Post-transplant lymphoproliferative disease (PTLD) emerged in the mid-1990s as a major graft- and life-threatening complication\\u000a of pediatric kidney transplantation. This condition, usually involving uncontrolled B lymphocyte proliferation, straddles\\u000a the border between infection and malignancy, since Epstein–Barr virus (EBV) is intimately associated with the pathogenesis.\\u000a PTLD is seen more in younger children (more likely to be EBV seronegative), Caucasian race, and in
Vikas R. Dharnidharka; Carlos E. Araya
Patients after solid organ transplantation (SOT) carry a substantially increased risk to develop malignant lymphomas. This is in part due to the immunosuppression required to maintain the function of the organ graft. Depending on the transplanted organ, up to 15% of pediatric transplant recipients acquire posttransplant lymphoproliferative disease (PTLD), and eventually 20% of those succumb to the disease. Early diagnosis of PTLD is often hampered by the unspecific symptoms and the difficult differential diagnosis, which includes atypical infections as well as graft rejection. Treatment of PTLD is limited by the high vulnerability towards antineoplastic chemotherapy in transplanted children. However, new treatment strategies and especially the introduction of the monoclonal anti-CD20 antibody rituximab have dramatically improved outcomes of PTLD. This review discusses risk factors for the development of PTLD in children, summarizes current approaches to therapy, and gives an outlook on developing new treatment modalities like targeted therapy with virus-specific T cells. Finally, monitoring strategies are evaluated.
This is the first reported case of lymphoproliferative disease presenting with adrenal insufficiency after liver transplantation. A 38-year-old white man was admitted 8 months after transplantation for cryptogenic cirrhosis with fever (38-39 degrees C), chills, cough, and dyspnea. His blood pressure was 100/70 mm Hg, there was pallor of the conjunctiva, and a lymph node was palpable in the left groin. Laboratory analyses revealed the following values: serum sodium concentration (112 mmol/L), potassium (5.4 mmol/L), hemoglobin (7.8 g/L), white blood cell count (7.7 x 10(9)/L), glucose 3.9 (mmol/L), and mildly elevated liver functions. Abdominal ultrasound showed multiple hypoechoic solid-appearing lesions throughout the liver and spleen. Results of a biopsy specimen of the groin node confirmed polymorphic B-cell lymphoma. A negative Epstein- Barr virus screen before transplant became positive. The patient's fever increased to 40 degrees C. He subsequently developed sepsis and later, multiple organ failure. Autopsy confirmed extensive abdominal disease. The adrenal glands had been completely replaced by the tumor. Primary Epstein-Barr virus infection is associated with posttransplant lymphoproliferative disease. Replacement of the adrenal glands with a tumor produces a clinical picture of adrenal insufficiency. PMID:15989681
Khan, Abdaal; Ortiz, Jorge; Jacobson, Laura; Reich, David; Manzarbeitia, Cosme
In 1968, Starzl reported the clinical observation that transplant patients are prone to develop lymphomatous growths (1).\\u000a The term posttransplant lymphoproliferative disorder (PTLD) is applied to a group of lymphoproliferative disorders arising in a pharmacologically immunocompromised host after\\u000a solid-organ or allogeneic stem cell transplantation. Among iatrogenic immune deficiency states, PTLD is quite common (2).\\u000a PTLDs are the most serious complications
Thomas M. Habermann
Allogeneic hematopoietic stem cell transplantation is a successful treatment for hematologic malignancies and a variety of genetic and metabolic disorders. In the period following stem cell transplantation, the immune-compromised milieu allows opportunistic pathogens to thrive. Epstein-Barr virus-associated post-transplant lymphoproliferative disease can be a life-threatening complication for transplanted patients because of suppressed T-cell-mediated immunity. We analyzed possible risk factors associated with post-transplant lymphoproliferative disease in a cohort of over 1,000 patients. The incidence of post-transplant lymphoproliferative disease was 4%. Significant risk factors identified by multivariate analysis were: human leukocyte antigen-mismatch (P<0.001), serological Epstein-Barr virus mismatch recipient?/donor+ (P<0.001), use of reduced intensity conditioning (P=0.002), acute graft-versus-host disease grade II to IV (P=0.006), pre-transplant splenectomy (P=0.008) and infusion of mesenchymal stromal cells (P=0.015). The risk of post-transplant lymphoproliferative disease has increased in more recent years, from less than 2% before 1998 to more than 6% after 2011. Additionally, we show that long-term survival of patients with post-transplant lymphoproliferative disease is poor despite initial successful treatment. The 3-year survival rate among the 40 patients with post-transplant lymphoproliferative disease was 20% as opposed to 62% among patients without post-transplant lymphoproliferative disease (P<0.001). The study identifies patients at risk of post-transplant lymphoproliferative disease after transplantation in need of pre-emptive measures.
Uhlin, Michael; Wikell, Helena; Sundin, Mikael; Blennow, Ola; Maeurer, Markus; Ringden, Olle; Winiarski, Jacek; Ljungman, Per; Remberger, Mats; Mattsson, Jonas
\\u000a The increased risk of malignancy, especially of lymphoid tumors, in solid-organ and hematopoietic stem cell transplant (HST)\\u000a recipients has been recognized for many years [1-3]. Post-transplant lymphoproliferative disorder (PTLD) represents a heterogeneous\\u000a group of abnormal lymphoid proliferations, generally of B-cell origin, that occur in the setting of ineffective T-cell function\\u000a due to pharmacologic immunosuppression after organ transplantation. Unlike most other
Ran Reshef; Alicia K. Morgans; Donald E. Tsai
We performed a multicenter, International analysis of solid organ transplant (SOT)-related primary central nervous system (PCNS) posttransplant lymphoproliferative disease (PTLD). Among 84 PCNS PTLD patients, median time of SOT-to-PTLD was 54 months, 79% had kidney SOT, histology was monomorphic in 83% and tumor was EBV+ in 94%. Further, 33% had deep brain involvement, 10% had CSF involvement, while none had ocular disease. Immunosuppression was reduced in 93%; additional first-line therapy included high-dose methotrexate (48%), high-dose cytarabine (33%), brain radiation (24%) and/or rituximab (44%). The overall response rate was 60%, while treatment-related mortality was 13%. With 42-month median follow-up, three-year progression-free survival (PFS) and overall survival (OS) were 32% and 43%, respectively. There was a trend on univariable analysis for improved PFS for patients who received rituximab and/or high-dose cytarabine. On multivariable Cox regression, poor performance status predicted inferior PFS (HR 2.61, 95% CI 1.32-5.17, p = 0.006), while increased LDH portended inferior OS (HR 4.16, 95% CI 1.29-13.46, p = 0.02). Moreover, lack of response to first-line therapy was the most dominant prognostic factor on multivariable analysis (HR 8.70, 95% CI 2.56-29.57, p = 0.0005). Altogether, PCNS PTLD appears to represent a distinct clinicopathologic entity within the PTLD spectrum that is associated with renal SOT, occurs late, is monomorphic and retains EBV positivity. PMID:23721553
Evens, A M; Choquet, S; Kroll-Desrosiers, A R; Jagadeesh, D; Smith, S M; Morschhauser, F; Leblond, V; Roy, R; Barton, B; Gordon, L I; Gandhi, M K; Dierickx, D; Schiff, D; Habermann, T M; Trappe, R
We performed a multicenter, International analysis of solid organ transplant (SOT)-related primary central nervous system (PCNS) posttransplant lymphoproliferative disease (PTLD). Among 84 PCNS PTLD patients, median time of SOT-to-PTLD was 54 months, 79% had kidney SOT, histology was monomorphic in 83% and tumor was EBV+ in 94%. Further, 33% had deep brain involvement, 10% had CSF involvement, while none had ocular disease. Immunosuppression was reduced in 93%; additional first-line therapy included high-dose methotrexate (48%), high-dose cytarabine (33%), brain radiation (24%) and/or rituximab (44%). The overall response rate was 60%, while treatment-related mortality was 13%. With 42-month median follow-up, three-year progression-free survival (PFS) and overall survival (OS) were 32% and 43%, respectively. There was a trend on univariable analysis for improved PFS for patients who received rituximab and/or high-dose cytarabine. On multivariable Cox regression, poor performance status predicted inferior PFS (HR 2.61, 95% CI 1.32-5.17, p?=?0.006), while increased LDH portended inferior OS (HR 4.16, 95% CI 1.29-13.46, p?=?0.02). Moreover, lack of response to first-line therapy was the most dominant prognostic factor on multivariable analysis (HR 8.70, 95% CI 2.56-29.57, p?=?0.0005). Altogether, PCNS PTLD appears to represent a distinct clinicopathologic entity within the PTLD spectrum that is associated with renal SOT, occurs late, is monomorphic and retains EBV positivity. PMID:23551686
Evens, A M; Choquet, S; Kroll-Desrosiers, A R; Jagadeesh, D; Smith, S M; Morschhauser, F; Leblond, V; Roy, R; Barton, B; Gordon, L I; Gandhi, M K; Dierickx, D; Schiff, D; Habermann, T M; Trappe, R
Three cases of Epstein-Barr virus (EBV)-negative post-transplant lymphoproliferative disease that occurred 6 to 8 years after renal transplantation are reported. The patients respectively had gastric mucosa-associated lymphoid tissue lymphoma, gastric diffuse large B-cell lymphoma, and atypical Burkitt lymphoma. Absence of EBV in the tissue samples was demonstrated by both in situ hybridization for EBV early RNA and polymerase chain reaction for EBV DNA. Patients were treated with reduction in immunosuppression and combined chemotherapy plus an anti-CD20 monoclonal antibody, rituximab. Despite the reduction in immunosuppression, patients had stable renal functions without loss of graft functions. The patient with atypical Burkitt lymphoma had an abnormal karyotype, did not respond to treatment completely, and died due to disease progression. The other patients are still alive and in remission 5 and 3 years after diagnosis, respectively. EBV-negative post-transplant lymphoproliferative diseases are usually late-onset and are reported to have poor prognosis. Thus, reduction in immunosuppression is usually not sufficient for treatment and more aggressive approaches like rituximab with combined chemotherapy are required.
Bakanay, Sule Mine; Kaygusuz, Gulsah; Topcuoglu, Pervin; Sengul, Sule; Tuncal?, Timur; Keven, Kenan; Kuzu, Is?nsu; Uysal, Ak?n; Arat, Mutlu
Summary: Post-transplant lymphoproliferative disorder complicates approximately 1% of all renal transplants (1). The usual site of occurrence is within the abdomen, thorax, allograft, or head and neck. Central nervous system in- volvement is uncommon but, when present, occurs in iso- lation, sparing other organ systems. Few articles in the radiology literature have focused on the acute and fol- low-up central
Kimberly C. Brennan; Lisa H. Lowe; Gabrielle A. Yeaney
Background Post-transplant lymphoproliferative disorder (PTLD) is a complication of solid organ and allogeneic hematopoietic stem cell transplantation (HSCT); following autologous HSCT only rare cases of PTLD have been reported. Here, a case of Hodgkin's disease (HD), as unusual presentation of PTLD after autologous HSCT for malignant glioma is described. Case presentation 60-years old man affected by cerebral anaplastic astrocytoma underwent subtotal neurosurgical excision and subsequent high-dose chemotherapy followed by autologous HSCT. During the post HSCT course, cranial irradiation and corticosteroids were administered as completion of therapeutic program. At day +105 after HSCT, the patient developed HD, nodular sclerosis type, with polymorphic HD-like skin infiltration. Conclusion The clinical and pathological findings were consistent with the diagnosis of PTLD.
Zambelli, Alberto; Lilleri, Daniele; Baldanti, Fausto; Scelsi, Mario; Villani, Laura; Da Prada, Gian Antonio
Thymic hyperplasia is usually associated with the treatment of malignant tumours and is sometimes linked with endocrine diseases. For the first time, we report a case of thymic hyperplasia in a patient 2 years after bilateral lung transplantation. Contrast-enhanced chest CT scan was highly suspicious for a posttransplant lymphoma or thymoma. Therefore, the patient received total thymectomy. Excised specimens were sent to the Department of Pathology. Unexpectedly, the histological examination revealed hyperplastic thymic tissue without evidence for a posttransplant lymphoproliferative disorder or malignancy.
Steger, Christina Maria; Semsroth, Severin; Hager, Thomas; Rieker, Ralf; Muller, Ludwig
Post-transplant lymphoproliferative disorders (PTLD) are a life-threatening complication of solid organ transplantation or, more rarely, hematopoietic stem cell transplantation. The majority of PTLD is of B-cell origin and associated with Epstein–Barr virus (EBV) infection. PTLD generally display involvement of extranodal sites, aggressive histology and aggressive clinical behavior. The molecular pathogenesis of PTLD involves infection by oncogenic viruses, namely EBV, as well as genetic or epigenetic alterations of several cellular genes. At variance with lymphoma arising in immunocompetent hosts, whose genome is relatively stable, a fraction of PTLD are characterized by microsatellite instability as a consequence of defects in the DNA mismatch repair mechanism. Apart from microsatellite instability, molecular alterations of cellular genes recognized in PTLD include alterations of cMYC, BCL6, TP53, DNA hypermethylation, and aberrant somatic hypermutation of protooncogenes. The occurrence of IGV mutations in the overwhelming majority of PTLD documents that malignant transformation targets germinal centre (GC) B-cells and their descendants both in EBV–positive and EBV–negative cases. Analysis of phenotypic markers of B-cell histogenesis, namely BCL6, MUM1 and CD138, allows further distinction of PTLD histogenetic categories. PTLD expressing the BCL6+/MUM1+/-/CD138? profile reflect B-cells actively experiencing the GC reaction, and comprise diffuse large B-cell lymphoma (DLBCL) centroblastic and Burkitt lymphoma. PTLD expressing the BCL6?/MUM1+/CD138? phenotype putatively derive from B-cells that have concluded the GC reaction, and comprise the majority of polymorphic PTLD and a fraction of DLBCL immunoblastic. A third group of PTLD is reminiscent of post-GC and preterminally differentiated B-cells that show the BCL6?/MUM1+/CD138+ phenotype, and are morphologically represented by either polymorphic PTLD or DLBCL immunoblastic.
Capello, Daniela; Gaidano, Gianluca
Posttransplant malignancy is one of the most important complications of organ transplantation. Immunosuppressive drugs, viral infections such as human herpes virus 8 or Epstein-Barr virus, exposure to carcinogenic factors such as sun, and host factors can be etiologic factors in the development of malignant disease. In this paper we report 2 cases of late posttransplant lymphoproliferative disorder with malign behavior. Conflict of interest:None declared.
Paydas, Saime; Paydas, Semra; Balal, Mustafa; Ac?kal?n, Arbil; Ergin, Melek; Gurkan, Emel; Baslam?sl?, Fikri
Lymphoproliferative diseases (LPDs) associated with Epstein-Barr virus (EBV) infection cause significant morbidity and mortality in bone marrow and solid organ transplant recipients. To gain insight into LPD pathogenesis and to identify potential effective therapeutic approaches, we investigated early molecular events leading to B-cell transformation by gene expression profiling of EBV-infected B-cells from tonsils by Affymetrix microarray 72 hr postinfection when the B-cells hyperproliferation phase starts. Cell cycle and apoptosis were the most significantly affected pathways and enriched gene sets. In particular, we found significantly increased expression of cyclin-dependent kinase (CDK)1 and CCNB1 (cyclin B1) and of one of their downstream targets BIRC5 (survivin). Importantly, the strong upregulation of the antiapoptotic protein survivin was confirmed in lymphoblastoid cell lines (LCLs) and 71% of EBV-positive post-transplant EBV-LPD lesions scored positive for survivin. The validity of early transforming events for the identification of therapeutic targets for EBV-LPD was confirmed by the marked antiproliferative effect of the CDK inhibitor flavopiridol on LCLs and by the strong induction of apoptosis by survivin inhibition with YM155 or terameprocol. Our results suggest that targeting of CDKs and/or survivin in post-transplant EBV-LPD by specific inhibitors might be an important approach to control and eliminate EBV-transformed B-cells that should be further considered. PMID:23640782
Bernasconi, Michele; Ueda, Seigo; Krukowski, Patricia; Bornhauser, Beat C; Ladell, Kristin; Dorner, Marcus; Sigrist, Juerg A; Campidelli, Cristina; Aslandogmus, Roberta; Alessi, Davide; Berger, Christoph; Pileri, Stefano A; Speck, Roberto F; Nadal, David
Post-transplant lymphoproliferative disorders (PTLD) are a well-recognised and potentially fatal complication after solid organ transplantation. They include a spectrum of disorders ranging from benign hyperplasia to invasive malignant lymphoma. The majority of cases are associated with Epstein Barr virus (EBV)-driven tumour formation in B cells and are a consequence of the detrimental effect of immunosuppressive agents on the immune-control of
Anna L. Taylor; Robert Marcus; J. Andrew Bradley
Calcineurin Inhibitor-free Graft-Versus-Host Disease Prophylaxis With Sirolimus and Mycophenolate Mofetil in a Second Allogeneic Stem Cell Transplantation for Engraftment Failure and Rituximab-refractory Epstein-Barr Virus-induced Posttransplant Lymphoproliferative Disease.
Posttransplant lymphoproliferative disease (PTLD) is a life-threatening complication after allogeneic hematopoietic stem cell transplantation. We describe here the case of a boy with history of induction failure of a T-cell acute lymphoblastic leukemia, who presented a life-threatening situation of nonengraftment and rituximab-refractory PTLD after the first hematopoietic stem cell transplantation. We decided to use an unusual strategy of combining a nonmyeloablative conditioning (fludarabine and cyclophosphamide) with a calcineurin inhibitor-free GvHD prophylaxis (sirolimus and mycophenolate mofetil). This strategy had permitted the control of an Epstein-Barr virus PLTD in umbilical cord blood transplantation without further reactivation. PMID:24977404
Ceppi, Francesco; Duval, Michel; Teira, Pierre; Therrien, Roxane; Ovetchkine, Philippe; Mallette, Brigitte; Bittencourt, Henrique
The possible correlation among Epstein-Barr virus (EBV) load, interleukin-6 (IL-6) and interleukin-10 (IL-10) levels has become an attractive issue and can provide a useful tool for diagnosis and monitoring of patients at risk for post-transplant lymphoproliferative disease (PTLD) development. At the time of diagnosis of PTLD, 11 patients were prospectively enrolled and 55 nested controls were selected from a 1800 renal transplant cohort. Real-time polymerase chain reaction (PCR) was used to quantify EBV load in peripheral blood mononuclear cells (PBMC). Serum IL-6 and IL-10 levels were determined using an enzyme-linked immunosorbent assay (ELISA). The median EBV load of PTLD cases was 17400 copies/10(6) PBMC, statistically different from controls (P=0.001). The median IL-6 level of PTLD cases was not different from controls (P=0.079). However, median IL-10 levels showed a significant difference in both groups (P < or = 0.001). The receiver-operating characteristic (ROC) curve analysis was applied to estimate the IL-10 cut-off value predictive of PTLD development. We found that 73.5 pg/ml has high sensitivity (1.00) and specificity (0.85). Also, Pearson's analysis showed a strong correlation between EBV load and serum IL-10 concentration (P < or = 0.001). This nested case-control study demonstrates that EBV load at diagnosis of PTLD correlates with IL-10 levels, and that monitoring of IL-10 can provide a less expensive and less time-consuming tool for PTLD diagnosis and close follow-up of patients at risk. Furthermore, we were able to define a cut-off value of IL-10 mostly predictive of PTLD development in this cohort. Our data suggest that serial measurements prior to PTLD development must be carried out to validate our hypothesis. PMID:16019481
Baiocchi, Otávio C G; Colleoni, Gisele W B; Caballero, Otávia L; Vettore, André L; Bulgarelli, Adriana; Dalbone, Maria Aparecida; Granato, Celso F H; Franco, Marcello F; Pestana, José O M
\\u000a Organ transplantations can lead to post-transplant lymphoproliferative disorders (PT-LPDs) as a result of immunosuppressive\\u000a therapy. PT-LPDs clearly differ from non-Hodgkin’s lymphomas occurring in immunocompetent patients, in terms of clinical presentation,\\u000a pathological findings and treatment response. Several studies have tried to establish some prognostic factors but the small\\u000a number of patients hinders the analysis. We studied 61 patients from two transplant
Sylvain Choquet; Marie-France Mamzer Bruneel; Olivier Hermine; Raphaël Porcher; Stephanie Nguyen Quoc; Frédéric Davi; Frédéric Charlotte; Richard Dorent; Benoit Barrou; Jean-Paul Vernant; Martine Raphael; Vincent Levy; Véronique Leblond
The treatment of Epstein-Barr virus (EBV)-associated lymphoproliferative disease (PTLD) in EBV seronegative solid organ transplant recipients who acquire their EBV infection after engraftment poses a considerable challenge because of underlying immunosuppression that inhibits the virus-specific cytotoxic T cell (CTL) response in vivo. We have developed a protocol for activating autologous EBV-specific CTL lines from these patients and show their potential
Rajiv Khanna; Scott Bell; Martina Sherriti; Andrew Galbraith; Scott R. Burrows; Lee Rafter; Belinda Clarke; Richard Slaughter; Michael C. Falk; Jo Douglass; Trevor Williams; Suzanne L. Ellioti; Denis J. Moss
Post-transplant lymphoproliferative disorder (PTLD) is a neoplastic complication with a potentially fatal outcome that develops as a consequence of immunosuppression, and is mainly associated with Epstein-Barr virus (EBV) infection. A 70-year-old woman underwent a live unrelated, ABO-incompatible renal transplant for end-stage renal disease. One year after transplantation, protocol biopsy revealed pathological changes indicative of the histological subtype of 'early lesions of PTLD' according to the World Health Organization classification, while the patient showed no clinical signs or symptoms. The patient was finally diagnosed with EBV-positive PTLD by in situ hybridization for EBER (EBV-encoded RNA), and was successfully treated based on the reduction of immunosuppression. Protocol biopsy within the first post-transplant year is the only diagnostic measure to detect asymptomatic early PTLD, which allows for early intervention and leads to better outcomes. PMID:24842822
Kitajima, Kazuki; Sasaki, Hideo; Koike, Junki; Nakazawa, Ryuto; Sato, Yuichi; Yazawa, Masahiko; Tsuruoka, Kayo; Kawarazaki, Hiroo; Imai, Naohiko; Shirai, Sayuri; Shibagaki, Yugo; Chikaraishi, Tatsuya
Post-transplant Lymphoproliferative Disorder; Recurrent Adult Burkitt Lymphoma; Recurrent Adult Diffuse Large Cell Lymphoma; Stage III Adult Burkitt Lymphoma; Stage III Adult Diffuse Large Cell Lymphoma; Stage IV Adult Burkitt Lymphoma; Stage IV Adult Diffuse Large Cell Lymphoma; Waldenström Macroglobulinemia
Posttransplant lymphoproliferative disease (PTLD) is closely linked to primary Epstein–Barr virus (EBV) infection. A defect of EBV specific cellular immunity is postulated to play a pivotal role in the etiology of PTLD, but there is some debate as to whether EBV load in the peripheral blood of transplant patients predicts onset of PTLD or relapse after treatment. The current prospective,
Stephan Oertel; Ralf Ulrich Trappe; Kristin Zeidler; Nina Babel; Petra Reinke; Manfred Hummel; Sven Jonas; Matthias Papp-Vary; Marion Subklewe; Bernd Dörken; Hanno Riess; Barbara Gärtner
Post-transplant lymphoproliferative disorder (PTLD) is a complication of allogeneic bone marrow transplantation (BMT). Rare cases of PTLD after autologous BMT have been reported only in adults. This case report is the first to describe PTLD in a pediatric patient after autologous peripheral stem cell transplantation (PSCT). This 2-year-old male with stage IV neuroblastoma underwent autologous PSCT. The post-PSCT course was
MA Lones; I Kirov; JW Said; IP Shintaku; S Neudorf
Post-transplant lymphoproliferative disorder (PTLD) in the central nervous system (CNS) has a poor prognosis. New therapeutic approaches should be explored. We report our experience with intrathecal administration of rituximab in a 10-year-old kidney allograft recipient with PTLD in the CNS. After standard treatment had failed, we tried to treat the patient by administering rituximab directly into the cerebral ventricle through
Gretha van de Glind; Siebold de Graaf; Christoph Klein; Marlies Cornelissen; Britta Maecker; Jan Loeffen
Post-transplantation lymphoproliferative disorders (PTLD) are the second most frequent malignancies after solid organ transplantation and cover a wide spectrum ranging from polyclonal early lesions to monomorphic lymphoma. Available treatment modalities include immunosuppression reduction, immunotherapy with anti-B-cell monoclonal antibodies, chemotherapy, antiviral therapy, cytotoxic T-cell therapy as well as surgery and irradiation. Owing to the small number of cases and the heterogeneity of PTLD, current treatment strategies are mostly based on case reports and small, often retrospective studies. Moreover, many studies on the treatment of PTLD have involved a combination of different treatment options, complicating the evaluation of individual treatment components. However, there has been significant progress over the last few years. Three prospective phase II trials on the efficacy of rituximab monotherapy have shown significant complete remission rates without any relevant toxicity. A prospective, multicenter, international phase II trial evaluating sequential treatment with rituximab and CHOP-based chemotherapy (cyclophosphamide, doxorubicin, vincristine, prednisone) is ongoing and preliminary results have been promising. Cytotoxic T-cell therapy targeting Epstein–Barr virus (EBV)-infected B cells has shown low toxicity and high efficacy in a phase II trial and will be a future therapeutic option at specialized centers. Here, we review the currently available data on the different treatment modalities with a focus on PTLD following solid organ transplantation in adult patients.
