 7th-11th century A.D. had little impact of the North African gene pool. PMID:26317228

  8. Lack of association between alopecia areata and HLA class I and II in a southeastern Brazilian population.

    PubMed

    Barbosa, Ângela Marques; Prestes-Carneiro, Luiz Euribel; Sobral, Aldri Roberta Sodoschi; Sakiyama, Marcelo Jun; Lemos, Bruna Cerávolo; Abreu, Marilda Aparecida Milanez Morgado de; Martos, Luciana Leite Crivelin; Moliterno, Ricardo Alberto

    2016-01-01

    Alopecia areata (AA) is a common disorder of unknown etiology that affects approximately 0.7% to 3.8% of patients among the general population. Currently, genetic and autoimmune factors are emphasized as etiopathogenic. Studies linking Human Leukocyte Antigens (HLA) to AA have suggested that immunogenetic factors may play a role in the disease's onset/development. To investigate an association between AA and HLA class I/II in white Brazilians. Patients and control groups comprised 33 and 112 individuals, respectively. DNA extraction was performed by column method with BioPur kit. Allele's classification was undertaken using the PCR-SSO technique. HLA frequencies were obtained through direct counting and subjected to comparison by means of the chi-square test. Most patients were aged over 16, with no familial history, and developed partial AA, with no recurrent episodes. Patients showed a higher frequency of HLA-B*40, HLA-B*45, HLA-B*53 and HLA-C*04 compared with controls, although P was not significant after Bonferroni correction. Regarding HLA class II, only HLA-DRB1*07 revealed statistical significance; nevertheless, it featured more prominently in controls than patients (P=0.04; Pc=0.52; OR=0.29; 95%; CI=0.07 to 1.25). P was not significant after Bonferroni correction. The development of AA does not seem to be associated with HLA in white Brazilians, nor with susceptibility or resistance. The studies were carried out in populations with little or no miscegenation, unlike the Brazilian population in general, which could explain the inconsistency found.

  9. Influence of the HLA characteristics of Italian patients on donor search outcome in unrelated hematopoietic stem cell transplantation.

    PubMed

    Testi, M; Andreani, M; Locatelli, F; Arcese, W; Troiano, M; Battarra, M; Gaziev, J; Lucarelli, G

    2014-08-01

    The information regarding the probability of finding a matched unrelated donor (MUD) within a relatively short time is crucial for the success of hematopoietic stem cell transplantation (HSCT), particularly in patients with malignancies. In this study, we retrospectively analyzed 315 Italian patients who started a search for a MUD, in order to assess the distribution of human leukocyte antigen (HLA) alleles and haplotypes in this population of patients and to evaluate the probability of finding a donor. Comparing two groups of patients based on whether or not a 10/10 HLA-matched donor was available, we found that patients who had a fully-matched MUD possessed at least one frequent haplotype more often than the others (45.6% vs 14.3%; P = 0.000003). In addition, analysis of data pertaining to the HLA class I alleles distribution showed that, in the first group of patients, less common alleles were under-represented (20.2% vs 40.0%; P = 0.006). Therefore, the presence of less frequent alleles represents a negative factor for the search for a potential compatible donor being successful, whereas the presence of one frequent haplotype represents a positive predictive factor. Antigenic differences between patient and donor observed at C and DQB1 loci, were mostly represented by particular B/C or DRB1/DQB1 allelic associations. Thus, having a particular B or DRB1 allele, linked to multiple C or DQB1 alleles, respectively, might be considered to be associated with a lower probability of a successful search. Taken together, these data may help determine in advance the probability of finding a suitable unrelated donor for an Italian patient.

  10. Different functions and associations of HLA-DR and HLA-DQ(DC) antigens shown by serological, cellular and DNA assays.