Post-transplant lymphoproliferative disorder is a lymphocyte proliferating disease, usually of B cell origin, and rarely of T cell. Involvement of liver itself in liver transplant recipients as the primary organ is not common. Herein we report our experience in two patients who primarily presented in the allografted liver, both of whom were promptly diagnosed after liver biopsy and treated successfully .Now after a few months; both of the patients are alive with normal liver function tests and negative imaging studies.
Geramizadeh, Bita; Nikeghbalian, Sama; Dehghani, Seyed Mohsen; Bahador, Ali; Salahi, Heshmatollah; Malekhosseini, Seyedali
Posttransplant lymphoproliferative disorders (PTLDs) were diagnosed in 43 patients from the Pittsburgh-Denver series between June 1980 and March 1987. This constitutes a detection rate of 1.7%. Major categories of clinical presentation included a mononucleosislike syndrome, gastrointestinal/abdominal disease, and solid organ disease. The median time of onset in patients initially immunosuppressed with cyclosporine-A (CsA)-containing regimens was 4.4 months after transplant, regardless of tumor clonality. A strong association of PTLD with Epstein-Barr virus (EBV) was observed. A histologic spectrum of lesions from polymorphic to monomorphic was observed. Whereas polymorphic lesions could be either clonal or nonclonal, monomorphic lesions appeared to be clonal in composition. The presence of large atypical cells (atypical immunoblasts) or necrosis did not appreciably worsen the prognosis. Twelve patients had clonal, 13 had nonclonal, and five had both clonal and nonclonal tumors. Clonality was indeterminate in 13 cases. Most patients were treated with a regimen based on reduced immunosuppression and supportive surgery. Almost all nonclonal and about half of the clonal lesions respond to this conservative therapy, indicating that it is an appropriate first line of treatment. This behavior suggests that a spectrum of lesions ranging from infectious mononucleosis to malignant lymphoma constitutes the entity known as PTLD. Some monoclonal tumors can undergo regression, however, apparently in response to host immune control mechanisms. Because of its short latency and strong association with EBV, PTLD is an important model for the study of virus-associated tumor progression in humans. Images Figure 1 Figure 2A Figure 2B Figure 3 Figure 4 Figure 5 Figure 6
Nalesnik, M. A.; Jaffe, R.; Starzl, T. E.; Demetris, A. J.; Porter, K.; Burnham, J. A.; Makowka, L.; Ho, M.; Locker, J.
Posttransplant lymphoproliferative disorders (PTLD) represent a spectrum of lymphoid diseases complicating the clinical course of transplant recipients. Most PTLD are Epstein-Barr virus (EBV) associated with viral latency type III. Several in vitro studies have revealed an interaction between EBV latency proteins and molecules of the apoptosis pathway. Data on human PTLD regarding an association between Bcl-2 family proteins and EBV are scarce. We analyzed 60 primary PTLD for expression of 8 anti- (Bcl-2, Bcl-XL, and Mcl-1) and proapoptotic proteins (Bak and Bax), the so-called BH3-only proteins (Bad, Bid, Bim, and Puma), as well as the apoptosis effector cleaved PARP by immunohistochemistry. Bim and cleaved PARP were both significantly (p = 0.001 and p = 5.251e-6) downregulated in EBV-positive compared to EBV-negative PTLD [Bim: 6/40 (15%), cleaved PARP: 10/43 (23%), vs. Bim: 13/16 (81%), cleaved PARP: 12/17 (71%)]. Additionally, we observed a tendency toward increased Bcl-2 protein expression (p = 0.24) in EBV-positive PTLD. Hence, we provide evidence of a distinct regulation of Bcl-2 family proteins in EBV-positive versus negative PTLD. The low-expression pattern of the proapoptotic proteins Bim and cleaved PARP together with the high-expression pattern of the antiapoptotic protein Bcl-2 by trend in EBV-positive tumor cells suggests disruption of the apoptotic pathway by EBV in PTLD, promoting survival signals in the host cells. PMID:22868923
Ghigna, Maria-Rosa; Reineke, Tanja; Rincé, Patricia; Schüffler, Peter; El Mchichi, Bouchra; Fabre, Monique; Jacquemin, Emmanuel; Durrbach, Antoine; Samuel, Didier; Joab, Irène; Guettier, Catherine; Lucioni, Marco; Paulli, Marco; Tinguely, Marianne; Raphael, Martine
Post-transplant lymphoproliferative disorders are mostly Epstein–Barr virus-related, B-cell tumors that develop as a consequence of immunosuppressive therapy in recipients of solid organ or bone marrow transplants. These disorders range from reactive, polyclonal plasmacytic hyperplasia to those that are morphologically and genotypically indistinguishable from typical non-Hodgkin's lymphomas. Plasma cell myeloma occurring after solid organ transplantation is rare. We report three plasma
Xiaoping Sun; LoAnn C Peterson; Yun Gong; Ann E Traynor; Beverly P Nelson
Dyskeratosis congenita (DC) is a rare inherited disorder characterized by bone marrow failure and cancer predisposition. We present a case of a 28-year-old woman with DC who was admitted for hematopoietic stem cell transplantation (HSCT) for aplastic anemia and who developed acute myeloid leukemia with complex genetic karyotype abnormalities including the MLL (11q23) gene, 1q25, and chromosome 8. After transplantation, a monomorphic Epstein-Barr virus (EBV) negative posttransplant-associated lymphoproliferative disorder (PTLD) diffuse large B-cell lymphoma was discovered involving the liver, omental tissue, and peritoneal fluid samples showing additional MLL (11q23) gene abnormalities by fluorescence in situ hybridization. Despite treatment, the patient died of complications associated with transplantation and invasive fungal infection. This case represents the first bona fide documented case of EBV-negative monomorphic PTLD host derived, with MLL gene abnormalities in a patient with DC, and shows another possible mechanism for the development of a therapy-related lymphoid neoplasm after transplantation. PMID:23222806
Bohn, Olga L; Whitten, Joseph; Spitzer, Barbara; Kobos, Rachel; Prockop, Susan; Boulad, Farid; Arcila, Maria; Wang, Lu; Teruya-Feldstein, Julie
Post-transplant lymphoproliferative disorder (PTLD) is a major complication caused by immune-suppression after transplantation. Survival outcome is known to be poor and the characteristics are not fully understood because of its rare incidence. This single center retrospective study enrolled 41 adult PTLD patients after kidney-transplantation (KT, n = 28) and hematopoietic stem cell transplantation (HSCT, n = 13) from 1992 to 2012. We compared the characteristics and estimated the survival outcomes according to several factors [age-adjusted-IPI (aaIPI), pathologic subtype, viral status, extranodal manifestation] and added some significant parameters to aaIPI scoring system. Post-HSCT-PTLD patients were younger and showed earlier onset, and viral status was more frequently identified. Ten-year OS of the entire group was 44% but the 10-year OS was not significantly different between post-KT-PTLD and post-HSCT-PTLD (39% vs. 56%, P = 0.860). The time onset of PTLD and viral statuses were not meaningful, however, aaIPI, age > 50, extranodal manifestation and monomorphic subtype were predictive for OS. We used those factors for PTLD-specific scoring which showed intermediate-risk (HR = 7.1, P = 0.019) and high-risk (HR = 16.5, P = 0.001) presented worse OS compared to low-risk subgroup. Although the treatment strategies were heterogenous, this study showed comprehensive PTLD data between KT versus HSCT, and our PTLD-specific scoring might be validated by another larger studies. PMID:24684689
Yoon, Jae-Ho; Lee, Seok; Kim, Hee-Je; Lee, Jong-Wook; Min, Woo-Sung; Chung, Byung Ha; Yang, Chul Woo; Kim, Yong-Soo; Kim, Ji-Il; Moon, In Sung; Oh, Eun Ji; Park, Gyeong-Sin; Cho, Seok-Goo
Up to 35% of posttransplant lymphoproliferative disorder (PTLD) cases occur within 1 year of transplantation, and over 50% are associated with Epstein-Barr virus (EBV). EBV primary infection and reactivation are PTLD predictive factors, but there is no consensus for their treatment. We conducted a prospective single-center study on 299 consecutive heart-transplant patients treated with the same immunosuppressive regimen and monitored by repetitive EBV viral-load measurements and endomyocardial biopsies to detect graft rejection. Immunosuppression was tapered on EBV reactivation with EBV viral loads >10(5) ?copies/mL or primary infection. In the absence of response at 1 month or a viral load >10(6) ?copies/mL, patients received one rituximab infusion (375?mg/m(2) ). All patients responded to treatment without increased graft rejection. One primary infection case developed a possible PTLD, which completely responded to diminution of immunosuppression, and one patient, whose EBV load was unevaluable, died of respiratory complications secondary to PTLD. Compared with a historical cohort of 820 patients, PTLD incidence was decreased (p?=?0.033) by a per-protocol analysis. This is the largest study on EBV primary infection/reactivation treatment, the first using rituximab following solid organ transplantation to prevent PTLD and the first to demonstrate an acceptable tolerability profile in this setting. PMID:24666832
Choquet, S; Varnous, S; Deback, C; Golmard, J L; Leblond, V
Posttransplant lymphoproliferative disorders (PTLDs) may occur as a complication of immunosuppression in patients who have received solid organ or bone marrow allografts. Most PTLDs are of B-cell lineage, whereas T-cell proliferations are rare. The majority of B-cell lesions are associated with Epstein-Barr virus infection. The occurrence of both B-cell and T-cell PTLDs in the same patient is extremely rare and only 6 cases have been previously published. We report a case of a 63-year-old man who developed 2 metachronous Epstein-Barr virus-related PTLDs beginning 10 years after heart transplantation. A polymorphic B-cell PTLD developed first that completely regressed after immunosuppressive therapy was partially withdrawn. Then, a monomorphic T-cell PTLD developed 31 months later. The patient died 17 months later owing to disease progression. We highlight the diagnostic challenge of this case that required numerous ancillary studies for lineage assessment and classification. Such studies are often needed in patients with a history of immunosuppression. PMID:18941401
Morovic, Anamarija; Jaffe, Elaine S; Raffeld, Mark; Schrager, Jeffrey A
Posttransplant lymphoproliferative disorders (PTLDs) are potentially fatal, EBV-driven B-cell malignancies that develop in immunocompromised solid organ or hematopoietic stem cell recipients. In PTLD, the expression of EBV proteins, including latent membrane protein 1 (LMP1) and LMP2A, viral immune evasion strategies, and impaired host immune surveillance foster the proliferation of EBV-transformed B cells. Current PTLD treatment strategies include reduction of immunosuppression, which increases the risk of graft rejection, anti-CD20 treatment, combination chemotherapy, and administration of EBV-specific cytotoxic T cells. In the present study, we report that EBV-transformed lymphoblastoid B-cell lines (LCLs) and primary PTLDs overexpress galectin-1 (Gal1), a carbohydrate-binding lectin that induces tolerogenic dendritic cells and triggers the selective apoptosis of CD4(+) Th1 and Th17 cells and cytotoxic T cells. In transcriptional reporter assays, LMP2A and LMP1 each increased Gal1-driven luciferase expression, and the combination of LMP2A and LMP1 was additive. In addition, small interfering RNA (siRNA)-mediated depletion of LMP2A decreased Gal1 protein abundance in EBV-transformed LCLs. Gal1 expression in LCLs was dependent on both activating protein 1 (AP-1) and PI3K. A newly developed neutralizing Gal1 mAb selectively inhibited Gal1-mediated apoptosis of EBV-specific CD8(+) T cells. Given the tolerogenic and immunosuppressive function of Gal1, antibody-mediated Gal1 neutralization may represent a novel immunotherapeutic strategy for PTLD and other Gal1-expressing tumors. PMID:21300977
Ouyang, Jing; Juszczynski, Przemyslaw; Rodig, Scott J; Green, Michael R; O'Donnell, Evan; Currie, Treeve; Armant, Myriam; Takeyama, Kunihiko; Monti, Stefano; Rabinovich, Gabriel A; Ritz, Jerome; Kutok, Jeffery L; Shipp, Margaret A
149 patients with non Hodgkin lymphomas (NHL) were observed at the III. Medical Department of the Hanusch Hospital during 1972--1978. 15 out of 106 patients with low malignant NHL had autoimmune hemolytic anemia (AHA). None of the patients with high malignant NHL showed evidence of hemolysis. In 10 cases AHA was diagnosed together with the lymphoproliferative disease. In 4 cases diagnosis of AHA and NHL was established at the same time and in only 1 patient diagnosis of AHA preceded the lymphatic disease. All patients had distinct signs of hemolysis with moderate to severe anemia. 4 patients with immunocytic lymphomas had IgM paraproteins and an elevation of gamma-globulins, all other patients had mild to severe hypogammaglobulinemia. Therapy in all cases consisted of corticosteroids and cytostatics (Chlorambucil, Cyclophosphamide). In none of our cases splenectomy was performed. AHA seems to be a bad prognostic factor in patients with chronic lymphocytic leukemia. Survival time in patients with chronic lymphocytic leukemia and AHA was 18 months shorter than in all other patients suffering from chronic lymphocytic leukemia. PMID:555212
Banihashemi, A; Heinz, R
We have studied the thrombocytopenia of IgG. Five of the patients with CIL had lymphoproliferative disorders using a mea- positive direct antiglobulin (Coombs) tests surement of membrane-bound IgG by an on red cells; of these, 3 patients had hemo- antiglobulin consumption assay. Nine pa- lytic anemia. In eight of the 9 patients with tients with chronic Iymphocytic leukemia CLI, thrombocytopenia,
Bruce R. Kaden; Wendell F. Rosse; Thomas W. Hauch
Transplant patients are at high risk of post-transplant lymphoproliferative disorder (PTLD). A strong correlation between Epstein-Barr virus (EBV) and PTLD is observed in pediatric patients with primary infection after transplant. Because many patients have responded to reversal of immunosuppressive therapy, an early identification of EBV is essential for the reduction of immunosuppression and/or introduction of antiviral therapy to prevent PTLD. Polymerase chain reaction (PCR) is a specific and sensitive method to identify EBV DNA in blood. The aim of our study was to establish a protocol for monitoring EBV infection in transplanted patients for early identification those at high risk of PTLD. Viral presence in peripheral blood leukocytes (PBL) and serum samples was revealed by Nested PCR; positive specimens were quantified with Real Time PCR (RT-PCR). DNA in PBL was observed in 12 cases and 6 showed EBV in sera. Quantitative analysis showed a wide range of EBV DNA copies in leukocytes that were higher than in sera. Two patients displayed high viral load values in both PBL and sera associated with clinical evidence of PTLD. Our data suggest that the study of the EBV load represents an essential approach in the diagnosis of PTLD and the analysis of serum samples could provide useful information in the post-transplant monitoring of high-risk patients. PMID:17201089
Gaeta, Aurelia; Nazzari, Cristina; Verzaro, Simona; Latte, Maria Cristina; Fabri, Giovanni; Scateni, Simona; Raggi, Claudia; Lubrano, Riccardo; Mancini, Carlo
In the attempt to harmonize clinical practices between different French transplantation centers, the French Society of Bone Marrow Transplantation and Cell Therapy (SFGM-TC) set up the third annual series of workshops which brought together practitioners from all member centers and took place in October 2012 in Lille. Here the SFGM-TC addressed the issue of post-transplant CMV and EBV reactivation, and EBV-related Lymphoproliferative Disorders. PMID:24011961
Bay, J-O; Peffault de Latour, R; Bruno, B; Coiteux, V; Guillaume, T; Hicheri, Y; Paillard, C; Suarez, F; Turlure, P; Alain, S; Bulabois, C-E; Socié, G; Bauters, F; Yakoub-Agha, I
Post-transplant lymphoproliferative disorder (PTLD)-associated Epstein Barr virus (EBV)+ B-cell lymphomas are serious complications of solid organ and bone marrow transplantation. The EBV protein LMP2a, a B-cell receptor (BCR) mimic, provides survival signals to virally-infected cells through Syk tyrosine kinase. Therefore, we explored whether Syk inhibition is a viable therapeutic strategy for EBV-associated PTLD. We have shown that R406, the active metabolite of the Syk inhibitor fostamatinib, induces apoptosis and cell cycle arrest while decreasing downstream phosphatidylinositol-3?-kinase (PI3K)/Akt signaling in EBV+ B-cell lymphoma PTLD lines in vitro. However, Syk inhibition did not inhibit or delay the in vivo growth of solid tumors established from EBV-infected B-cell lines. Instead, we observed tumor growth in adjacent inguinal lymph nodes exclusively in fostamatinib-treated animals. In contrast, direct inhibition of PI3K/Akt significantly reduced tumor burden in a xenogeneic mouse model of PTLD without evidence of tumor growth in adjacent inguinal lymph nodes. Taken together, our data indicate that Syk activates PI3K/Akt signaling which is required for survival of EBV+ B-cell lymphomas. PI3K/Akt signaling may be a promising therapeutic target for PTLD, and other EBV-associated malignancies.
Hatton, O.; Lambert, S. L.; Phillips, L. K.; Vaysberg, M.; Natkunam, Y.; Esquivel, C. O.; Krams, S. M.; Martinez, O. M.
X linked lymphoproliferative disease (XLP; Duncan’s disease) is a rare disorder affecting boys and characterised by a defective immune response to Epstein- Barr virus caused by a mutation in a gene located at chromosome Xq25. Three siblings with XLP in a single UK family are reported and the variation in phenotypic expression of the disease in these siblings described. One
Peter D Arkwright; Guy Makin; Andrew M Will; Michelle Ayres; David A Gokhale; William D Fergusson; G Malcolm Taylor
X-linked lymphoproliferative disease (XLP) is an inherited immunodeficiency characterized by an extreme susceptibility to\\u000a Epstein-Barr virus (EBV) infection. Patients with XLP mainly present with the 3 clinical manifestations of fulminant infectious\\u000a mononucleosis, lymphoproliferative disorder, and dysgammaglobulinemia and in rare cases have aplastic anemia and lymphocytic\\u000a vasculitis.The causative gene for XLP was identified asSH2D1A\\/DSHP\\/SLAM-associated protein (SAP) in 1998, and genetic analysis
Takumi Hoshino; Hirokazu Kanegane; Noriko Doki; Hiroyuki Irisawa; Tohru Sakura; Yoshihisa Nojima; Shuichi Miyawaki; Toshio Miyawaki
Purpose Programmed cell death ligand 1 (PD-L1) is a molecule expressed on antigen-presenting cells that engages the PD-1 receptor on T cells and inhibits T-cell receptor signaling. The PD-1 axis can be exploited by tumor cells to dampen host anti-tumor immune responses and foster tumor cell survival. PD-1 blockade has shown promise in multiple malignancies but should be directed towards patients in whom it will be most effective. In recent studies, we found that the chromosome 9p24.1 amplification increased the gene dosage of PD-L1 and its induction by JAK2 in a subset of patients with classical Hodgkin lymphoma (cHL). However, cHLs with normal 9p24.1 copy numbers also expressed detectable PD-L1, prompting analyses of additional PD-L1 regulatory mechanisms. Experimental Design Herein, we utilized immunohistochemical, genomic and functional analyses to define alternative mechanisms of PD-L1 activation in cHL and additional EBV+ lymphoproliferative disorders. Results We identified an AP-1-responsive enhancer in the PD-L1 gene. In cHL Reed Sternberg cells, which exhibit constitutive AP-1 activation, the PD-L1 enhancer binds AP-1 components and increases PD-L1 promoter activity. In addition, we defined EBV infection as an alternative mechanism for PD-L1 induction in cHLs with diploid 9p24.1. PD-L1 was also expressed by EBV-transformed lymphoblastoid cell lines as a result of latent membrane protein 1-mediated, JAK/STAT-dependent promoter and AP-1-associated enhancer activity. In addition, over 70% of EBV+ post-transplant lymphoproliferative disorders expressed detectable PD-L1. Conclusions AP-1 signaling and EBV infection represent alternative mechanisms of PD-L1 induction and extend the spectrum of tumors in which to consider PD-1 blockade.
Green, Michael R.; Rodig, Scott; Juszczynski, Przemyslaw; Ouyang, Jing; Sinha, Papiya; O'Donnell, Evan; Neuberg, Donna; Shipp, Margaret A.
Aim of the study Epstein-Barr virus-related post-transplant lymphoproliferative disorder (EBV-PTLD) is a serious complication after stem cell transplantation (SCT) and the number of patients at risk is increasing over time. Available data do not reflect general practice of diagnosis and treatment of this complication. Material and methods In 2009 a survey on management of the pre-emptive strategy of EBV infection was done and results from 74 European transplant centers were registered and analyzed. Results Regular monitoring for EBV after SCT is done by most of the participating centers (73%). In 68% of them the monitoring is performed in all alloSCT patients, while in remaining centers it is done in high-risk patients only. Quantitative EBV-DNA is performed in 97% of centers, mainly in whole blood (78%) and usually repeated once a week (60.9%). The monitoring for EBV reactivation is performed for a period of 3 months (37%) to 6 months (30%) or adjusted to risk factors (20%). Rituximab as a pre-emptive therapy for EBV-PTLD is routinely administered in 80% of responding centers. The number of EBV-DNA copies as an indicator for pre-emptive therapy with rituximab varies between the centers. Conclusions The strategy of management of EBV infection exists in most of the responding centers. Different approaches regarding indications for preemptive therapy are seen between centers: rituximab is administered as pre-emptive therapy in most participating transplant centers.
Styczynski, Jan; Komarnicki, Mieczyslaw
X-linked lymphoproliferative disease (XLP) is a rare familial disorder resulting in selective immunodeficiency to the Epstein-Barr\\u000a virus (EBV), characterized by uncontrolled proliferation of EBV-infected lymphocytes. Phenotypes of this disease are variable\\u000a and include fulminant infectious mononucleosis, hypogammaglobulinemia, and malignant lymphoma. In this article, we describe\\u000a a case of a previously healthy 4-year-old boy with serologic evidence of acute EBV infection
Diane M. Maia; Christopher P. Garwacki
Linkage studies have been carried out with 28 X-linked polymorphic probes to try to locate the gene for X-linked lymphoproliferative disease (XLP). DNA from three families has been analysed, including three affected boys among 21 family members. None of the probes tested has been found to be linked to XLP. However, the data are recorded for the use of other workers on this rare disease. PMID:2896078
Harris, A; Lenoir, G M; Lankester, S A
A family study was performed in order to diagnose X-linked lymphoproliferative (XLP) disease in a fetus. The molecular genetic analysis indicated that the fetus, as well as its healthy 7-year-old brother, inherited XLP. Analysis of immunoglobulin subclasses from the 7-year-old brother supported the DNA-based diagnosis. This is the first XLP family of African descent. PMID:1355632
Skare, J; Madan, S; Glaser, J; Purtilo, D; Nitowsky, H; Pulijaal, V; Milunsky, A
HE LYMPHOPROLIFERATIVE disease of granular T lymphocytes (LDGL) results from a chronic prolifer- ation of large granular lymphocytes (LGLs) that may have either a CD3+ or CD3- phenotype.'-' It is conceivable that LDGL could encompass both neoplastic or reactive condi- tion~.',~ Most patients with a CD3+ LGL disorder have clonal rearrangements of the T-cell receptor (TCR) \\/3 gene, sup- porting
Richard Nash; Peter McSweeney; Renato Zambello; Gianpietro Semenzato; Thomas P. Loughran
Polyclonal Epstein-Barr virus (EBV)-infected B cell line (lymphoblastoid cell lines; LCL)-stimulated T-cell preparations have been successfully used to treat EBV-positive post-transplant lymphoproliferative disorders (PTLD) in transplant recipients, but function and specificity of the CD4+ component are still poorly defined. Here, we assessed the tumor-protective potential of different CD4+ T-cell specificities in a PTLD-SCID mouse model. Injection of different virus-specific CD4+ T-cell clones showed that single specificities were capable of prolonging mouse survival and that the degree of tumor protection directly correlated with recognition of target cells in vitro. Surprisingly, some CD4+ T-cell clones promoted tumor development, suggesting that besides antigen recognition, still elusive functional differences exist among virus-specific T cells. Of several EBV-specific CD4+ T-cell clones tested, those directed against virion antigens proved most tumor-protective. However, enriching these specificities in LCL-stimulated preparations conferred no additional survival benefit. Instead, CD4+ T cells specific for unknown, probably self-antigens were identified as principal antitumoral effectors in LCL-stimulated T-cell lines. These results indicate that virion and still unidentified cellular antigens are crucial targets of the CD4+ T-cell response in this preclinical PTLD-model and that enriching the corresponding T-cell specificities in therapeutic preparations may enhance their clinical efficacy. Moreover, the expression in several EBV-negative B-cell lymphoma cell lines implies that these putative autoantigen(s) might also qualify as targets for T-cell-based immunotherapy of virus-negative B cell malignancies.
Linnerbauer, Stefanie; Behrends, Uta; Adhikary, Dinesh; Witter, Klaus; Bornkamm, Georg W.; Mautner, Josef
Polyclonal Epstein-Barr virus (EBV)-infected B cell line (lymphoblastoid cell lines; LCL)-stimulated T-cell preparations have been successfully used to treat EBV-positive post-transplant lymphoproliferative disorders (PTLD) in transplant recipients, but function and specificity of the CD4+ component are still poorly defined. Here, we assessed the tumor-protective potential of different CD4+ T-cell specificities in a PTLD-SCID mouse model. Injection of different virus-specific CD4+ T-cell clones showed that single specificities were capable of prolonging mouse survival and that the degree of tumor protection directly correlated with recognition of target cells in vitro. Surprisingly, some CD4+ T-cell clones promoted tumor development, suggesting that besides antigen recognition, still elusive functional differences exist among virus-specific T cells. Of several EBV-specific CD4+ T-cell clones tested, those directed against virion antigens proved most tumor-protective. However, enriching these specificities in LCL-stimulated preparations conferred no additional survival benefit. Instead, CD4+ T cells specific for unknown, probably self-antigens were identified as principal antitumoral effectors in LCL-stimulated T-cell lines. These results indicate that virion and still unidentified cellular antigens are crucial targets of the CD4+ T-cell response in this preclinical PTLD-model and that enriching the corresponding T-cell specificities in therapeutic preparations may enhance their clinical efficacy. Moreover, the expression in several EBV-negative B-cell lymphoma cell lines implies that these putative autoantigen(s) might also qualify as targets for T-cell-based immunotherapy of virus-negative B cell malignancies. PMID:24853673
Linnerbauer, Stefanie; Behrends, Uta; Adhikary, Dinesh; Witter, Klaus; Bornkamm, Georg W; Mautner, Josef
A registry of posttransplant lymphoproliferative disorders (PTLD) was set up for the entire population of adult kidney transplant recipients in France. Cases of PTLD were prospectively enrolled between January 1, 1998, and December 31, 2007. Ten-year cumulative incidence was analyzed in patients transplanted after January 1, 1989. PTLD risk factors were analyzed in patients transplanted after January 1, 1998 by Cox analysis. Cumulative incidence was 1% after 5 years, 2.1% after 10 years. Multivariate analysis showed that PTLD was significantly associated with: older age of the recipient 47-60 years and >60 years (vs. 33-46 years, adjusted hazard ratio (AHR) = 1.87, CI = 1.22-2.86 and AHR = 2.80, CI = 1.73-4.55, respectively, p < 0.0001), simultaneous kidney-pancreas transplantation (AHR = 2.52, CI = 1.27-5.01 p = 0.008), year of transplant 1998-1999 and 2000-2001 (vs. 2006-2007, AHR = 3.36, CI = 1.64-6.87 and AHR = 3.08, CI = 1.55-6.15, respectively, p = 0.003), EBV mismatch (HR = 5.31, CI = 3.36-8.39, p < 0.001), 5 or 6 HLA mismatches (vs. 0-4, AHR = 1.54, CI = 1.12-2.12, p = 0.008), and induction therapy (AHR = 1.42, CI = 1-2.02, p = 0.05). Analyses of subgroups of PTLD provided new information about PTLD risk factors for early, late, EBV positive and negative, polymorphic, monomorphic, graft and cerebral lymphomas. This nationwide study highlights the increased risk of PTLD as long as 10 years after transplantation and the role of cofactors in modifying PTLD risk, particularly in specific PTLD subgroups. PMID:22226336
Caillard, S; Lamy, F X; Quelen, C; Dantal, J; Lebranchu, Y; Lang, P; Velten, M; Moulin, B
X-linked lymphoproliferative disease (XLP) is a rare worldwide occurring inherited immunodeficiency which is triggered by Epstein-Barr virus infection. Clinical phenotypes in 21 affected males from 5 German families with XLP ranged from severe and fatal infectious mononucleosis (57%) to acquired hypogammaglobulinaemia (28%), malignant lymphoma (28%), aplastic anaemia (19%) and hypergammaglobulinaemia M (19%). Molecular genetic studies with various polymorphic X-chromosomal DNA markers in 14 XLP families mapped the XLP gene locus to Xq25-q26. Haplotype analysis enables detection of XLP-positive and XLP-negative males already before EBV-infection as well as diagnosis of healthy female carriers within XLP families. PMID:7500602
Schuster, V; Grimm, T; Kress, W; Seidenspinner, S; Belohradsky, B H; Müller, P; Kreth, H W
X linked lymphoproliferative disease (XLP; Duncan's disease) is a rare disorder affecting boys and characterised by a defective immune response to Epstein-Barr virus caused by a mutation in a gene located at chromosome Xq25. Three siblings with XLP in a single UK family are reported and the variation in phenotypic expression of the disease in these siblings described. One of the siblings with life threatening fulminant infectious mononucleosis was successfully treated by chemotherapy, followed by bone marrow transplantation using an unaffected brother as the donor. A healthy baby boy recently born into the family was identified as carrying the defective maternal X chromosome using molecular genetic linkage analysis. This family illustrates the extent of present understanding of this often fatal condition. PMID:9771253
Arkwright, P D; Makin, G; Will, A M; Ayres, M; Gokhale, D A; Fergusson, W D; Taylor, G M
Although bisphosponates are proposed as first-line treatment for posttransplant bone disease they are not optimal in all situations. A kidney transplant recipient developed hypercalcemia from mobilization of extraskeletal calcium. He had low serum parathyroid hormone and vitamin D; high calcium excretion; and normal calcium intake. Bone biopsy revealed severe osteomalacia. Bisphosphonates, used in the early treatment of acute hypercalcemia, were not indicated to treat osteomalacia. However, over several months serum calcium declined sufficiently to allow treatment of the bone disease with oral calcitriol. Dual-energy radiographic absorptiometry over the next 2 years documented dramatic improvements in bone density (percent of young-normal controls) : from 63 to 85%, at the lumbar spine; from 38 to 67%, at the femoral neck. This response to treatment could not have been achieved with an antiresorptive strategy. Optimal management of posttransplant bone disease requires a diagnostic approach, which considers all plausible contributing factors. PMID:11455270
Dhingra, R K; Sprague, S M; Ojo, A O; Leavey, S F
The soluble form of CD30 (sCD30), a member of tumor necrosis factor receptor superfamily, has been used as a marker of disease activity in various lymphomas. Epstein-Barr virus (EBV) is a potent stimulator of CD30 expression. The study aims to evaluate whether sCD30 can be used as a diagnostic marker for EBV-associated infectious mononucleosis (IM) and post-transplant lymphoproliferative disease (PTLD). Plasma from EBV seropositive healthy controls (N?=?90), acute IM patients (n?=?90), non-PTLD heart/lung transplant recipients (N?=?30) and EBV-positive PTLD patients (N?=?23) was tested for sCD30 using a commercially available ELISA kit. EBV DNA was tested by real time quantitative polymerase chain reaction assay. Significantly higher sCD30 levels were observed in acute IM patients (median 242.9?ng/ml) compared to EBV seropositive controls (median 15.7?ng/ml; P?0.0001). These levels were highest in IM patients within 14 days of onset of illness. PTLD patients had significantly higher sCD30 levels (median 94?ng/ml) than healthy controls (P?0.0001) and transplant patients (median 27?ng/ml; P?=?0.0007). EBV DNA was detected mostly in acute IM and PTLD patients. In both cases there was a significant correlation between sCD30 and EBV DNA levels in plasma (P?0.0001). This study demonstrates that sCD30 and EBV DNA levels can be used as potential markers for diagnosis of IM and PTLD. PMID:21181928
Haque, Tanzina; Chaggar, Turren; Schafers, Jenna; Atkinson, Claire; McAulay, Karen A; Crawford, Dorothy H
X-linked lymphoproliferative disease (XLP1) is a rare immunodeficiency characterized by severe immune dysregulation and caused by mutations in the SH2D1A/SAP gene. Clinical manifestations are varied and include hemophagocytic lymphohistiocytosis (HLH), lymphoma and dysgammaglobulinemia, often triggered by Epstein-Barr virus infection. Historical data published before improved treatment regimens shows very poor outcome. We describe a large cohort of 91 genetically defined XLP1 patients collected from centers worldwide and report characteristics and outcome data for 43 patients receiving hematopoietic stem cell transplant (HSCT) and 48 untransplanted patients. The advent of better treatment strategies for HLH and malignancy has greatly reduced mortality for these patients, but HLH still remains the most severe feature of XLP1. Survival after allogeneic HSCT is 81.4% with good immune reconstitution in the large majority of patients and little evidence of posttransplant lymphoproliferative disease. However, survival falls to 50% in patients with HLH as a feature of disease. Untransplanted patients have an overall survival of 62.5% with the majority on immunoglobulin replacement therapy, but the outcome for those untransplanted after HLH is extremely poor (18.8%). HSCT should be undertaken in all patients with HLH, because outcome without transplant is extremely poor. The outcome of HSCT for other manifestations of XLP1 is very good, and if HSCT is not undertaken immediately, patients must be monitored closely for evidence of disease progression.
Booth, Claire; Gilmour, Kimberly C.; Veys, Paul; Gennery, Andrew R.; Slatter, Mary A.; Chapel, Helen; Heath, Paul T.; Steward, Colin G.; Smith, Owen; O'Meara, Anna; Kerrigan, Hilary; Mahlaoui, Nizar; Cavazzana-Calvo, Marina; Fischer, Alain; Moshous, Despina; Blanche, Stephane; Pachlopnick-Schmid, Jana; Latour, Sylvain; de Saint-Basile, Genevieve; Albert, Michael; Notheis, Gundula; Rieber, Nikolaus; Strahm, Brigitte; Ritterbusch, Henrike; Lankester, Arjan; Hartwig, Nico G.; Meyts, Isabelle; Plebani, Alessandro; Soresina, Annarosa; Finocchi, Andrea; Pignata, Claudio; Cirillo, Emilia; Bonanomi, Sonia; Peters, Christina; Kalwak, Krzysztof; Pasic, Srdjan; Sedlacek, Petr; Jazbec, Janez; Kanegane, Hirokazu; Nichols, Kim E.; Hanson, I. Celine; Kapoor, Neena; Haddad, Elie; Cowan, Morton; Choo, Sharon; Smart, Joanne; Arkwright, Peter D.