    PubMed

    Navarrete, C; Jaraquemada, D; Hui, K; Awad, J; Okoye, R; Festenstein, H

    1985-03-01

    Two consanguineous Caucasoid HTCs, DHI and FPA, were investigated, the latter having an unusual HLA-DR/DQ(DC) association. Both these HTCs typed clearly as HLA-DRw11. However, while DHI typed as DRw11/DQw3(DC4) as expected, FPA typed as DRw11/DQw1(DC1) instead. Although extremely rare in Caucasoids, DRw11/DQw1 is a common pattern of association in Nigerian Negroids. Southern blots of DNA extracted from EBV cell line derived from FPA, hybridized with HLA-DC alpha and HLA-DC beta probes, confirmed this unusual DRw11/DQw1(DC1) association. In addition the DC alpha probe showed a unique additional restriction fragment length polymorphism (8 kb) attributable to the DX gene in the FPA DNA. When DHI and FPA were used as stimulators in MLC, the patterns to typing responses obtained were not completely concordant although they overlap to some extent. For this reason FPA has been locally designated Dw'F5', distinct from Dw5. Furthermore, the HLA-DQ antigens of the responder cells were not necessarily the same as those of the HTCS to which they gave typing responses (FPA and DHI). Functional studies using these two HTCs showed that the DQ(DC) antigens probably have no direct lymphocyte activating properties but rather have a regulatory role in controlling responses to allodeterminants in MLC.

  11. HLA class II variation in the Gila River Indian Community of Arizona: alleles, haplotypes, and a high frequency epitope at the HLA-DR locus.

    PubMed

    Williams, R C; McAuley, J E

    1992-01-01

    A genetic distribution for the HLA class II loci is described for 349 "full-blooded" Pima and Tohono O'odham Indians (Pimans) in the Gila River Indian Community. A high frequency epitope in the *DRw52 family was defined by reactions with 31 alloantisera, which we have designated *DR3X6. It segregates as a codominant allele at HLA-DR with alleles *DR2, *DR4, and *DRw8, and has the highest frequency yet reported for an HLA-DR specificity, 0.735. It forms a common haplotype with *DRw52 and *DQw3 that is a valuable marker for genetic admixture and anthropological studies. Phenotype and allele frequencies, and haplotype frequencies for two and three loci, are presented. Variation at these loci is highly restricted, the mean heterozygosity for HLA-DR and HLA-DQ being 0.361. The Pimans represent a contemporary model for the Paleo-Indians who first entered North America 20,000 to 40,000 years ago.

  12. Derivation of HLA types from shotgun sequence datasets.

    PubMed

    Warren, René L; Choe, Gina; Freeman, Douglas J; Castellarin, Mauro; Munro, Sarah; Moore, Richard; Holt, Robert A

    2012-01-01

    The human leukocyte antigen (HLA) is key to many aspects of human physiology and medicine. All current sequence-based HLA typing methodologies are targeted approaches requiring the amplification of specific HLA gene segments. Whole genome, exome and transcriptome shotgun sequencing can generate prodigious data but due to the complexity of HLA loci these data have not been immediately informative regarding HLA genotype. We describe HLAminer, a computational method for identifying HLA alleles directly from shotgun sequence datasets (http://www.bcgsc.ca/platform/bioinfo/software/hlaminer). This approach circumvents the additional time and cost of generating HLA-specific data and capitalizes on the increasing accessibility and affordability of massively parallel sequencing.

  13. [Immunogenetics--HLA-association, molecular chaperones and "related" diseases].

    PubMed

    Melchers, I

    2005-09-01

    The association of rheumatoid arthritis (RA) with the HLA complex has been well established since 1978. But what does that mean? After reminding the reader of some existing immunological interpretations, a more recent variant is introduced. Antigens and molecular chaperones of the HSP70 family form complexes, which interact with HLA-DR beta-chains, especially of the DRB1*0401 genotype, which is the most common among patients with RA in our region. This mechanism might bring *0401(+) persons an advantage in defence against microorganisms, but a disadvantage concerning autoimmunity. Chaperone machines are upregulated in synovial tissue of RA patients. As their number and variety is huge in humans, there exist many possibilities for function, reaching from antigen presentation to immune regulation. In addition to the HLA complex, the "genetic background" plays an important role for the development of an autoimmune disease. This is demonstrated in families of patients with RA or scleroderma, where a high percentage of first degree relatives suffer from a "related" disease.