Post-transplant skin malignancies have been extensively studied [1–6], but the role of the transplanted organ in the occurrence\\u000a of tumours is still discussed. This chapter reviews the epidemiological, clinical, and therapeutic aspects of skin cancers\\u000a in populations of kidney (KTR), heart (HTR), and liver transplant recipients (LTR). Furthermore, some data on the impact of\\u000a the pre-existing disease leading to organ
Sylvie Euvrard; Alain Claudy
X-linked lymphoproliferative disease (XLP) is a rare familial disorder resulting in selective immunodeficiency to the Epstein-Barr virus (EBV), characterized by uncontrolled proliferation of EBV-infected lymphocytes. Phenotypes of this disease are variable and include fulminant infectious mononucleosis, hypogammaglobulinemia, and malignant lymphoma. In this article, we describe a case of a previously healthy 4-year-old boy with serologic evidence of acute EBV infection who died of fulminant hepatic failure. Histopathological examination of tissue obtained postmortem showed hemophagocytosis and prominent polymorphous infiltrates associated with necrosis in the liver, spleen, and lymph nodes. Semiquantitative polymerase chain reaction (PCR) utilizing primers complementary to the EBV gene LMP2a performed on samples of liver tissue demonstrated approximately 0.6 copies of the EBV gene per cell. Immunohistochemistry demonstrated light chain restriction and PCR studies of the immunoglobulin V-D-J region revealed two strong bands, consistent with a clonal B cell proliferation. Extended family history revealed that the boy's family was followed by the XLP Registry, which was established in 1978 to follow kindreds with XLP. The genetic abnormality associated with XLP has been localized to the Xq25, allowing RFLP analysis to identify female carriers and affected boys. PMID:9841710
Maia, D M; Garwacki, C P
X-linked lymphoproliferative disease (XLP) is an inherited immune defect caused by mutations in the Src homology 2 domain-containing gene 1A, which encodes the adapter protein, signaling lymphocytic activation molecule (SLAM)-associated protein (SAP). SAP is expressed in T cells, natural killer (NK) cells, and NKT cells, where it binds to the cytoplasmic domain of the surface receptor SLAM (CD150) and the related receptors, 2B4 (CD244), CD84, Ly9 (CD229), NK-T-B-antigen, and CD2-like receptor-activating cytotoxic T cells. SAP also binds to the Src family tyrosine kinase Fyn and recruits it to SLAM, which leads to the generation of downstream phosphotyrosine signals. While the roles of the SLAM family receptors are only beginning to be understood, experiments suggest that these molecules regulate important aspects of lymphocyte function, such as proliferation, cytokine secretion, cytotoxicity, and antibody production. Thus, in XLP patients who lack functional SAP, the SLAM family receptors may not signal properly. This property likely contributes to the phenotypes of XLP, including fulminant infectious mononucleosis, lymphoma, and hypogammaglobulinemia. Further studies of SAP and the SLAM family receptors will provide insights into XLP and elucidate the signaling events regulating lymphocyte ontogeny and function. PMID:15661030
Nichols, Kim E; Ma, Cindy S; Cannons, Jennifer L; Schwartzberg, Pamela L; Tangye, Stuart G
Systemic vasculitis is an uncommon manifestation of X-linked lymphoproliferative disease (XLP), a disorder in which there is a selective immune deficiency to Epstein-Barr virus (EBV). The molecular basis for XLP has recently been ascribed to mutations within SLAM-associated protein (SAP), an SH2 domain-containing protein expressed primarily in T cells. The authors describe a patient who died as a result of chronic systemic vasculitis and fulfilled clinical criteria for the diagnosis of XLP. Sequencing of this patient's SAP gene uncovered a novel point mutation affecting the SH2 domain. The patient presented with virus-associated hemophagocytic syndrome (VAHS) and later had chorioretinitis, bronchiectasis, and hypogammaglobulinemia develop. He further developed mononeuritis and fatal respiratory failure. Evidence of widespread small and medium vessel vasculitis was noted at autopsy with involvement of retinal, cerebral, and coronary arteries as well as the segmental vessels of the kidneys, testes, and pancreas. Immunohistochemical analysis using antibodies to CD20, CD45RO, and CD8 revealed that the vessel wall infiltrates consisted primarily of CD8(+) T cells, implying a cytotoxic T-lymphocyte response to antigen. EBV DNA was detected by polymerase chain reaction (PCR) in arterial wall tissue microdissected from infiltrated vessels further suggesting that the CD8(+) T cells were targeting EBV antigens within the endothelium. The authors propose that functional inactivation of the SAP protein can impair the immunologic response to EBV, resulting in systemic vasculitis. PMID:11133747
Dutz, J P; Benoit, L; Wang, X; Demetrick, D J; Junker, A; de Sa, D; Tan, R
X-linked lymphoproliferative (XLP) disease is a human immune dysfunction characterized primarily by an inappropriate response to Epstein-Barr virus infection. In 1998, it was discovered that XLP is caused by inactivating mutations in the SAP/SH2D1A/DSHP gene. This gene codes for an immune cell-specific polypeptide termed SAP (SLAM-associated protein) that is composed almost exclusively of an Src homology 2 (SH2) domain. By way of its SH2 domain, SAP interacts with tyrosine-based motifs located in the cytoplasmic region of members of the SLAM (signaling lymphocyte activation molecule) family of receptors. Recent findings indicate that SAP is required for the function of SLAM-related receptors, as a consequence of its capacity to promote the recruitment and activation of the Src-related protein tyrosine kinase FynT, thereby allowing SLAM receptor-mediated protein tyrosine phosphorylation signals in immune cells. Functional and genetic analyses suggest that the phenotype associated with XLP is caused in large part by defects in the functions of SLAM-related receptors due to SAP deficiency. PMID:12670406
Latour, Sylvain; Veillette, André
The occurrence of smooth muscle neoplasms and lymphoproliferative disorders in immunocompromised patients is well recognized. We report the case of an 8-year-old girl with adenosine deaminase (ADA)-deficient severe combined immunodeficiency (SCID) status post-bone marrow transplant (BMT), in whom Epstein-Barr virus (EBV) was detected in innumerable leiomyomas involving the gallbladder (leiomyomatosis), and multifocal leiomyomas in liver, spleen, pancreas, intestinal tract, and lung. The leiomyomas of the gallbladder, liver, spleen, and lung were asymptomatic, while those located in the colon became clinically manifest by recurrent lower intestinal hemorrhage. The patient also developed extensive EBV-associated polymorphic lymphoproliferative disorder (PTLD) in nodal and extranodal sites. In addition, there were pulmonary and gastric adenovirus and small and large intestine cryptosporidum infections. Our case appears to be the first example of leiomyomatosis of the gallbladder coexisting with multifocal leiomyomas of the liver, spleen, pancreas, intestinal tract, and lung, as well as EBV-derived lymphoproliferative disorder in a young girl with ADA-deficient SCID. Awareness of the pattern of involvement and of the coexistence of benign leiomyomatous proliferations with lymphoproliferative disorder is of value when gallbladder, pancreatic, biliary tree, lung, and intestinal lesions become clinically manifest in these patients. The demonstration of EBV infection in both leiomyomata and the PTLD suggests a common pathogenesis that may have therapeutic and prognostic implications. PMID:14708738
Monforte-Muñoz, Hector; Kapoor, Neena; Saavedra, Jorge Albores
STAT5 is activated in a broad spectrum of human hematologic malignancies. We addressed whether STAT5 activation is necessary for the myelo- and lymphoproliferative disease induced by TEL\\/JAK2 using a genetic approach. Whereas mice transplanted with bone marrow transduced with retrovirus expressing TEL\\/JAK2 develop a rapidly fatal myelo- and lymphoproliferative syndrome, reconstitution with bone marrow derived from Stat5ab-deficient mice expressing TEL\\/JAK2
Juerg Schwaller; Evan Parganas; Demin Wang; Danielle Cain; Jon C. Aster; Ifor R. Williams; Chien-Kuo Lee; Rachel Gerthner; Toshio Kitamura; Julie Frantsve; Ema Anastasiadou; Mignon L. Loh; David E. Levy; James N. Ihle; D. Gary Gilliland
Bronchiectasis may occur with various congenital and acquired immunodeficiency diseases. The association of bronchiectasis and the X-linked lymphoproliferative disease (XLP), also known as Duncan's disease is unknown. We describe the case of a 39-year-old man with XLP, the oldest surviving, who developed chronic bronchiectasis with hemoptysis and required a pneumonectomy to control his symptoms. PMID:10475441
Mehta, V K; Massad, M G; Tripathi, S P; Koshy, M; Geha, A S
Celiac disease (CD) is associated with both lymphoproliferative malignancy (LPM) and increased death from LPM. Research suggests that co-existing autoimmune disease may influence survival in LPM. Through Cox regression we examined overall and cause-specific mortality in 316 individuals with CD+LPM versus 689 individuals with LPM only. CD was defined as having villous atrophy according to biopsy reports at any of Sweden's 28 pathology departments, and LPM as having a relevant disease code in the Swedish Cancer Register. During follow-up, there were 551 deaths (CD: n = 200; non-CD: n = 351). Individuals with CD+LPM were at an increased risk of death compared with LPM-only individuals [adjusted hazard ratio (aHR) = 1.23; 95% confidence interval (CI) = 1.02-1.48]. However, this excess risk was only seen in the first year after LPM diagnosis (aHR = 1.76), with HRs decreasing to 1.09 in years 2-5 after LPM diagnosis and to 0.90 thereafter. Individuals with CD and non-Hodgkin lymphoma (NHL) were at a higher risk of any death as compared with NHL-only individuals (aHR = 1.23; 95% CI = 0.97-1.56). This excess risk was due to a higher proportion of T cell lymphoma in CD patients. Stratifying for T- and B cell status, the HR for death in individuals with CD+NHL was 0.77 (95% CI = 0.46-1.31). In conclusion, we found no evidence that co-existing CD influences survival in individuals with LPM. The increased mortality in the first year after LPM diagnosis is related to the predominance of T-NHL in CD individuals. Individuals with CD+LPM should be informed that their prognosis is similar to that of individuals with LPM only. However, this study had low statistical power to rule our excess mortality in patients with CD and certain LPM subtypes. PMID:23463575
Ludvigsson, Jonas F; Lebwohl, Benjamin; Rubio-Tapia, Alberto; Murray, Joseph A; Green, Peter H R; Ekbom, Anders; Granath, Fredrik
Celiac disease (CD) is associated with both lymphoproliferative malignancy (LPM) and increased death from LPM. Research suggests that co-existing autoimmune disease may influence survival in LPM. Through Cox regression we examined overall and cause-specific mortality in 316 individuals with CD+LPM vs. 689 individuals with LPM only. CD was defined as having villous atrophy according to biopsy reports at any of Sweden’s 28 pathology departments, and LPM as having a relevant disease code in the Swedish Cancer Register. During follow-up, there were 551 deaths (CD: n=200; non-CD: n=351). Individuals with CD+LPM were at an increased risk of death compared with LPM-only individuals (adjusted hazard ratio (aHR)=1.23; 95% confidence interval (CI)=1.02–1.48). However, this excess risk was only seen in the first year after LPM diagnosis (aHR=1.76), with HRs decreasing to 1.09 in years 2–5 after LPM diagnosis and to 0.90 thereafter. Individuals with CD and non-Hodgkin lymphoma (NHL) were at a higher risk of any death as compared with NHL-only individuals (aHR=1.23; 95%CI=0.97–1.56). This excess risk was due to a higher proportion of T-cell lymphoma in CD patients. Stratifying for T- and B-cell status, the HR for death in individuals with CD+NHL was 0.77 (95%CI=0.46–1.31 In conclusion, we found no evidence that co-existing CD influences survival in individuals with LPM. The increased mortality in the first year after LPM diagnosis is related to the predominance of T-NHL in CD individuals. Individuals with CD+LPM should be informed that their prognosis is similar to that of individuals with LPM only. However, this study had low statistical power to rule our excess mortality in patients with CD and certain LPM subtypes.
Ludvigsson, Jonas F; Lebwohl, Benjamin; Rubio-Tapia, Alberto; Murray, Joseph A.; Green, Peter HR; Ekbom, Anders; Granath, Fredrik
X-linked lymphoproliferative disorder (XLP) was first described almost 30 years ago; remarkably, the three major manifestations\\u000a of XLP, fulminant infectious mononucleosis (FIM), lymphoma, and dysgammaglobulinemia, are all described in the report of the\\u000a initial kindred. Subsequent establishment of an XLP registry has led to recognition of more unusual phenotypes in affected\\u000a males; concurrently, much progress has been made in caring
Andrew J. MacGinnitie; Raif Geha
Patients with autoimmune lymphoprolif- erative syndrome (ALPS) and systemic lupus erythematosis (SLE) have T-cell dysregulation and produce abnormal, activated T lymphocytes and an atypical peripheral T-cell population, termed double negative T cells (DNTs). T-cell functions, including DNT transition in T- cell development and T-cell activation, are critically dependent on Notch signal- ing. We hypothesized that inhibiting Notch signaling would be
David T. Teachey; Alix E. Seif; Valerie I. Brown; Marlo Bruno; Ralph M. Bunte; Yueh J. Chang; John K. Choi; Jonathan D. Fish; Gregor S. Reid; Theresa Ryan; Cecilia Sheen; Patrick Zweidler-McKay; Stephan A. Grupp
Three families with X-linked lymphoproliferative disease were studied. Affected males clinically presented with severe or fatal infectious mononucleosis, acquired hypogammaglobulinaemia, hypergammaglobulinaemia M, and malignant lymphoma including Hodgkin disease. Haplotype analysis using various DNA markers from Xq25-q27 allowed the prediction of the carrier status in females and identification of the XLP status in asymptomatic males.
V. Schuster; S. Seidenspinner; T. Grimm; W. Kreß; S. Zielen; M. Bock; H. W. Kreth
Three families with X-linked lymphoproliferative disease were studied. Affected males clinically presented with severe or fatal infectious mononucleosis, acquired hypogammaglobulinaemia, hypergammaglobulinaemia M, and malignant lymphoma including Hodgkin disease. Haplotype analysis using various DNA markers from Xq25-q27 allowed the prediction of the carrier status in females and identification of the XLP status in asymptomatic males. PMID:7916289
Schuster, V; Seidenspinner, S; Grimm, T; Kress, W; Zielen, S; Bock, M; Kreth, H W
Transplant patients are at risk for post-transplant lymphoproliferative disease (PTLD), a virally driven malignancy. Induction with the depleting antibody preparations Thymoglobulin and OKT3 is associated with PTLD, suggesting that T cell depletion increases PTLD risk. We therefore studied 59,560 kidney recipients from the OPTN/UNOS database for a relationship between induction agent use and PTLD. Two agents with comparable depletional effects, alemtuzumab and Thymoglobulin, were compared to non-depletional induction agents or no induction. Univariate and multivariate Cox regression analyses were performed to examine the association between induction regimen and PTLD. The overall incidence of PTLD was 0.42% and differed significantly by induction strategy (p<0.01): without induction (0.43%), basiliximab (0.38%), daclizumab (0.33%), Thymoglobulin (0.67%), and alemtuzumab (0.37%). Thymoglobulin was associated with a significantly increased risk of PTLD (p=0.0025), but alemtuzumab (p=0.74), basiliximab (p=0.33), and daclizumab, which trended toward a protective effect (p=0.06), were not. Alemtuzumab and Thymoglobulin treated patients did not differ in any established parameter affecting PTLD risk. Interestingly, maintenance therapy with an mTOR inhibitor was strongly associated with PTLD (0.71%, p<0.0001). Thus, depletional induction is not an independent risk factor for PTLD. Rather, aggregate chronic immunosuppression or maintenance drug selection may be a more relevant determinant of PTLD risk.
Kirk, Allan D.; Cherikh, Wida S.; Ring, Michael; Burke, George; Kaufman, Dixon; Knechtle, Stuart J.; Potdar, Santosh; Shapiro, Ron; Dharnidharka, Vikas R.; Kauffman, H. Myron
Seven male patients in the David T Purtilo International X-linked Lymphoproliferative Disease (XLP) Registry have undergone allogeneic hematopoietic stem cell transplantation (HSCT). All patients received HSCT from HLA-identical donors: sibling BM, five; unrelated BM, one; and sibling umbilical cord blood, one. Ages at time of HSCT ranged from 5 to 30 years. Pre-HSCT clinical course varied, but four boys had a significant history of chronic and/or serious infections. Conditioning regimens varied: TBI containing regimens, four, chemotherapy only, three. All patients engrafted. Six developed grade I-II acute GVHD but no chronic GVHD. Four are alive and well with normal immune function greater than 3 years following HSCT. Three died within 100 days: disseminated adenovirus, one; polymicrobial sepsis, one; and multiple organ system failure and bleeding diathesis, one. No EBV-associated post-transplant complications were observed, even though all donors except the umbilical cord blood were EBV-seropositive. Unsuccessful HSCT was associated with age at HSCT (> 15 years), TBI-containing regimen and significant history for pre-HSCT infections. These results provide evidence that HSCT performed during childhood with HLA-identical sibling donors, regardless of EBV serostatus, offers the only curative therapy for XLP. PMID:8733691
Gross, T G; Filipovich, A H; Conley, M E; Pracher, E; Schmiegelow, K; Verdirame, J D; Vowels, M; Williams, L L; Seemayer, T A
The risk of lymphoproliferative disorders (LDs) has become a major concern for clinicians managing patients with inflammatory bowel disease (IBD). Yet it is difficult to distinguish the possible responsibility of immunosuppressive therapy from the background risk due to the inflammatory disorder itself. LDs are clonal B or T cell proliferation showing considerable heterogeneity and the incidence has increased since the
H Sokol; L Beaugerie
Gene rearrangement and monoclonality have been detected in normal cells and in lymphoproliferative disease by using the polymerase chain reaction and primers for the V and J regions of the lg heavy chain gene or T-cell receptor ychain gene. Using the lg primers monoclonality was detected in 20 of 20 normal B-lymphocyte clones and in 39 of 52 cases of
K. J. Trainor; M. J. Brisco; J. H. Wan; S. Neoh; S. Grist; A. A. Morley
PTLD is a potentially life-limiting complication of pediatric transplantation. Previous registry-based studies in renal transplantation have suggested a link between rhGH use and PTLD. In this study, demographic and transplant data on those aged <18 yr and transplanted between 1991 and 2008 were collected from the ANZDATA Registry. Associations between gender, age at time of transplant, recipient CMV and EBV status, use of monoclonal antibody therapy, and use of rhGH were studied as potential predictors of PTLD. Among 650 transplants, there were 20 cases (3.1%) of PTLD, with half presenting within two yr post-transplant. Eight patients exposed to rhGH at any time developed PTLD, and this association was not statistically significant (RR = 1.5[0.6-3.4], p = 0.36). On multivariate analysis, there were no significant predictors for PTLD. In this study, previously identified potential risk factors were not identified as significant predictors for the development of PTLD. Although limited sample size may affect our ability to infer safety, this large retrospective cohort study does not suggest an increased risk of PTLD in pediatric kidney transplant recipients who received rhGH treatment. PMID:24164826
Longmore, Danielle K; Conwell, Louise S; Burke, John R; McDonald, Stephen P; McTaggart, Steven J
X-linked lymphoproliferative disorder (XLP) was first described almost 30 years ago; remarkably, the three major manifestations of XLP, fulminant infectious mononucleosis (FIM), lymphoma, and dysgammaglobulinemia, are all described in the report of the initial kindred. Subsequent establishment of an XLP registry has led to recognition of more unusual phenotypes in affected males; concurrently, much progress has been made in caring for boys with XLP, including treatment for the three major phenotypes, and curative bone marrow transplantation (BMT). The immunologic and genetic mechanisms resulting in XLP have also been intensively studied. Several years ago, the gene defective in XLP was identified as SAP (SLAM-associated protein), and recent data suggest that SAP plays a broad role in immune signaling. Here, we review the clinical manifestations and therapy of XLP, and briefly summarize recent research into the structure and function of SAP. PMID:12165201
MacGinnitie, Andrew J; Geha, Raif
Clinical features of 40 lymphoproliferative neoplasm patients in the setting of systemic autoimmune diseases managed in the\\u000a Clinic of Hematology during 1994–2006 were analyzed retrospectively. The classification of systemic autoimmune disease patients\\u000a was as follows: 15 systemic lupus erythematosus—SLE, 11 rheumatoid arthritis—RA, 12 Sjögren’s syndrome—SS, 1 scleroderma,\\u000a and 1 dermatomyositis. Patients comprised 31 women and 9 men of mean age
Nada Suvajdzic; Predrag Djurdjevic; Milena Todorovic; Maja Perunicic; Roksanda Stojanovi?; Aleksandra Novkovic; Biljana Mihaljevic
X-linked lymphoproliferative disease (XLP) is an inherited immunodeficiency, partially characterized by a defect in cytotoxicity to Epstein-Barr virus. This viral infection is therefore often fatal in affected boys, whilst a variety of immune disorders or proliferative diseases may occur in surviving patients.We report an atypical case of a 41year-old male who presented with a primitive B-cell cerebral lymphoma, revealing an
B. Hervier; S. Latour; D. Loussouarn; M. Rimbert; G De-Saint-Basile; C. Picard; M. Hamidou
Metabolic syndrome (MS) is a cluster of metabolic derangements associated with insulin resistance and an increased risk of cardiovascular mortality. MS has become a major health concern worldwide and is considered to be the etiology of the current epidemic of diabetes and cardiovascular disease. In addition to cardiovascular disease, the presence of MS is also closely associated with other comorbidities including nonalcoholic fatty liver disease (NAFLD). The prevalence of MS in patients with cirrhosis and end-stage liver disease is not well established and difficult to ascertain. Following liver transplant, the prevalence of MS is estimated to be 44–58%. The main factors associated with posttransplant MS are posttransplant diabetes, obesity, dyslipidemia, and hypertension. In addition to developing NAFLD, posttransplant MS is associated with increased cardiovascular mortality that is 2.5 times that of the age- and sex-matched individuals. Additionally, the presence of posttransplant MS has been associated with rapid progression to fibrosis in individuals transplanted for HCV cirrhosis. There is an urgent need for well-designed prospective studies to fully delineate the natural history and risk factors associated with posttransplant MS. Until then, early recognition, prevention, and treatment of its components are vital in improving outcomes in liver transplant recipients.
Siddiqui, M. Shadab; Sterling, Richard K.
Our understanding of the X-linked lymphoproliferative syndrome (XLP) has advanced significantly in the last two years. The gene that is altered in the condition (SAP/SH2D1A) has been cloned and its protein crystal structure solved. At least two sets of target molecules for this small SH2 domain-containing protein have been identified: A family of hematopoietic cell surface receptors, i.e. the SLAM family, and a second molecule, which is a phosphorylated adapter. A SAP-like protein, EAT-2, has also been found to interact with this family of surface receptors. Several lines of evidence, including structural studies and analyses of missense mutations in XLP patients, support the notion that SAP/SH2D1A is a natural inhibitor of SH2-domain-dependent interactions with members of the SLAM family. However, details of its role in signaling mechanisms are yet to be unravelled. Further analyses of the SAP/SH2D1A gene in XLP patients have made it clear that the development of dys-gammaglobulinemia and B cell lymphoma can occur without evidence of prior EBV infection. Moreover, preliminary results of virus infections of a mouse in which the SAP/SH2D1A gene has been disrupted suggest that EBV infection is not per se critical for the development of XLP phenotypes. It appears therefore that the SAP/SH2D1A gene controls signaling via the SLAM family of surface receptors and thus may play a fundamental role in T cell and APC interactions during viral infections. PMID:11244050
Morra, M; Howie, D; Grande, M S; Sayos, J; Wang, N; Wu, C; Engel, P; Terhorst, C
Cytotoxic T cells (CTLs) and natural killer cells play a major role in the immune response to Epstein-Barr virus (EBV) in- fection. In X-linked lymphoproliferative (XLP) disease, a severe immunodefi- ciency, immunodysregulatory phenom- ena are observed following EBV infec- tion, suggesting that defects exist in these effector populations. The gene defective in XLP is SAP (signaling lymphocytic activation molecule (SLAM)-associated
Reza Sharifi; Joanna C. Sinclair; Kimberly C. Gilmour; Peter D. Arkwright; Christine Kinnon; Adrian J. Thrasher; H. Bobby Gaspar
X-linked lymphoproliferative disease (XLP) is a rare, often fatal genetic disorder characterized by extreme vulnerability to Epstein-Barr virus (EBV). EBV-induced hemophagocytic lymphohistiocytosis (HLH) is a known presentation in XLP. In EBV-induced HLH in XLP, the brain imaging findings in the acute phase include a non specific pattern. In this report, we highlight the magnetic resonance imaging and magnetic resonance spectroscopy findings in a child with EBV induced HLH in XLP.
Sankararaman, Senthilkumar; Riel-Romero, Rosario Maria; Jeroudi, Majed; Gonzalez-Toledo, Eduardo
X-linked lymphoproliferative disease (XLP) is an inherited immunodeficiency, partially characterized by a defect in cytotoxicity to Epstein-Barr virus. This viral infection is therefore often fatal in affected boys, whilst a variety of immune disorders or proliferative diseases may occur in surviving patients. We report an atypical case of a 41year-old male who presented with a primitive B-cell cerebral lymphoma, revealing an XLP. This presentation was unusual because of its late onset, the broad spectrum of the familial characteristics, its initial presentation as a cerebral lymphoma, and the occurrence of B-cell alymphocytosis associated with a-gamma-globulinemia. PMID:19906447
Hervier, B; Latour, S; Loussouarn, D; Rimbert, M; De-Saint-Basile, G; Picard, C; Hamidou, M
The correction of post-transplant hyperlipidaemia warrants the judicious and timely use of pharmacological agents with dietary modification and exercise. Reduction in hyperlipidaemia may have some role in decreasing the incidence of chronic rejection of allografts. The awareness that the morbidity and mortality of atherosclerotic disease may be lowered by active intervention will result in a better quality of life for transplant recipients.
Jindal, R. M.
Common variable immunodeficiency (CVID) and X-linked lymphoproliferative (XLP) disease are two immunodeficiencies that may share a similar immunological phenotype making differential diagnosis difficult. We report two patients initially diagnosed as affected with CVID who, using molecular analysis, have been subsequently found to be affected with XLP disease. Distinguishing between these two diseases is essential since they have different prognosis, treatment
Annarosa Soresina; Vassilis Lougaris; Silvia Giliani; Fabio Cardinale; Lucio Armenio; Marco Cattalini; Luigi D. Notarangelo; Alessandro Plebani
Epstein–Barr virus (EBV) is implicated in a variety of human diseases, some of which have fatal outcomes. Some EBV related diseases are considered to be candidates for the treatment of hematopoietic stem cell transplantation (HSCT). X-linked lymphoproliferative (XLP) syndrome is one of the representative diseases in which more than half of affected males die of infectious mononucleosis (IM) within a
Keisei Kawa; Takayuki Okamura; Masahiro Yasui; Emiko Sato; Masami Inoue
Analysis of immunoglobulin gene rearrangements in 16 B-cell lineages clonally propagated from two mononucleosis patients supported the notion that mononucleosis is a polyclonal B-lymphoproliferative disorder. Three of seven cell clones from a patient with a fatal B lymphoma revealed the same pattern of immunoglobulin gene rearrangement, indicating that this patient's disease was oligoclonal. The three similar clones were propagated from two sites (blood and spleen), indicating that they represent a metastatic cell lineage which arose during the patient's fatal B lymphoproliferation. Images
Brown, N A; Liu, C; Garcia, C R; Wang, Y F; Griffith, A; Sparkes, R S; Calame, K L
High resolution chromosome analysis was done on lymphoblastoid cell lines, established during the past decade from affected males with X-linked lymphoproliferative disease (XLP) or from obligate female carriers, from 14 families. One cell line, from a male with XLP, has a partial deletion of band Xq25. The constitutional nature of the deletion is confirmed in chromosome studies of peripheral blood from the affected individual and represents the first such structural defect to be described in this disorder. Cell lines from the remaining 13 families do not have cytogenetically detectable deletions. This observation will facilitate precise localization, cloning and sequencing of the gene causing XLP. PMID:2801783
Wyandt, H E; Grierson, H L; Sanger, W G; Skare, J C; Milunsky, A; Purtilo, D T
T/NK cell proliferative EBV associated disease is a rare one which is more common in eastern Asian countries. EBV is originally associated with B cells, and EBV associated T cell lymphoma is so rare. Hence we decided to describe a patient treated with misleading diagnoses such as TB and sarcoidosis for almost two years. The liver was biopsied after admission in this center, and gastric and colonic biopsy was also performed due to gastrointestinal bleeding. Diffuse infiltration of chronic inflammatory cells was seen, especially lymphocytes some of which were atypical. T lymphocyte markers were seen in these cells by immunohistochemical staining. Further studies demonstrated T lymphocytes associated with EBV to be positive which is very rare event. Although going under chemotherapy, there were no response and the patient died. PMID:24901859
Kheyri, Zahedin; Mojtahedzadeh, Aydin; Zamani, Farhad; Zaremehrjerdi, Ali; Babaheidarian, Pegah
A five-year-old boy in the acute phase of X-linked lymphoproliferative (XLP) syndrome (Duncan disease) with high fever and hepatosplenomegaly was treated successfully with high-dose methylprednisolone and VP-16 for 15 months. He had been alive for four years after diagnosis as of this writing. We recommend high-dose methylprednisolone and VP-16 in patients with XLP who have to wait for a suitable donor before bone marrow transplantation. PMID:8701487
Gürgey, A; Sayli, T; Kara, A; Kale, G; Berkel, I
We report the occurrence of X-linked lymphoproliferative disease (XLP) in two brothers in a Malaysian family. In this disorder, a primary Epstein-Barr virus (EBV) infection is followed by an abnormal proliferation of transformed B-cells that cannot be controlled by suppressor T-cells, leading to the development of deranged immune function. This results in fatal infectious mononucleosis, acquired hypogammaglobulinaemia, virus-infected haemophagocytic syndrome and non-Hodgkin's lymphoma. The diagnosis should be considered when there is a family history of any male having a fulminant course of infectious mononucleosis, an otherwise benign disease. Early diagnosis is important as bone marrow transplantation is the only curative option in this disorder. PMID:8942243
Hany, A; Thong, M K; Lin, H P
Immunophenotypes in lymphoproliferative diseases (LPD) are prognostically significant, yet causative factors for these conditions, and specifically those associated with heritable risk, remain elusive. The full spectrum of LPD seen in humans occurs in dogs, but the incidence and lifetime risk of naturally occurring LPD differs among dog breeds. Taking advantage of the limited genetic heterogeneity that exists within dog breeds,
Jaime F. Modiano; Matthew Breen; Robert C. Burnett; Heidi G. Parker; Seidu Inusah; Rachael Thomas; Paul R. Avery; Kerstin Lindblad-Toh; Elaine A. Ostrander; Gary C. Cutter; Anne C. Avery
The unique manifestation of the inherited immunodeficiency, X-linked lymphoproliferative disease (XLP), is the impaired control of EBV infection. The gene, which carries mutations or is deleted in the patients, has been identified (Xq25). The encoded protein (SAP, 128 aa) contains a single SH2 domain and binds to signaling lymphocytic activation molecule (SLAM) and to other related surface molecules that are
Noémi Nagy; Karin Mattsson; Akihiko Maeda; Anquan Liu; László Székely; Eva Klein
Background & objectives: Molecular events that precede transformations from lymphomatoid palulosis (LyP) to mycosis fungoides (MF) or to cutaneous anaplastic large cell lymphoma (ALCL) in the CD 30+ cutaneous lymphoproliferative diseases (LPDs) are not known. Altered p53 gene may be responsible since overexpression of the p53 gene product has been reported in higher, but not in lower grades of cutaneous
Sujala Kapur; Markus Tiemann; Martin A. O. H. Menke; Christoph Schubert; Reza Parwaresch
Lymphoproliferative disease of granular lymphocytes (LDGL) is a heterogeneous disorder and the pathogenesis is likely to be complex. Some patients with chronic active EBV (CAEBV) infection also have LDGL. To investigate the relationship between EBV infection and the pathogenesis of LDGL, we conducted a survey for EBV DNA sequences by Southern blot analysis of DNA obtained from the peripheral blood of seven patients with LDGL, including one with CAEBV infection. Interestingly, EBV DNA was detected in the sample from the patient with CAEBV infection, and in the samples from four other patients with CD3-LDGL. Moreover, a single band for the joined termini of the EBV genome was demonstrated in two samples, suggesting a clonal disorder of those LDGL. These findings strongly suggest that EBV may play a pathogenic role in some cases of LDGL. Images
Kawa-Ha, K; Ishihara, S; Ninomiya, T; Yumura-Yagi, K; Hara, J; Murayama, F; Tawa, A; Hirai, K
X-linked lymphoproliferative disease (XLP) results in exquisite vulnerability to EBV infection: fatal infectious mononucleosis (IM), acquired hypogammaglobulinemia and/or malignant lymphoma occur invariably following infection with the virus. We have identified the XLP locus using the DXS42 DNA probe having restriction length polymorphisms (RFLP). We report an interstitial deletion involving a portion of the Xq25 region in the X chromosome of an affected male, one sister, and their mother. Concordance has been established between the presence of a deletion and RFLP linkage analysis with the DXS42 probe in the kindred. This finding will contribute substantially to the mapping, cloning, and sequencing of the gene responsible for XLP. PMID:1972651
Sanger, W G; Grierson, H L; Skare, J; Wyandt, H; Pirruccello, S; Fordyce, R; Purtilo, D T
During the past decade, 240 males with X-linked lymphoproliferative disease (XLP) within 59 unrelated kindreds have been identified worldwide. One half of the patients have developed fatal infections mononucleosis, about one third have acquired hypogammaglobulinemia, and another one fourth have developed malignant lymphoma. Less commonly occurring phenotypes include hyperimmunoglobulinemia M, bone marrow hypoplasia, and necrotizing lymphoid vasculitis. The fatal infectious mononucleosis phenotype occurs at about 2.5 years of age, and median survival is only 33 days following onset of illness. The acquired hypogammaglobulinemia and malignant lymphoma phenotypes are associated with longer survivals, but to date no patient has been documented as living into the fifth decade of life. We summarized recent research findings and technological advances that permit accurate diagnosis of carrier females and detection of males with the XLP gene before Epstein-Barr virus infection. PMID:1847089
Purtilo, D T; Grierson, H L
Turkeys inoculated with spleen extracts from lymphoproliferative disease (LPD)-affected birds developed viremia, followed by typical LPD lesions. Electron microscopy and biochemical characterization established that the virus present in the blood of infected turkeys is a type C retrovirus. The viral particles possess a buoyant density of 1.17 g/ml in sucrose gradients; they contain high-molecular-weight RNA and an RNA-instructed DNA polymerase with efficient exogenous and endogenous activity. The LPD virus polymerase is preferentially activated by magnesium ions. Cross nucleic acid hybridization assays revealed no sequence homology between the viral genome of LPD and avian myeloblastosis virus or reticuloendotheliosis virus, thus indicating that the LPD virus belongs to a distinct group unrelated to the avian leukosis-sarcoma virus complex or to the reticuloendotheliosis virus group. Images
Yaniv, A; Gazit, A; Ianconescu, M; Perk, K; Aizenberg, B; Zimber, A
While the outcome for pediatric patients with lymphoproliferative disorders (LPD) or lymphoid malignancies, such as acute lymphoblastic leukemia (ALL), has improved dramatically, patients often suffer from therapeutic sequelae. Additionally, despite intensified treatment, the prognosis remains dismal for patients with refractory or relapsed disease. Thus, novel biologically targeted treatment approaches are needed. These targets can be identified by understanding how a loss of lymphocyte homeostasis can result in LPD or ALL. Herein, we review potential molecular and cellular therapeutic strategies that (i) target key signaling networks (e.g., PI3K/AKT/mTOR, JAK/STAT, Notch1, and SRC kinase family-containing pathways) which regulate lymphocyte growth, survival, and function; (ii) block the interaction of ALL cells with stromal cells or lymphoid growth factors secreted by the bone marrow microenvironment; or (iii) stimulate innate and adaptive immune responses.
Seif, Alix E.; Reid, Gregor S. D.; Teachey, David T.; Grupp, Stephan A.
X-linked lymphoproliferative disease is a rare T and NK cell immune deficiency which most frequently presents as fulminant\\u000a infectious mononucleosis following infection with the Epstein-Barr virus (EBV). We report the case of a 4-year-old boy from\\u000a a Spanish family presenting with severe infectious mononucleosis. In the course of the disease he developed hepatic failure,\\u000a pancytopenia and neurologic impairment, leading to
Boris Hügle; Itziar Astigarraga; Jan-Inge Henter; Anna Porwit-MacDonald; Alfons Meindl; Volker Schuster
A 14-year-old male and a maternally related cousin were diagnosed with X-linked lymphoproliferative disease (XLP) after developing recurrent B-NHL, characterized by long disease-free intervals and absence of an increased chemoresistance of the recurrent lymphomas. The demonstration of different clonal IgH gene rearrangements in two of the lymphomas from one of the patients further supports that the lymphomas were clonally unrelated.
T Hoffmann; C Heilmann; HO Madsen; L Vindeløv; K Schmiegelow
The X-linked lymphoproliferative disease (XLP), one of six described X-linked immunodeficiencies, stems from a mutation at Xq25 which renders males impotent to mount an effective immune response to the ubiquitous EBV. Purtilo, who first observed this disease in 1969, established a Registry in 1980 to serve as a worldwide resource for the diagnosis, treatment, and research of this condition. Since Purtilo's death in late 1992, the Registry and research unit have not only continued to function as a worldwide consultative service, but have contributed the following. First, the number of affected boys has continued to grow; some 272 among 80 kindreds have been identified. Second, some boys (10%) who inherit the mutated XLP gene are immunologically abnormal even before evidence of EBV exposure. Third, the search for the XLP gene has been narrowed to a small region on Xq25. Its identification is near at hand; once cloned, this gene may well illustrate how the body orchestrates the complex immune response to EBV. Therein lies the justification for the quest for this gene, not only for the benefit of the few surviving boys and those to be born to female carriers, but also for defining its role in defending the body against a ubiquitous DNA virus. PMID:8559596
Seemayer, T A; Gross, T G; Egeler, R M; Pirruccello, S J; Davis, J R; Kelly, C M; Okano, M; Lanyi, A; Sumegi, J
DAP-IV activity (Gly-Pro-MCA hydrolysis, pH 7.8) was found in lysates of peripheral blood lymphocytes of patients with T- and B-cell forms of malignant lymphoproliferative diseases. The highest DAP-IV activity was seen in the cells of patients with a rare variant of T-cell lymphocytic leukemia (T-CLL); these cells expressed simultaneously the antigens of T helpers and T suppressors (Th and Ts) (OKT4+ and OKT8+). The DAP-IV activity about ten times less was found in the pathological cells with a phenotype of mature Th (Sezary disease), as well as in the cells expressing antigens of both Ts and natural killers (a rare variant of T-CLL). The same activity was also found in Ts (T gamma-lymphocytosis). The data obtained show that the differences in DAP-IV expression are connected with the differentiation step rather than with the belonging to a particular subpopulation of T-cells. DAP-IV activity, which was somewhat lower than that of T-cells, was found in B-lymphocytes of patients with B-CLL, hair-cellular leukemia, and non-Hodgkin's lymphoma. No correlation of DAP-IV activity with the level of E-cellular differentiation was observed. PMID:2572281
Bylinkina, V S; Golubeva, N V; Gureeva, T A; Lokshina, L A; Polianskaia, A M; Samo?lova, R S
A major focus of our research is to understand the molecular and cellular basis of X-linked lymphoproliferative disease (XLP),\\u000a a rare and often fatal immunodeficiency caused by mutations in the SH2D1A gene, which encodes the adaptor molecule SAP. Recently, we observed that SAP is essential for the development of natural\\u000a killer T (NKT) cells, a lymphocyte population that participates in
Hamid Bassiri; W. C. Janice Yeo; Jennifer Rothman; Gary A. Koretzky; Kim E. Nichols
Thirty-one females with incontinentia pigmenti (IP), 42 controls, and 11 females from four families segregating for X linked lymphoproliferative disease (XLP) were studied for evidence of skewed X inactivation by analysis of methylation at sites in the HPRT, PGK, and M27 beta (DXS255) regions of the X chromosome. Extensive skewing of X inactivation was present in blood from 4\\/42 (9.5%)
A Harris; J Collins; D Vetrie; C Cole; M Bobrow
Hypogammaglobulinemia is a common symptom in different immunodeficiencies. It is, however, not usually associated with Epstein–Barr virus (EBV) infections. The X-linked lymphoproliferative disease (XLP) on the other hand shows immunological changes in response to the EBV. Here we report three previously healthy boys, all of which developed persistent hypogammaglobulinemia following severe acute infectious mononucleosis. All three patients revealed T-cell abnormalities
B. Hügle; P. Suchowerskyj; H. Hellebrand; B. Adler; M. Borte; U. Sack; U. Schulte Overberg-Schmidt; N. Strnad; J. Otto; A. Meindl; V. Schuster
X-linked lymphoproliferative disease (XLP) is characterized by a marked vulnerability to Epstein–Barr virus (EBV) infection. Infection of XLP patients with EBV invariably results in fatal mononucleosis, agammaglobulinemia, or malignant lymphoma. Initially the XLP gene was assigned to a 10-cM region in Xq25 between DXS42 and DXS37. Subsequently, an interstitial, cytogenetically visible deletion in Xq25 was identified in one XLP family,
Arpad Lanyi; BiFang Li; ShaoBing Li; Catherine B. Talmadge; Beda Brichacek; Jack R. Davis; Beth A. Kozel; Barbara Trask; Ger van den Engh; Eva Uzvolgyi; Eric J. Stanbridge; David L. Nelson; Craig Chinault; Helen Heslop; Thomas G. Gross; Thomas A. Seemayer; George Klein; David T. Purtilo; Janos Sumegi
X-linked lymphoproliferative disease (XLP) is a rare immunodeficiency caused by mutations in the signaling lymphocyte activating molecule-associated protein\\/SH2D1A gene and characterized by a dysregulated immune response to Epstein–Barr virus and other pathogens. The clinical presentation is heterogeneous and includes fulminant infectious mononucleosis, lymphoma, hypogammaglobulinemia and aplastic anemia. XLP is associated with a high morbidity and overall outcome is poor. At
A C Lankester; L F A Visser; N G Hartwig; R G M Bredius; H B Gaspar; M van der Burg; M J D van Tol; T G Gross; R M Egeler
X-linked lymphoproliferative disease is a rare congenital immunodeficiency that is most often caused by mutations in SH2D1A, the gene encoding signaling lymphocyte activation molecule (SLAM)-associated protein (SAP). XLP caused by SAP deficiency is most often characterized by fulminant mononucleosis\\/EBV- associated hemophagocytic lymphohistiocytosis (HLH), lymphoma, and dysgammaglobulinemia. XLP has also been found to be caused by mutations in BIRC4, the gene
Rebecca A. Marsh; Jack J. Bleesing; Alexandra H. Filipovich
Background Epstein-Barr virus (EBV)-associated hemophagocytic lymphohistiocytosis (HLH), EBV-positive systemic T-cell lymphoproliferative disease (STLPD) of childhood, and chronic active EBV (CAEBV) infection may develop after primary EBV infection. This study reviewed the clinicopathological spectrum of EBV-associated T- and natural killer (NK)-cell LPD, including STLPD and CAEBV infection, with an analysis of T-cell clonality. Methods Clinicopathological features of seven patients with EBV-associated HLH or STLPD and 12 patients with CAEBV infection were reviewed. Immunohistochemical staining and a T-cell receptor (TCR) gene rearrangement study were performed. Results STLPD and EBV-positive HLH showed significantly overlapping clinicopathological findings. One patient with STLPD and one patient with EBV-positive HLH demonstrated moderate to severe atypia of the infiltrating lymphocytes, whereas the remaining patients lacked significant atypia. Twelve patients had CAEBV infection, four of whom suffered mosquito-bite hypersensitivity, five showed NK lymphocytosis, and one suffered hydroa vacciniforme. Infiltrating lymphocytes were predominantly small and devoid of atypia. Hemophagocytic histiocytosis was found in seven of 11 patients. Monoclonality was detected in three (50%) of the six patients with successful TCR gene analysis. Conclusions EBV-positive HLH and STLPD share similar clinicopathological findings and may constitute a continuous spectrum of acute EBV-associated T- or NK-cell proliferative disorders. The distinction of EBV-positive T-cell LPD from EBV-positive HLH may be difficult during routine diagnoses because of the technical limitations of clonality assessment.
Hong, Mineui; Yoo, Keon Hee; Koo, Hong Hoe; Kim, Seok Jin; Kim, Won Seog
X-linked lymphoproliferative disease (XLP) is an inherited immunodeficiency in which affected boys show abnormal responses to Epstein-Barr virus infection. The gene defective in XLP has been identified and designated SH2D1A and encodes a protein termed SLAM-associated protein (SAP). Mutation analysis in individuals with typical XLP presentations and family histories has only detected abnormalities in approximately 60% of patients. Thus, genetic analysis alone cannot confirm a diagnosis of XLP We have developed a SAP expression assay that can be used as a diagnostic indicator of XLP We show that SAP is constitutively expressed in normal individuals, in patients with severe sepsis and in patients with other primary immunodeficiencies. In six XLP patients, four with classical and two with atypical presentations, SAP expression was absent. In the latter two, who were previously assigned as having common variable immunodeficiency (CVID), the diagnosis of XLP was initially made using the protein expression assay. In two further patients in whom no mutation could be detected by genetic analysis, lack of SAP expression strongly suggests that these individuals have XLP. We therefore suggest that XLP should be suspected in certain boys previously diagnosed as having CVID and recommend that patients are investigated both by genetic analysis of SH2D1A and by expression of SAP protein. PMID:10898506
Gilmour, K C; Cranston, T; Jones, A; Davies, E G; Goldblatt, D; Thrasher, A; Kinnon, C; Nichols, K E; Gaspar, H B
Lymphoma is seen in up to 30% of patients with X-linked lymphoproliferative disease (XLP), but cerebral vasculitis related with XLP after cure of Burkitt lymphoma is rarely reported. We describe a case of a 5-year-old boy with XLP who developed cerebral vasculitis two years after cure of Burkitt lymphoma. He had Burkitt lymphoma at the age of 3 years and received chemotherapy (non-Hodgkin's lymphoma-Berlin-Frankfurt-Milan-90 protocol plus rituximab), which induced complete remission over the following two years. At the age of 5 years, the patient first developed headache, vomiting, and then intellectual and motorial retrogression. His condition was not improved after anti-infection, dehydration, or dexamethasone therapy. No tumor cells were found in his cerebrospinal fluid. Magnetic resonance imaging showed multiple non-homogeneous, hypodense masses along the bilateral cortex. Pathology after biopsy revealed hyperplasia of neurogliocytes and vessels, accompanied by lymphocyte infiltration but no tumor cell infiltration. Despite aggressive treatment, his cognition and motor functions deteriorated in response to progressive cerebral changes. The patient is presently in a vegetative state. We present this case to inform clinicians of association between lymphoma and immunodeficiency and explore an optimal treatment for lymphoma patients with compromised immune system.
Zhu, Jia; Zhang, Yu; Zhen, Zi-Jun; Chen, Yan; Wang, Juan; Cai, Rui-Qing; Sun, Xiao-Fei
Lymphoma is seen in up to 30% of patients with X-linked lymphoproliferative disease (XLP), but cerebral vasculitis related with XLP after cure of Burkitt lymphoma is rarely reported. We describe a case of a 5-year-old boy with XLP who developed cerebral vasculitis two years after cure of Burkitt lymphoma. He had Burkitt lymphoma at the age of 3 years and received chemotherapy (non-Hodgkin's lymphoma-Berlin-Frankfurt-Milan-90 protocol plus rituximab), which induced complete remission over the following two years. At the age of 5 years, the patient first developed headache, vomiting, and then intellectual and motorial retrogression. His condition was not improved after anti-infection, dehydration, or dexamethasone therapy. No tumor cells were found in his cerebrospinal fluid. Magnetic resonance imaging showed multiple non-homogeneous, hypodense masses along the bilateral cortex. Pathology after biopsy revealed hyperplasia of neurogliocytes and vessels, accompanied by lymphocyte infiltration but no tumor cell infiltration. Despite aggressive treatment, his cognition and motor functions deteriorated in response to progressive cerebral changes. The patient is presently in a vegetative state. We present this case to inform clinicians of association between lymphoma and immunodeficiency and explore an optimal treatment for lymphoma patients with compromised immune system. PMID:23816555
Zhu, Jia; Zhang, Yu; Zhen, Zi-Jun; Chen, Yan; Wang, Juan; Cai, Rui-Qing; Sun, Xiao-Fei
A 4-year-old boy with X-linked lymphoproliferative disease (XLP) developed life-threatening acute lymphoproliferative crisis and failed to respond to conventional treatment of dexamethasone and etoposide. With the knowledge that uncontrolled alloreactive cytotoxic T-cell responses triggered by EBV-transformed B cells is the main cause of XLP, anti-CD20 monoclonocal antibody (Rituximab) which directed against B lymphocytes was use to damp down the patient's
Post-transplant lymphoproliferative disorders(PTLD) after allogeneic hematopoietic stem cell transplantation (allo-HSCT) are a group of rare, but are grievous complications. The occurrence of these diseases are most associated with EBV infection. The clinical manifestations usually include recurrent fever, lymph node enlargement, progressive decline of three lineage cells of hemogram, EB viremia and response failure to formal broad-spectrum antibiotics therapy, then the disease rapidly deteriorated in the short term, which result in high mortality. Therefore, early diagnosis and timely effective treatment such as rituximab, donor lymphocyte infusion and/or EB virus-specific cytotoxic T lymphocytes are needed to improve the prognosis. This review briefly summarized the diagnosis and therapy advance on the lymphoproliferative disorders after allogeneic hematopoietic stem cell transplantation. PMID:24763039
Gu, Bin; Chen, Guang-Hua; Wu, De-Pei
Epstein-Barr virus (EBV) is implicated in a variety of human diseases, some of which have fatal outcomes. Some EBV related diseases are considered to be candidates for the treatment of hematopoietic stem cell transplantation (HSCT). X-linked lymphoproliferative (XLP) syndrome is one of the representative diseases in which more than half of affected males die of infectious mononucleosis (IM) within a few weeks of primary infection, whereas the minority who survive have an increased risk of acquired hypogammaglobulinemia and lymphoma. Patients with XLP usually die by the age 40. Similarly, the majority of patients with chronic active EBV infection develop hemophagocytic syndrome, organ failure, opportunistic infection, and/or lymphoma and die within 5-10 years from onset. Recently, HSCT has provided successful outcomes in these patients. In this review, progress in the new therapeutic strategy is summarized, focusing on EBV-associated T/NK-cell lymphoproliferative disease (LPD), which is one of the heterogeneous EBV-associated disorder. PMID:12467965
Kawa, Keisei; Okamura, Takayuki; Yasui, Masahiro; Sato, Emiko; Inoue, Masami
Serologic diagnosis for Epstein-Barr virus (EBV) infection is problematic when patients receive exogenous immunoglobulin. We recently diagnosed primary EBV infection by detecting EBV-determined nuclear antigen (EBNA) and EBV-DNA in peripheral blood mononuclear cells (PBMC) using immunofluorescence, in situ hybridization and polymerase chain reaction (PCR) techniques in a patient with X-linked lymphoproliferative disease (XLP) who received prophylactic immunoglobulins for EBV infection. These combined techniques may be helpful for early and accurate diagnosis of EBV infection in highly vulnerable patients. PMID:1849350
Okano, M; Bashir, R M; Davis, J R; Purtilo, D T
X-linked lymphoproliferative disease is a rare T and NK cell immune deficiency which most frequently presents as fulminant infectious mononucleosis following infection with the Epstein-Barr virus (EBV). We report the case of a 4-year-old boy from a Spanish family presenting with severe infectious mononucleosis. In the course of the disease he developed hepatic failure, pancytopenia and neurologic impairment, leading to death after less than 2 months. The results of bone marrow biopsy and autopsy indicated a histological diagnosis of both high-grade B-cell lymphoma and virus-associated haemophagocytic syndrome, thereby confirming the simultaneous presence of two different manifestations of X-linked lymphoproliferative disease (XLP) in this patient. The family history revealed four close male relatives dying under similar circumstances, one of whom died following a vaccination against measles. Molecular genetic studies identified a novel mutation in the SH2D1A gene in several members of the family, establishing the diagnosis of XLP. Fatal EBV infection in male infants is highly indicative of XLP. Virus-associated haemophagocytic syndrome and B-cell lymphoma can occur concomitantly and may be difficult to distinguish due to their similar histological pictures. PMID:17058098
Hügle, Boris; Astigarraga, Itziar; Henter, Jan-Inge; Porwit-MacDonald, Anna; Meindl, Alfons; Schuster, Volker
A 46-year-old man, who had been treated for Kimura disease, was found to have abnormal findings on a chest radiograph. Chest CT showed a mass shadow in the right lower lobe. Histological findings of a transbronchial biopsy specimen showed inflammatory cells infiltrating the alveolar septum. Inflammatory cells consisted of plasma cells, lymphocytes and eosinophils. He had had sustained eosinophilia and elevation of IgE for 8 years, and his serum IgG and IgG4 (3480 mg/dl) levels were elevated. Contrast-enhanced computed tomography showed multiple low density areas in both kidneys. Since immunohistochemical staining of the lung specimens revealed infiltration of IgG4-positive plasma cells (IgG4-positive/IgG-positive plasma cells=35%), we diagnosed IgG4-positive multiorgan lymphoproliferative syndrome. The mass shadow had disappeared after treatment with celestamine (0.25 mg betamethasone and 2 mg dexchlorpheniramine) for Kimura disease, but another solid consolidation appeared in the contralateral lower lobe 5 months later. After the steroid dosage was increased, the consolidation improved. To the best of our knowledge, this case is the first report of IgG4-positive multi-organ lymphoproliferative syndrome associated with Kimura disease. PMID:20684218
Tsubouchi, Kazuya; Imanaga, Tomotoshi; Yamamoto, Makiko; Hirata, Kei; Nakano, Takako
Calcineurin-inhibitor refractory bronchiolitis obliterans (BO) represents the leading cause of late graft failure after lung transplantation. T helper (Th)2 and Th17 lymphocytes have been associated with BO development. Taking advantage of a fully allogeneic trachea transplantation model in mice, we addressed the pathogenicity of Th cells in obliterative airway disease (OAD) occurring in cyclosporine A (CsA)-treated recipients. We found that CsA prevented CD8(+) T cell infiltration into the graft and downregulated the Th1 response but affected neither Th2 nor Th17 responses in vivo. In secondary mixed lymphocyte cultures, CsA dramatically decreased donor-specific IFN-? production, enhanced IL-17 production and did not affect IL-13. As CD4(+) depletion efficiently prevented OAD in CsA-treated recipients, we further explored the role of Th2 and Th17 immunity in vivo. Although IL-4 and IL-17 deficient untreated mice developed an OAD comparable to wild-type recipients, a single cytokine deficiency afforded significant protection in CsA-treated recipients. In conclusion, CsA treatment unbalances T helper alloreactivity and favors Th2 and Th17 as coexisting pathways mediating chronic rejection of heterotopic tracheal allografts. PMID:23331973
Lemaître, P H; Vokaer, B; Charbonnier, L-M; Iwakura, Y; Field, K A; Estenne, M; Goldman, M; Leo, O; Remmelink, M; Le Moine, A
Background X-linked lymphoproliferative disease (XLP) is a primary immunodeficiency presenting with a variety of clinical manifestations, the most common being dysgammaglobulinemia and B-cell lymphoma. The first gene causing XLP, when defective, was termed SH2D1A or SAP for signaling lymphocyte activation molecule (SLAM)-associated protein. The absence of SH2D1A leads to an overwhelming and uncontrolled TH1- shifted cytotoxic immune response, which might, at least in part, explain the severe clinical picture. A second gene, XIAP (X-linked inhibitor of apoptosis), was later identified. Methods An 8 year old Mexican boy was admitted in June 2008 for bronchopneumonia, with no previous history of recurrent or severe infections. He had a family history of a brother deceased at 7 years from fulminate hepatitis, who was diagnosed with agammaglobulinemia. A laboratory evaluation for primary immunodeficiency was made, including serum immunoglobulins: IgG 30 mg/dL, IgA <5 mg/dL IgM 8.6 mg/dL; and flow citometry for lymphocyte subpopulations: CD3+ 2590 mm3 (56%) CD4+ 1004 mm3 (42%), CD8+ 1267 mm3(53%) CD16/56 171mm3 (41%) CD19+ 1493 mm3 (35%). The patient was started on monthly intravenous gammaglobulin (IVIG) therapy. He was admitted in December 2008 with fever and severe abdominal pain; an exploratory laparotomy revealed a rectal-sigmoid tumor. The biopsy reported an atypical Burkitt lymphoma (Immunophenotype “B”: Bcl 2+, CD10+) with surgical margins negative for malignancy. Bone marrow aspirate and biopsy were negative for malignancy. In February 2009, management with chemotherapy was started with the diagnosis of Burkitt's lymphoma stage III. Patient received 6 courses of chemotherapy with complete response to induction; for consolidation, 4 doses of rituximab were given. PCR amplification and direct automated sequencing by the Sanger method was performed in both genes known to be responsible for XLP in chromosome X. Results A hemizygous splice-site deletion in SAP was found, in intron 2: c.187_201+10del25, which deletes exon 2 splice donor site, and is predicted to result in the skipping of exon 2, and thus in a truncated, nonfunctional protein. XIAP was also sequenced and no mutation was found. Conclusions Final diagnosis: XLP.The patient is currently in the program for hematopoietic stem-cell transplantation.
Gamez, Luisa; Yamazaki, Marco Antonio; Espinosa, Sara; Lugo-Reyes, Saul; Hernandez, Victor
SAP (signalling lymphocytic activation molecule (SLAM)-associated protein) is a T- and natural killer (NK)-cell-specific protein containing a single SH2 domain encoded by a gene that is defective or absent in patients with X-linked lymphoproliferative syndrome (XLP). The SH2 domain of SAP binds with high affinity to the cytoplasmic tail of the haematopoietic cell-surface glycoprotein SLAM and five related receptors. SAP
Michael J. Eck; Cox Terhorst; Pablo Engel
The Epstein-Barr virus (EBV)-induced diseases of males with X-linked lymphoproliferative disease (XLP) include fatal infectious mononucleosis (IM), non-Hodgkin lymphoma (ML), agammaglobulinemia, and aplastic anemia. These phenotypes also occur as sporadic cases in families, and EBV seronegative males in these families must be considered at risk for XLP until they seroconvert normally to EBV. Given that 50% of males inheriting the defective XLP gene die following primary EBV infection, it is vital that they be identified pre-EBV infection. Here we report results using molecular genetic techniques to provide information as to the relative risks of EBV negative males and potential carrier females in ten families wherein a single male had died of IM. PMID:8256804
Grierson, H L; Skare, J; Church, J; Silberman, T; Davis, J R; Kobrinsky, N; McGregor, R; Israels, S; McCarty, J; Andrews, L G
A 14-year-old male and a maternally related cousin were diagnosed with X-linked lymphoproliferative disease (XLP) after developing recurrent B-NHL, characterized by long disease-free intervals and absence of an increased chemoresistance of the recurrent lymphomas. The demonstration of different clonal IgH gene rearrangements in two of the lymphomas from one of the patients further supports that the lymphomas were clonally unrelated. The cousin underwent matched related BMT, whereas the proband received a deliberately delayed MUD BMT in third CR. Both are in CR 68 months and 21 months, respectively, post-BMT. Delaying BMT probably contributes to reducing treatment-related morbidity. We suggest MUD BMT as a feasible curative strategy for XLP patients with B-NHL lacking matched related donors. PMID:9758353
Hoffmann, T; Heilmann, C; Madsen, H O; Vindeløv, L; Schmiegelow, K
The microtubule associated tumor suppressor gene 1 (MTUS1) is a recently published tumor suppressor gene, which has also been shown to act as an early component in the growth inhibitory signaling cascade of the angiotensin II type 2 receptor (AT2R). In this study we report the generation of MTUS1 knock-out (KO) mice, which develop normally but reveal higher body weights and slightly decreased blood pressure levels. Twenty-eight percent of the studied MTUS1 KO mice also developed heart hypertrophy and 12% developed nephritis, independent of blood pressure levels. Forty-three percent of the MTUS1 KO mice revealed lymphoid hyperplasia affecting spleen (20%), kidney (37%), lung (23%), lymph nodes (17%), and liver (17%) accompanied with leukocytosis, lymphocytosis, and mild anemia. One animal (3%) developed a marginal zone B-cell lymphoma affecting submandibular salivary gland and regional lymph nodes. The symptoms of all mentioned animals are consistent with a B-cell lymphoproliferative disease with features of systemic lupus erythematosus. In addition, body weight of the MTUS1 KO mice was significantly increased and isolated skin fibroblasts showed increased cell proliferation and decreased cell size, compared to wild-type (WT) fibroblasts in response to depleted FCS concentration and lack of growth factors. In conclusion we herein report the first generation of a MTUS1 KO mouse, developing spontaneous heart hypertrophy and increased cell proliferation, confirming once more the anti-proliferative effect of MTUS1, and a SLE-like lymphoproliferative disease suggesting crucial role in regulation of inflammation. These MTUS1 KO mice can therefore serve as a model for further investigations in cardiovascular disease, autoimmune disease and carcinogenesis. PMID:22200760
Zuern, Christina; Krenacs, Laszlo; Starke, Stephanie; Heimrich, Jutta; Palmetshofer, Alois; Holtmann, Bettina; Sendtner, Michael; Fischer, Tobias; Galle, Jan; Wanner, Christoph; Seibold, Stefan
Prevention of EBV-associated lymphoproliferative diseases in immune deficient individuals is preferred; however, standard therapy for the B cell lymphomas has been successful. Chemotherapy must be given cautiously lest further immune compromise result in opportunistic infections. Recently, Acyclovir has decreased morbidity of patients with acute infectious mononucleosis in immune competent persons. In contrast, immunodeficient patients with X-linked lymphoproliferative (XLP) syndrome do not seem to respond favorably. Hence, a prospective study is underway using prophylactic immunoglobulin containing (EBV)-specific antibodies. The mortality rate is 85% following EBV infection in XLP due to fatal infectious mononucleosis associated with fulminant hepatitis and virus-associated hemophagocytic syndrome, acquired hypogammaglobulinemia or malignant B cell lymphoma. We can detect XLP by noting failure of switching from IgM to IgG antibody production on secondary challenge with bacteriophage phi X174. Also, linkage studies with the XLP locus using restriction fragment length polymorphisms are being done to detect affected males pre-EBV infection. Our rationale for prevention of phenotypes of XLP is based on observations that infants in tropical Africa and males with XLP do not develop EBV-induced diseases while neutralizing maternal antibodies are present. An EBV vaccine will be used, when available, in seronegative males with XLP. Prevention of acquired immune deficiency by screening blood for human immune deficiency virus, encouraging prudent life styles, development of specific immunosuppressive agents, development of new antiviral agents (i.e., DHPG), and identification of high risk seronegative patients offer possibilities for preventing life-threatening EBV-induced diseases. PMID:2435295
Purtilo, D T
A major focus of our research is to understand the molecular and cellular basis of X-linked lymphoproliferative disease (XLP), a rare and often fatal immunodeficiency caused by mutations in the SH2D1A gene, which encodes the adaptor molecule SAP. Recently, we observed that SAP is essential for the development of natural killer T (NKT) cells, a lymphocyte population that participates in protection against certain tumors, infections, and autoimmune states. In this review, we describe the approaches that we are taking to understand the role of SAP in immune cells, including NKT cells. By using SAP as the focal point of our studies, we hope to identify novel signaling pathways that could be targeted to improve the treatment for patients with XLP as well as more common disorders, such as autoimmunity and cancer. PMID:18815745
Bassiri, Hamid; Janice Yeo, W C; Rothman, Jennifer; Koretzky, Gary A; Nichols, Kim E
SAP (signalling lymphocytic activation molecule (SLAM)-associated protein) is a T- and natural killer (NK)-cell-specific protein containing a single SH2 domain encoded by a gene that is defective or absent in patients with X-linked lymphoproliferative syndrome (XLP). The SH2 domain of SAP binds with high affinity to the cytoplasmic tail of the haematopoietic cell-surface glycoprotein SLAM and five related receptors. SAP regulates signal transduction of the SLAM-family receptors by recruiting SRC kinases. Similarly, the SAP-related proteins EAT2A and EAT2B are thought to control signal transduction that is initiated by SLAM-related receptors in professional antigen-presenting cells. In this review, we discuss recent findings on the structure and function of proteins of the SAP and SLAM families. PMID:14523387
Engel, Pablo; Eck, Michael J; Terhorst, Cox
A rare association of Epstein-Barr virus-associated T- and B-lymphoproliferative disease (EBV+ T- and EBV+ B-LPD) in a patient with WHIM (warts, hypogammaglobulinemia, infections, and myelokathexis) syndrome is reported. A 26-year-old Japanese female, who had been treated for WHIM syndrome since early childhood, developed hemophagocytic syndrome associated with EBV+ T-LPD at the lymph nodes and spleen. The disease rapidly resolved in
S. Imashuku; A. Miyagawa; T. Chiyonobu; H. Ishida; T. Yoshihara; T. Teramura; K. Kuriyama; T. Imamura; S. Hibi; A. Morimoto; S. Todo
X-linked lymphoproliferative disease (XLP) is a rare immunodeficiency caused by mutations in the signaling lymphocyte activating molecule-associated protein/SH2D1A gene and characterized by a dysregulated immune response to Epstein-Barr virus and other pathogens. The clinical presentation is heterogeneous and includes fulminant infectious mononucleosis, lymphoma, hypogammaglobulinemia and aplastic anemia. XLP is associated with a high morbidity and overall outcome is poor. At present, allogeneic stem cell transplantation (alloSCT) is the only curative treatment. XLP patients may be recognized in various stages of disease and even when symptoms are not yet evident. We here present two related XLP patients in different stages of disease that were both treated successfully with alloSCT using a matched unrelated donor. In addition, we have reviewed all reported cases of alloSCTs in XLP patients. Based on these results and in order to improve the final outcome, we conclude that alloSCT should be recommended in both symptomatic and asymptomatic XLP patients. PMID:15908972
Lankester, A C; Visser, L F A; Hartwig, N G; Bredius, R G M; Gaspar, H B; van der Burg, M; van Tol, M J D; Gross, T G; Egeler, R M
Thirty-one females with incontinentia pigmenti (IP), 42 controls, and 11 females from four families segregating for X linked lymphoproliferative disease (XLP) were studied for evidence of skewed X inactivation by analysis of methylation at sites in the HPRT, PGK, and M27 beta (DXS255) regions of the X chromosome. Extensive skewing of X inactivation was present in blood from 4/42 (9.5%) control females and 11/31 (35%) of those with IP. This frequency of skewed inactivation was seen in both familial and sporadic cases of IP. Analysis of inactivation in mother/daughter pairs, both affected and control subjects, showed no familial consistency of pattern, arguing against specific mutations being associated with particular patterns of inactivation. In the only informative family where both mother and daughter were affected by IP and showed skewed inactivation, the IP mutation was on the active X chromosome. This argues against cell selection during early embryogenesis being the explanation for the skewed inactivation observed. These data confirm that skewed inactivation of one X is observed in lymphocytes from a significant minority of normal females, and is seen with raised frequency in IP heterozygotes. It is not, however, a universally observed phenomenon, and the relationship of X inactivity to the IP mutation appears to be complex. In the case of XLP, though skewed X inactivation patterns are seen in most disease carriers, the frequency with which this phenomenon occurs in normal females renders it an unreliable diagnostic marker for XLP carriers. PMID:1404291
Harris, A; Collins, J; Vetrie, D; Cole, C; Bobrow, M
Treatment with rituximab is highly effective for EBV-associated post transplant lymphoproliferative disease. However, little is known about its immunological sequelae in pediatric allogeneic hematopoietic SCT (HSCT). Time to normal CD19+ B-lymphocyte values in blood and intravenous immunoglobulin (IVIG) substitution needed to maintain an IgG>400 mg per 100 ml in six consecutive pediatric allogeneic HSCT patients treated with rituximab for symptomatic
K Masjosthusmann; K Ehlert; B R Eing; J Roth; G Koehler; H Juergens; M Fruehwald; A H Groll
X-linked lymphoproliferative disease (XLP) is an inherited immunodeficiency characterized by extreme vulnerability to Epstein-Barr virus (EBV) infection, resulting in fatal infectious mononucleosis, dysgammaglobulinemia and malignant lymphoma. Recently, mutations in the SH2D1A gene, which encodes SLAM-associated protein (SAP), have been found to cause XLP. Although the molecular events behind XLP are largely unknown, there is evidence that affected males exhibited some
Kentaro Shinozaki; Hirokazu Kanegane; Hiroyoshi Matsukura; Ryo Sumazaki; Masahiro Tsuchida; Mika Makita; Yasuo Kimoto; Rie Kanai; Kumi Tsumura; Tatsuro Kondoh; Hiroyuki Moriuchi; Toshio Miyawaki
X-linked lymphoproliferative disease (XLP) is an immunodeficiency resulting from mutations in SH2D1A, which encodes signalling lymphocytic activation molecule (SLAM)-associated protein (SAP). In addition to SLAM, SAP associates with several other cell-surface receptors including 2B4 (CD244), Ly9 (CD229), CD84 and NTB-A. SAP contains a single src-homology-2 domain and acts as an intracellular adaptor protein by recruiting the protein tyrosine kinase FynT
Nathan J. Hare; Cindy S. Ma; Frank Alvaro; Kim E. Nichols; Stuart G. Tangye
X-linked lymphoproliferative syndrome (XLP or Duncan disease) is characterized by extreme sensitivity to Epstein-Barr virus (EBV), resulting in a complex phenotype manifested by severe or fatal infectious mononucleosis, acquired hypogammaglobulinemia and malignant lymphoma. We have identified a gene, SH2D1A, that is mutated in XLP patients and encodes a novel protein composed of a single SH2 domain. SH2D1A is expressed in
Oliver Brandau; Toshitaka Oohashi; Gareth R. Howell; Jacqueline M. Bye; Anthony P. Cahn; Jillian Durham; Paul Heath; Paul Wray; Rebecca Pavitt; Jane Wilkinson; Margaret Leversha; Elizabeth Huckle; Charles J. Shaw-Smith; Andrew Dunham; Susan Rhodes; Volker Schuster; Giovanni Porta; Luo Yin; Paola Serafini; Bakary Sylla; Massimo Zollo; Brunella Franco; Alessandra Bolino; Marco Seri; Arpad Lanyi; Jack R. Davis; David Webster; Ann Harris; Gilbert Lenoir; Genevieve de St Basile; Alison Jones; Bernd H. Behloradsky; Helene Achatz; Jan Murken; Reinhard Fassler; Janos Sumegi; Giovanni Romeo; Mark Vaudin; Mark T. Ross; Alfons Meindl; David R. Bentley; Alison J. Coffey; Robert A. Brooksbank
The purposes of this study were to deter- mine the frequency of mutations in SH2D1A in X-linked lymphoproliferative disease (XLP) and the role of SH2D1A mutations and Epstein-Barr virus (EBV) infection in determining the phenotype and outcome of patients with XLP. Analy- sis of 35 families from the XLP Registry revealed 28 different mutations in 34 fami- lies—large genomic deletions
Janos Sumegi; Dali Huang; Arpad Lanyi; Jack D. Davis; Thomas A. Seemayer; Akihiko Maeda; George Klein; Marco Seri; Hiroshi Wakiguchi; David T. Purtilo; Thomas G. Gross
SLAM (signaling lymphocyte activation molecule)-associated protein (SAP) is a Src homology 2 (SH2) domain-containing adaptor expressed in T cells and natural killer cells. Its essential role in immune responses is underscored by the recent finding that mutations in SAP result in a rare but fatal X-linked lymphoproliferative disease (XLP). Although SAP is known to associate with SLAM-family receptors, the exact
Cuiping Gu; Stuart G. Tangye; Xiaoqing Sun; Ying Luo; Zhixin Lin; Jun Wu
Post transplant lymphoproliferative disease (PTLD) is a severe complication after solid organ or bone marrow transplantation. In pediatric transplant recipients PTLD is the most common malignancy. The aim of this study was to evaluate a possible role for positron emission tomography with [18F]-2-fluoro-2-desoxy-glucose (FDG) in the initial staging and in therapy monitoring of pediatric patients suffering from biopsy-proven CD20-positive PTLD
C. von Falck; B. Maecker; E. Schirg; A. R. Boerner; W. H. Knapp; C. Klein; M. Galanski
A rare complication of infection with the Epstein-Barr virus is the development of hemophagocytic lymphohistio- cytosis. Although most cases of Epstein-Barr virus-induced hemophagocytic lymphohistiocytosis develop in immu- nocompetent individuals, the rare immunodeficiency X-linked lymphoproliferative disease is often unmasked by Epstein-Barr virus infection and is clinically indistinguishable from Epstein-Barr virus-induced hemophagocytic lymphohistiocytosis. We describe the clinical course and management of a
Matthew Mischler; Geoffrey M. Fleming; Thomas P. Shanley; Lisa Madden; John Levine; Valerie Castle; Alexandra H. Filipovich; Timothy T. Cornell; C. S. Mott
Lymphoproliferative disorders are heterogeneous malignancy characterized by the expansion of a lymphoid clone more or less differentiated. At the level of the oral cavity, the lymphoproliferative disorder can occur in various ways, most commonly as lymphoid lesions with extranodal externalization, but sometimes, oral lesions may represent a localization of a disease spread. With regard to the primary localizations of lymphoproliferative disorders, a careful examination of the head and neck, oral, and oropharyngeal area is necessary in order to identify suspicious lesions, and their early detection results in a better prognosis for the patient. Numerous complications have been described and frequently found at oral level, due to pathology or different therapeutic strategies. These complications require precise diagnosis and measures to oral health care. In all this, oral pathologists, as well as dental practitioners, have a central role in the treatment and long-term monitoring of these patients.
Castellarin, P.; Pozzato, G.; Tirelli, G.; Di Lenarda, R.; Biasotto, M.
Notch signaling is essential for the development of T cell progenitors through the interaction of NOTCH1 receptor on their surface with the ligand, Delta-like 4 (DLL4), which is expressed by the thymic epithelial cells. Notch signaling is quickly shut down once the cells pass ?-selection, and CD4/CD8 double positive (DP) cells are unresponsive to Notch. Over the past two decades a number of papers reported that over-activation of Notch signaling causes T cell acute lymphoblastic leukemia (T-ALL), a cancer that prominently features circulating monoclonal CD4/CD8 double positive T cells in different mouse models. However, the possible outcomes of Notch over-activation at different stages of T cell development are unknown, and the fine timing of Notch signaling that results in T-ALL is poorly understood. Here we report, by using a murine model that ectopically expresses DLL4 on developing T cells, that the T-ALL onset is highly dependent on a sustained Notch activity throughout the DP stage, which induces additional mutations to further boost the signaling. In contrast, a shorter period of Notch activation that terminates at the DP stage causes a polyclonal, non-transmissible lymphoproliferative disorder that is also lethal. These observations resolved the discrepancy of previous papers on DLL4 driven hematological diseases in mice, and show the critical importance of the timing and duration of Notch activity. PMID:24386421
Xiong, Huizhong; Maraver, Antonio; Latkowski, Jo-Ann; Henderson, Tanya; Schlessinger, Karni; Ding, Yi; Shen, Jie; Tadokoro, Carlos E; Lafaille, Juan J
Patients with X-linked lymphoproliferative (XLP) disease are characterized by extreme vulnerability to Epstein-Barr virus (EBV). Following infection with EBV, affected males develop fatal infectious mononucleosis (IM), hypogammaglobulinemia (H), or non-Hodgkin's lymphoma (NHL). In addition, hyper IgM, red cell aplasia, necrotizing lymphoid vasculitis (NLV), and aplastic anemia occur rarely. The recent use of DNA restriction fragment length polymorphism (RFLP) probes in linkage with the XLP gene now permit detection of affected males prior to primary EBV infection. We have measured immunoglobulin class and subclass levels in sera from EBV-negative males who were either positive or negative for the XLP genotype by RFLP analysis. Elevated IgA or IgM and/or variable deficiency of IgG, IgG1, and IgG3 occurred in the sera of 13/13 RFLP-positive, EBV-negative males. No consistent abnormalities were noted in 14 RFLP-negative, EBV-negative males. We conclude that the immune defect in XLP is not solely EBV-specific, although EBV is responsible for most of the morbidity and all of the mortality. Further, serial measurement of Ig levels may provide information regarding status of EBV-negative males at risk where RFLP analysis is uninformative or in families where sporadic cases of fatal IM, acquired hypogammaglobulinemia or NHL have occurred, but wherein the genotype of XLP cannot be documented. PMID:1683154
Grierson, H L; Skare, J; Hawk, J; Pauza, M; Purtilo, D T
The hemophagocytic lymphohistiocytoses (HLH) comprise a heterogeneous group of disorders characterized by dysregulated activation of T cells and macrophages. Although some patients with HLH harbor perforin gene mutations, the cause of the remaining cases is not known. The phenotype of HLH bears a strong resemblance to X-linked lymphoproliferative disease (XLP), an Epstein-Barr virus (EBV)-associated immunodeficiency resulting from defects in SH2D1A, a small SH2 domain-containing protein expressed in T lymphocytes and natural killer cells. Here it is shown that 4 of 25 male patients with HLH who were examined harbored germline SH2D1A mutations. Among these 4 patients, only 2 had family histories consistent with XLP. On the basis of these findings, it is suggested that all male patients with EBV-associated hemophagocytosis be screened for mutations in SH2D1A. Patients identified as having XLP should undergo genetic counseling, and be followed long-term for development of lymphoma and hypogammaglobulinemia. PMID:11159547
Arico, M; Imashuku, S; Clementi, R; Hibi, S; Teramura, T; Danesino, C; Haber, D A; Nichols, K E
X-linked lymphoproliferative disease (XLP1) arises from mutations in the gene encoding SLAM-associated protein (SAP) and leads to abnormalities of NKT-cell development, NK-cell cytotoxicity, and T-dependent humoral function. Curative treatment is limited to allogeneic hematopoietic stem cell (HSC) transplantation. We tested whether HSC gene therapy could correct the multilineage defects seen in SAP?/? mice. SAP?/? murine HSCs were transduced with lentiviral vectors containing either SAP or reporter gene before transplantation into irradiated recipients. NKT-cell development was significantly higher and NK-cell cytotoxicity restored to wild-type levels in mice receiving the SAP vector in comparison to control mice. Baseline immunoglobulin levels were significantly increased and T-dependent humoral responses to NP-CGG, including germinal center formation, were restored in SAP-transduced mice. We demonstrate for the first time that HSC gene transfer corrects the cellular and humoral defects in SAP?/? mice providing proof of concept for gene therapy in XLP1.
Rivat, Christine; Booth, Claire; Alonso-Ferrero, Maria; Blundell, Michael; Sebire, Neil J.; Thrasher, Adrian J.
Hypogammaglobulinemia is a common symptom in different immunodeficiencies. It is, however, not usually associated with Epstein-Barr virus (EBV) infections. The X-linked lymphoproliferative disease (XLP) on the other hand shows immunological changes in response to the EBV. Here we report three previously healthy boys, all of which developed persistent hypogammaglobulinemia following severe acute infectious mononucleosis. All three patients revealed T-cell abnormalities including inverted CD4/CD8 and increased CD8(+) T-cell numbers. The number of IFN-gamma-producing T cells were markedly increased in the two patients studied so far. In addition, patient 2 showed mainly T cells, instead of B cells, to be infected with the EBV. Apart from an uncle of patient 3, who died of malignant lymphoma, family history was unremarkable in all cases. All three patients exhibited mutations in the SH2D1A gene, establishing the diagnosis of XLP. Protein expression was found on immunoblot analysis in one patient with a missense mutation. Development of persistent hypogammaglobulinemia after severe primary EBV infection seems to be a specific diagnostic sign for XLP even in males with unremarkable family history. PMID:15359110
Hügle, B; Suchowerskyj, P; Hellebrand, H; Adler, B; Borte, M; Sack, U; Overberg-Schmidt, U Schulte; Strnad, N; Otto, J; Meindl, A; Schuster, V
X-linked lymphoproliferative disease is a rare congenital immunodeficiency that is most often caused by mutations in SH2D1A, the gene encoding signaling lymphocyte activation molecule (SLAM)-associated protein (SAP). XLP caused by SAP deficiency is most often characterized by fulminant mononucleosis/EBV- associated hemophagocytic lymphohistiocytosis (HLH), lymphoma, and dysgammaglobulinemia. XLP has also been found to be caused by mutations in BIRC4, the gene encoding X-linked inhibitor of apoptosis (XIAP). Patients with XIAP deficiency often present with HLH or recurrent HLH, which may or may not be associated with EBV. XLP is prematurely lethal in the majority of cases. While genetic sequencing can provide a genetic diagnosis of XLP, a more rapid means of diagnosis of XLP is desirable. Rapid diagnosis is especially important in the setting of HLH, as this may hasten the initiation of life-saving medical treatments and expedite preparations for allogeneic hematopoietic cell transplantation (HCT). Flow cytometry offers a means to quickly screen patients for XLP. Flow cytometry can be used to measure lymphocyte SAP or XIAP protein expression, and can also be used to observe lymphocyte phenotypes and functional defects that are unique to XLP. This review will give a brief overview of the clinical manifestations and molecular basis of SAP deficiency and XIAP deficiency, and will focus on the use of flow cytometry for diagnosis of XLP. PMID:20816973
Marsh, Rebecca A; Bleesing, Jack J; Filipovich, Alexandra H
Malignant B-1 cells derived from NZB mice, a murine model of spontaneous autoimmunity and B cell lymphoproliferative disease, produce significantly higher levels of IL-10 mRNA than normal B-1 or B cells. IL-10 may act as an autocrine growth factor for the expansion of malignant B-1 cells. In order to determine if elevated endogenous production of IL-10 was a required element for the malignant transformation of B-1 cells in NZB mice, backcross animals were studied for the linkage between elevated IL-10 expression and the presence of lymphoid malignancy. The phenotypes of aged (NZB x DBA/2)F1 x NZB animals were determined and a strong correlation was found between the elevated levels of IL-10 mRNA and the development of B-1 malignant clones. In contrast, an increased level of IL-10 message was not associated with elevated serum IgM or the presence of anemia or reticulocytosis which is mainly seen in response to autoantibody production. These results indicate that, at least in NZB, the autoimmunity and lymphoproliferation phenotypes are not linked genetically. IL-10 may enhance proliferation and the development of B-1 cell malignancy rather than antibody production by the B-1 cell subpopulation. Thus, IL-10 plays an important role in B-1 malignancies, and downregulation of IL-10 could be a likely site for intervention in B cell malignancies.
Ramachandra, S; Metcalf, R A; Fredrickson, T; Marti, G E; Raveche, E
Sentinel lymph node dissection (SLND) identifies melanoma patients with metastatic disease who would benefit from radical lymph node dissection (RLND). Rarely, patients with melanoma have an underlying lymphoproliferative disease, and melanoma metastases might develop as collision tumours in the sentinel lymph node (SLN). The aim of this study was to measure the incidence and examine the effect of collision tumours on the accuracy of SLND and on the validity of staging in this setting. Between 1998 and 2012, 750 consecutive SLNDs were performed in melanoma patients using the triple technique (lymphoscintigraphy, gamma probe and blue dye). The validity of SLND in collision tumours was analysed. False negativity was reflected by the disease-free survival. The literature was reviewed on collision tumours in melanoma. Collision tumours of melanoma and chronic lymphocytic leukaemia (CLL) were found in two SLN and in one RLND (0.4%). Subsequent RLNDs of SLND-positive cases were negative for melanoma. The patient with negative SLND developed relapse after 28 months with an inguinal lymph node metastasis of melanoma; RLND showed collision tumours. The literature review identified 12 cases of collision tumours. CLL was associated with increased melanoma incidence and reduced overall survival. This is, to our knowledge, the first assessment of the clinical value of SLND when collision tumours of melanoma and CLL are found. In this small series of three patients with both malignancies present in the same lymph node basin, lymphocytic infiltration of the CLL did not alter radioisotope uptake into the SLN. No false-negative result was observed. Our data suggest the validity of SLND in collision tumours, but given the rarity of the problem, further studies are necessary to confirm this reliability. PMID:24922190
Gero, Daniel; Queiros da Mota, Vanessa; Boubaker, Ariane; Berthod, Gregoire; de Leval, Laurence; Demartines, Nicolas; Matter, Maurice
Rheumatic manifestations may be the presenting features of dysproteinemias and lymphoproliferative disorders. Disease or therapy-related complications may mimic a number of primary rheumatic syndromes. This article emphasizes clinical aspects pertaining to prompt diagnosis and therapy. PMID:8907064
Duna, G F; Cash, J M
Immunophenotypes in lymphoproliferative diseases (LPD) are prognostically significant, yet causative factors for these conditions, and specifically those associated with heritable risk, remain elusive. The full spectrum of LPD seen in humans occurs in dogs, but the incidence and lifetime risk of naturally occurring LPD differs among dog breeds. Taking advantage of the limited genetic heterogeneity that exists within dog breeds, we tested the hypothesis that the prevalence of LPD immunophenotypes would differ among different breeds. The sample population included 1,263 dogs representing 87 breeds. Immunophenotype was determined by the presence of clonal rearrangements of immunoglobulin heavy chain or T-cell receptor gamma chain. The probability of observing the number of B-cell or T-cell tumors in a particular breed or breed group was compared with three reference populations. Significance was computed using chi2 test, and logistic regression was used to confirm binomial predictions. The data show that, among 87 breeds tested, 15 showed significant differences from the prevalence of LPD immunophenotypes seen across the dog population as a whole. More significantly, elevated risk for T-cell LPD seems to have arisen ancestrally and is retained in related breed groups, whereas increased risk for B-cell disease may stem from different risk factors, or combinations of risk factors, arising during the process of breed derivation and selection. The data show that domestic dogs provide a unique and valuable resource to define factors that mediate risk as well as genes involved in the initiation of B-cell and T-cell LPD. PMID:15994938
Modiano, Jaime F; Breen, Matthew; Burnett, Robert C; Parker, Heidi G; Inusah, Seidu; Thomas, Rachael; Avery, Paul R; Lindblad-Toh, Kerstin; Ostrander, Elaine A; Cutter, Gary C; Avery, Anne C
X-linked lymphoproliferative (XLP) disease is a primary immunodeficiency caused by a defect in the SH2D1A gene. At least 3 major manifestations characterize its clinical presentation: fatal infectious mononucleosis (FIM), lymphomas, and immunoglobulin deficiencies. Common variable immunodeficiency (CVID) is a syndrome characterized by immunoglobulin deficiency leading to susceptibility to infection. In some patients with CVID, a defective btk or CD40-L gene has been found, but most often there is no clearly identified etiology. Here, 2 unrelated families in whom male members were affected by CVID were examined for a defect in the XLP gene. In one family previously reported in the literature as having progressive immunoglobulin deficiencies, 3 brothers were examined for recurrent respiratory infections, whereas female family members showed only elevated serum immunoglobulin A levels. A grandson of one of the brothers died of a severe Aspergillus infection secondary to progressive immunoglobulin deficiency, FIM, aplastic anemia, and B-cell lymphoma. In the second family, 2 brothers had B lymphocytopenia and immunoglobulin deficiencies. X-linked agammaglobulinemia syndrome was excluded genetically, and they were classified as having CVID. The occurrence of FIM in a male cousin of the brothers led to the XLP diagnosis. Because the SH2D1A gene was found altered in both families, these findings indicate that XLP must be considered when more than one male patient with CVID is encountered in the same family, and SH2D1A must be analyzed in all male patients with CVID. Moreover, these data link defects in the SH2D1A gene to abnormal B-lymphocyte development and to dysgammaglobulinemia in female members of families with XLP disease. PMID:11520777
Morra, M; Silander, O; Calpe, S; Choi, M; Oettgen, H; Myers, L; Etzioni, A; Buckley, R; Terhorst, C
The unique manifestation of the inherited immunodeficiency, X-linked lymphoproliferative disease (XLP), is the impaired control of EBV infection. The gene, which carries mutations or is deleted in the patients, has been identified (Xq25). The encoded protein (SAP, 128 aa) contains a single SH2 domain and binds to signaling lymphocytic activation molecule (SLAM) and to other related surface molecules that are expressed on activated T, B and NK cells. SAP modifies signal transduction through its association with these molecules. Initially it was assumed that SAP acts passively by interfering and blocking active interactions involving other SH2 carrying molecules. We demonstrated that SAP protein is expressed in activated T and NK, but not in activated B cells. This finding is in line with the fact that in vitro performance of effector cells derived from XLP patients is impaired. However, it is still not known why the severe symptoms (fatal mononucleosis or malignant lymphoproliferation in the survivors of the primary infection) are elicited by EBV. We studied SAP expression in several Burkitt lymphoma (BL) derived lines. In contrast to normal B cells, certain lines expressed SAP. These were all type I cells in the Burkitt line nomenclature: they expressed only one of the EBV encoded proteins (EBNA-1) and their phenotype corresponded to resting B cells. Lymphoblastoid cell lines and type III BLs, whose phenotype resembled activated B cells and expressed all nine EBV encoded proteins, were devoid of SAP. The relationship between cell activation and SAP expression is reciprocal in T and B cells i.e. BL lines, activated T and NK cells express SAP, while BL blasts do not express SAP. This opposite relationship may be exploited for studies about the function of SAP. PMID:12008045
Nagy, Noémi; Mattsson, Karin; Maeda, Akihiko; Liu, Anquan; Székely, László; Klein, Eva
T cell immunity plays an important role in the clinicopathology of Epstein-Barr virus (EBV)-associated diseases. Acute EBV-induced infectious mononucleosis (IM) is a common self-limiting disease, however, other EBV-associated diseases, including chronic active EBV infection (CAEBV), NK cell lymphoma (NKL), and Hodgkin's lymphoma (HL), exhibit distinct clinical features. Chemokines are members of a family of small-secreted proteins. The relationships between chemokines and the chemokine receptor (R) are thought to be important for selectivity of local immunity. Some chemokines, chemokine R and cytokines closely associate with the T cell subtypes, Th1 and Th2 T cells and cytotoxic cells. To clarify the role of T cell immunity in EBV-associated diseases, we conducted gene expression profiling, using chemokine, chemokine R and cytokine DNA chips. Compared to EBV negative non-specific lymphadenitis, CAEBV and NKL exhibited diffuse down- and up-regulation, respectively, of these gene profiles. IM had a predominantly Th1-type profile, whereas HL had a mixed Th1/Th2-type profile. Reduction of the Th1-type cytokine interferon gamma (IFN-gamma) in CAEBV was confirmed by Reverse transcriptase-polymerase chain reaction, whereas IFN-gamma expression was markedly enhanced in NKL, and moderately enhanced in IM. Compared to IM, CAEBV showed slight elevation of "regulated upon activation, normal T expressed and secreted" (RANTES), but almost all other genes assayed were down-regulated. NKL exhibited elevated expression of numerous genes, particularly IFN-gamma-inducible-10 (IP-10) and monokine induced by IFN-gamma (MIG). HL showed variable elevated and reduced expression of various genes, with increased expression of IL-13 receptor and MIG. Our study demonstrated the enormous potential of gene expression profiling for clarifying the pathogenesis of EBV-associated diseases. PMID:12952231
Ohshima, Koichi; Karube, Kennosuke; Hamasaki, Makoto; Tutiya, Takeshi; Yamaguchi, Takahiro; Suefuji, Hiroaki; Suzuki, Keiko; Suzumiya, Junji; Ohga, Shouichi; Kikuchi, Masahiro
X-linked lymphoproliferative disease (XLP) is a primary immunodeficiency characterized by extreme susceptibility to Epstein-Barr virus. The XLP disease gene product SH2D1A (SAP) interacts via its SH2 domain with a motif (TIYXXV) present in the cytoplasmic tail of the cell-surface receptors CD150/SLAM, CD84, CD229/Ly-9, and CD244/2B4. Characteristically, the SH2D1A three-pronged interaction with Tyr(281) of CD150 can occur in absence of phosphorylation. Here we analyze the effect of SH2D1A protein missense mutations identified in 10 XLP families. Two sets of mutants were found: (i) mutants with a marked decreased protein half-life (e.g. Y7C, S28R, Q99P, P101L, V102G, and X129R) and (ii) mutants with structural changes that differently affect the interaction with the four receptors. In the second group, mutations that disrupt the interaction between the SH2D1A hydrophobic cleft and Val +3 of its binding motif (e.g. T68I) and mutations that interfere with the SH2D1A phosphotyrosine-binding pocket (e.g. C42W) abrogated SH2D1A binding to all four receptors. Surprisingly, a mutation in SH2D1A able to interfere with Thr -2 of the CD150 binding motif (mutant T53I) severely impaired non-phosphotyrosine interactions while preserving unaffected the binding of SH2D1A to phosphorylated CD150. Mutant T53I, however, did not bind to CD229 and CD224, suggesting that SH2D1A controls several critical signaling pathways in T and natural killer cells. Because no correlation is present between identified types of mutations and XLP patient clinical presentation, additional unidentified genetic or environmental factors must play a strong role in XLP disease manifestations. PMID:11477068
Morra, M; Simarro-Grande, M; Martin, M; Chen, A S; Lanyi, A; Silander, O; Calpe, S; Davis, J; Pawson, T; Eck, M J; Sumegi, J; Engel, P; Li, S C; Terhorst, C
The risk of invasive aspergillosis (IA) is considered to be low among autologous HSCT recipients, but an increase in the incidence has been observed recently in this setting. The aim of the study was to assess the influence of immunosuppressive drugs (steroids, rituximab, fludarabine, thalidomide), used in treatment of lymphoid malignancies during 6 months of pretransplant period, on IA incidence after autologous HSCT. A total of 109 patients with non-Hodgkin's lymphoma (NHL), Hodgkin's disease (HD) and multiple myeloma (MM), conditioned with carmustine, etoposide, cytarabine, melphalan or melphalan and transplanted with PBSC, were analyzed prospectively. Patients were monitored with twice-weekly galactomannan test. High-resolution computed tomograhy of the chest and bronchoscopy were performed in case of positive galactomanan test, persistent fever or pulmonary infiltrates. Documented IA was diagnosed in nine (8%) patients (three proven, six probable). The incidence of IA was comparable in NHL, HD and MM patients and not influenced by age, advanced disease or conditioning regimen. Factors significant for development of documented IA by univariate analysis were treatment with fludarabine (P=0.008) or rituximab (P=0.039). The only factor predicting documented IA by multivariate analysis was treatment with fludarabine (P=0.008). Patients treated with fludarabine or rituximab in pretransplant period are at risk of IA and require close monitoring and/or anti-mould prophylaxis. PMID:18794866
Gil, L; Kozlowska-Skrzypczak, M; Mol, A; Poplawski, D; Styczynski, J; Komarnicki, M
The aim of this study was to analyze the clinical features and laboratory findings of adult Epstein-Barr virus associated T/NK cell lymphoproliferative disease (EBV+T/NK-LPD) and to investigate the early diagnosis and prognosis of EBV+T/NK-LPD. The clinical data of 19 adult patients with EBV+T/NK-LPD were retrospectively analyzed. The results indicated that there were 11 males and 8 females. The median age was 32 years (range: 20-70 years). The average duration from onset of symptoms to diagnosis was 3.5 months. The median survival time was 2.5 months. Unkown fever, hepatosplenomegaly, liver dysfunction and interstitial pneumonia were the main clinical features. High levels of ?2-MG, LDH, TNF, IL-6 and significantly increased EBV-DNA level (median level > 10(6) copies/ml) were occurred in all the patients. Cytopenia was seen in 18 cases. Morphologically, atypical large granular lymphocytes and hemophagocytosis were common in bone marrow smears. Deletion of CD5 or CD7 were frequently observed in T/NK lymphocytes in bone marrow cells by flow cytometry. Bone marrow biopsy showed atypical lymphocyte interstitial infiltrated in 10 cases, while a few large cells infiltrated in 6 cases. Immunohistochemistry showed the expression of CD3(+)CD56(+) were seen in 2 cases, CD3(+)CD8(+) in 11 cases and CD3(+)CD4(+) in 3 cases. TIA-1 and EBER were positive in all biopsy specimens. Three cases underwent biopsy of lymph nodes showed reactive proliferations of lymphocytes. All the patients died of multiorgan failure. It is concluded that the fever, hepatosplenomegaly are the most common clinical features in adult EBV+T/NK-LPD, the bone marrow infiltration of EBV-infected T/NK lymphocytes and significantly increased EBV-DNA level can be observed in all cases, the clinical outcome of this disease is poor, these clinical and experimental features can be served as a reliable marker for the timely diagnosis of adult EBV+T/NK-LPD. PMID:23998592
Zhang, Qian; Zhang, Hong-Yu; Zhang, Wen-Li; Zhong, Feng-Luan; Feng, Jia; Meng, Qing-Xiang; Yin, Wei-Hua; Nie, Li-Ping
We report the prevalence of BK virus (BKV) infection before renal transplantation and the dynamics of BKV viremia from pre- to post-transplantation. We assessed 60 kidney transplanted patients from a single cohort in Italy, treated with identical immunosuppressive therapy, for BK viremia at pre-transplantation, 12 h, and three and six months post-transplantation. Polymerase chain reaction showed that the prevalence of plasma BKV replication--considered a marker of infection--was 20% in pre-transplant patients. All pre-transplant-positive patients remained positive post-transplant, whereas the majority of pre-transplant-negative patients remained negative. Viremia dynamics classification revealed three clusters of patients: Cluster A++, pre-transplant-positive patients (20%) who tested positive at least once post-transplant; Cluster B-+, pre-transplant-negative patients (28%) who tested positive at least once post-transplant; and Cluster C- -, pre-transplant-negative patients (52%) who remained negative throughout. These clusters presented significant differences related to the prevalence of substantially positive patients with high plasma viral load (>10(3) copies/mL) in cluster A, but not in donors' or grafts' characteristics. We suggest that pre-transplant viral status should be considered as an additional risk factor for post-transplant BKV replication. Therefore, pre-transplant BKV infection screening in kidney transplant patients should be performed for improving planning of personalized immunosuppressant schemes and specific post-transplant surveillance. PMID:24506672
Mitterhofer, Anna Paola; Tinti, Francesca; Pietropaolo, Valeria; Umbro, Ilaria; Anzivino, Elena; Bellizzi, Anna; Zavatto, Assunta; Poli, Luca; Berloco, Pasquale Bartolomeo; Taliani, Gloria
X-linked lymphoproliferative disease (XLP) is characterized by a marked vulnerability to Epstein-Barr virus (EBV) infection. Infection of XLP patients with EBV invariably results in fatal mononucleosis, agammaglobulinemia, or malignant lymphoma. Initially the XLP gene was assigned to a 10-cM region in Xq25 between DXS42 and DXS37. Subsequently, an interstitial, cytogenetically visible deletion in Xq25 was identified in one XLP family, 43. In this study we estimated the deletion in XLP patient 43-004 by dual-laser flow karyotyping to involve 2% of the X chromosome, or approximately 3 Mb of DNA sequence. From a human chromosome Xq25-specific yeast artificial chromosome (YAC) sublibrary, five YACs containing DNA sequences deleted in patient 43-004 have been isolated. Sequence-tagged sites (STSs) from these YACs have been used to identify interstitial deletions in unrelated XLP patients. Three more families with interstitial deletions were found. Two of the patients (63-003 and 73-032) carried an interstitial deletion of 3.0 Mb overlapping the 43-004 deletion. In one XLP patient (30-011) who exhibited the characteristic postinfectious mononucleosis phenotype of XLP with hypogammaglobulinemia and malignant lymphoma, a deletion of approximately 250 kb was detected overlapping the deletion detected in patients 43-004, 63-003, and 73-032. A YAC contig of 2.2 Mb spanning the XLP critical region, whose orientation on chromosome X was determined by double-color fluorescence in situ hybridization and which consists of 15 overlapping YAC clones, has been constructed. A detailed restriction enzyme map of the region has been constructed. YAC insert sizes were determined by counter-clamped homogenous electric field gel electrophoresis. Chimerism of YACs was determined by FISH and restriction mapping. On the basis of lambda subclones, YAC end-derived plasmids, and STSs with an average spacing of 100 kb, a long-range physical map was constructed using 5 rare-cutter restriction enzymes. The STSs and lambda subclones were used in Southern hybridization and PCR analyses. The work presented here substantially refines the critical region for XLP. The YAC contig with the overlapping interstitial deletions constitutes the basis for the construction of a transcriptional map of the critical region and facilitates the identification of the XLP gene. PMID:9027486
Lanyi, A; Li, B; Li, S; Talmadge, C B; Brichacek, B; Davis, J R; Kozel, B A; Trask, B; van den Engh, G; Uzvolgyi, E; Stanbridge, E J; Nelson, D L; Chinault, C; Heslop, H; Gross, T G; Seemayer, T A; Klein, G; Purtilo, D T; Sumegi, J
Recurrence of hepatitis is a well-documented complication of hepatitis B liver disease, post-transplantation. It is well established also that the earliest hepatocellular change is the appearance of hepatitis B viral (HBV) markers and that the disease is rapidly progressive. In this article on 17 liver transplants in 16 HBV positive patients with long-term follow-ups (100-1234 days), the distinctive pathologic features of this disease are emphasized: the extreme viral load, the steatosis, and/or fibrosis. An attempt to quantitate the magnitude of the viral burden was made and the result was a staggering figure. In one patient, an estimated 10(18) HBV core particles were present in the liver. One of two patterns of progression were noted. In four patients in addition to the massive nuclear hepatitis B core antigen (HBcAg) and cytoplasmic hepatitis B surface antigen (HBsAg) positivity, superimposed hepatitic changes led to diffuse hepatic fibrosis (fibroviral hepatitis B); and in another six patients, extraordinary hepatocellular viral marker positivity and steatosis were the hallmarks (steatoviral hepatitis B). Steatosis is not usually considered a feature of HBV liver pathology. These results suggest that more than one type of posttransfusion recurrent hepatitis B liver disease exists pathologically. Images Figure 1 Figure 2 Figure 3
Phillips, M. J.; Cameron, R.; Flowers, M. A.; Blendis, L. M.; Greig, P. D.; Wanless, I.; Sherman, M.; Superina, R.; Langer, B.; Levy, G. A.
X-linked lymphoproliferative (XLP) dis- ease is a primary immunodeficiency caused by a defect in the SH2D1A gene. At least 3 major manifestations character- ize its clinical presentation: fatal infec- tious mononucleosis (FIM), lymphomas, and immunoglobulin deficiencies. Com- mon variable immunodeficiency (CVID) is a syndrome characterized by immuno- globulin deficiency leading to susceptibil- ity to infection. In some patients with CVID,
Massimo Morra; Olin Silander; Silvia Calpe; Michelle Choi; Hans Oettgen; Laurie Myers; Amos Etzioni; Rebecca Buckley; Cox Terhorst
X-linked lymphoproliferative disease (XLP) is a rare congenital immunodeficiency that leads to an extreme, usually fatal increase in the number of lymphocytes upon infection with EBV. It is most commonly defined molecularly by loss of expression of SLAM-associated protein (SAP). Despite this, there is little understanding of how SAP deficiency causes lymphocytosis following EBV infection. Here we show that T cells from individuals with XLP are specifically resistant to apoptosis mediated by TCR restimulation, a process that normally constrains T cell expansion during immune responses. Expression of SAP and the SLAM family receptor NK, T, and B cell antigen (NTB-A) were required for TCR-induced upregulation of key pro-apoptotic molecules and subsequent apoptosis. Further, SAP/NTB-A signaling augmented the strength of the proximal TCR signal to achieve the threshold required for restimulation-induced cell death (RICD). Strikingly, TCR ligation in activated T cells triggered increased recruitment of SAP to NTB-A, dissociation of the phosphatase SHP-1, and colocalization of NTB-A with CD3 aggregates. In contrast, NTB-A and SHP-1 contributed to RICD resistance in XLP T cells. Our results reveal what we believe to be novel roles for NTB-A and SAP in regulating T cell homeostasis through apoptosis and provide mechanistic insight into the pathogenesis of lymphoproliferative disease in XLP. PMID:19759517
Snow, Andrew L; Marsh, Rebecca A; Krummey, Scott M; Roehrs, Philip; Young, Lisa R; Zhang, Kejian; van Hoff, Jack; Dhar, Deepali; Nichols, Kim E; Filipovich, Alexandra H; Su, Helen C; Bleesing, Jack J; Lenardo, Michael J
Hepatosplenic T-cell lymphoma (HSTL) is an aggressive lymphoma. In post-transplant immunosuppressed patients, HSTL is usually rapidly fatal. We report successful treatment of post-transplant HSTL in a 50-year-old renal allograft recipient by reducing immunosuppression and using intensive chemotherapy consisting of alternating cycles of HyperCVAD (cyclophosphamide, vincristine, doxorubicin, and dexamethasone) and MTX/HiDAC (methotrexate, Ara-C). Remission is ongoing at 8+ years. Literature review identified another 20 cases of HSTL in solid organ transplant recipients: median survival was 4 months; no other patients survived beyond 12 months. Bone marrow involvement was universal, but changes were often subtle: 6 of 12 cases had nondiagnostic examinations earlier on. High index of suspicion may lead to more timely diagnosis of this uncommon form of post-transplant lymphoproliferative disorder, and treatment with intensive chemotherapy such as HyperCVAD may be curative. PMID:17876769
Tey, Siok-Keen; Marlton, Paula V; Hawley, Carmel M; Norris, Debra; Gill, Devinder S
We report a 5.9-year-old boy with X-linked lymphoproliferative syndrome (XLP) who presented with acute severe infectious mononucleosis. Clinical symptoms rapidly improved after chemotherapy with etoposide. Allogeneic bone marrow transplantation (BMT) was performed after conditioning with etoposide, busulfan and cyclophosphamide. After successful hematopoietic recovery we were able to demonstrate seroconversion from an impaired antibody response to Epstein-Barr virus (EBV) to a normal antibody-producing state in an immunocompetent child. The only post-transplant complication was mild acute graft-versus-host disease (GVHD). Three years after BMT, the boy is healthy and shows no signs of immunodeficiency. This is the first report on successful allogeneic BMT in the severe course of acute infectious mononucleosis in a patient with XLP. We speculate that the application of etoposide contributed to the positive outcome in this patient. PMID:8054918
Pracher, E; Panzer-Grümayer, E R; Zoubek, A; Peters, C; Gadner, H
X-linked lymphoproliferative disease (XLP) is an inherited immunodeficiency, involving primarily T and natural killer (NK) cells, which in the majority of cases exacerbates following exposure to Epstein-Barr virus (EBV). Prior to EBV infection, most boys with the defective XLP gene appear to be clinically healthy EBV infection in males with the defective XLP gene leads to three main phenotypes: severe and mostly fatal infectious mononucleosis (58%), lymphoproliferative disorders mostly of B-cell origin (30%) and/or dysgammaglobulinemia (31%). Later in life, dysgammaglobulinemia and malignant lymphoma may also develop in about 53% and 56% of EBV-negative XLP males, respectively This fact suggests that EBV may only act as a potent trigger of the earliest and most serious clinical phenotype of XLP, i.e. fatal infectious mononucleosis. XLP has an unfavorable prognosis. Successful transplanta tion of hematopoietic stem cells can cure this immunodeficiency In the future, gene therapy may eventually become an additional option to prevent XLP. The gene responsible for XLP, SH2-domain containing gene 1A (SH2D1A) has recently been identified and sequenced. SH2D1A encodes a polypeptide of 128 amino acids containing a single SH2 domain. Until now, 45 different SH2D1A gene mutations have been identified in patients with XLP SH2D1A is thought to play an important role in signal transduction in T and NK cells. In vitro, SH2D1A has been shown to interact as an adaptor protein with the signaling pathways through SLAM, a T-cell co-stimulatory molecule, and 2B4, an NK-cell-activating receptor. Further functional studies of the SH2D1A protein will probably provide new insights into the pathogenesis of severe infectious mononucleosis, malignant lymphomas and immunodeficiency in patients with XLP. PMID:11213803
Schuster, V; Kreth, H W
Epstein-Barr virus (EBV)-associated post-transplant lymphoproliferative disorder (PTLD) is a serious complication of organ transplantation. The gastrointestinal (GI) tract is a common site involved, but non-specific signs and symptoms often delay the diagnosis. We report a case of EBV-associated GI-PTLD in a 68-year-old kidney transplant patient who received the kidney ten months earlier. He presented with chronic diarrhea and developed massive pneumo-peritoneum secondary to multiple colonic perforations. PMID:24821162
Singh, Neeraj; Samavedi, Singh; Rajab, Amer
X-linked lymphoproliferative disease (Duncan's Disease) was first encountered by David T. Purtilo in 1969. The first communication describing the disease was published in 1975. In 1989 the disease locus was mapped to Xq25. Ten years later the gene (SH2D1A, SAP, DSHP), which is absent or mutated in XLP patients was identified. Since that the protein crystal structure of this small, SH2-domain containing protein has been solved, target molecules of the protein have been identified, physiological and pathological protein/protein interactions have been characterized, and the mouse model of the gene mutation has been developed. That said, a complete understanding of the function of the normal SH2D1A protein in immunoregulation and of the altered immune responses in XLP patients is not yet at hand. Therein lies the legacy of Purtilo's discovery for, as with other primary immunodeficiencies, these "experiments of nature" offer a window on the beauty of the immune system. In due course, the manner by which this gene orchestrates an elegant response (akin to a Mozart divertimento) to EBV infection shall be defined. PMID:12152986
Sumegi, Janos; Seemayer, Thomas A; Huang, Dali; Davis, Jack R; Morra, Massimo; Gross, Thomas G; Yin, Luo; Romco, Giovanni; Klein, Eva; Terhorst, Cox; Lanyi, Arpad
Mutations in the SH2D1A gene have been described in most patients with the clinical syndrome of X-linked lymphoproliferative disease (XLP). The diagnosis of XLP is still difficult given its clinical heterogeneity and the lack of a readily available rapid diagnostic laboratory test, particularly in patients without a family history of XLP. XLP should always be a consideration in males with Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis (EBV-HLH). Four-color flow cytometric analysis was used to establish normal patterns of SH2D1A protein expression in lymphocyte subsets for healthy subjects. Three of 4 patients with XLP, as confirmed by the detection of mutations in the SH2D1A gene, had minimal intracellular SH2D1A protein in all cytotoxic cell types. The remaining patient lacked intracellular SH2D1A protein in CD56+ natural killer (NK) and T lymphocytes and had an abnormal bimodal pattern in CD8+ T cells. Carriers of SH2D1A mutations had decreased SH2D1A protein staining patterns compared with healthy controls. Eleven males with clinical syndromes consistent with XLP, predominantly EBV-HLH, had patterns of SH2D1A protein expression similar to those of healthy controls. Four-color flow cytometry provides diagnostic information that may speed the identification of this fatal disease, differentiating it from other causes of EBV-HLH. PMID:15632210
Tabata, Yasuhiro; Villanueva, Joyce; Lee, Susan Molleran; Zhang, Kejian; Kanegane, Hirokazu; Miyawaki, Toshio; Sumegi, Janos; Filipovich, Alexandra H
Epstein-Barr virus (EBV) induced polyclonal and monoclonal B-cell lymphoproliferative diseases occurring after renal transplantation. Clinical, pathologic, and virologic findings and implications for therapy.
Nineteen renal allograft recipients developed B-cell lymphoproliferative diseases. Clinically there were two groups: a) young patients (mean age, 23 years) who presented soon (mean, 9 months) after transplantation or antirejection therapy with fever, pharyngitis, and lymphadenopathy resembling infectious mononucleosis, and b) older patients (mean age, 48 years) who presented later (mean, 6 years) after transplantation with localized tumor masses. Histologically, the diseases were classified as polymorphic diffuse B-cell hyperplasia (PDBH) or polymorphic B-cell lymphoma (PBL). Immunologic cell typing revealed either polyclonal or monoclonal B-cell proliferations. Malignant transformation of polyclonal proliferations in two patients was suggested by the finding of clonal cytogenetic abnormalities. Epstein-Barr virus (EBV) specific serology, staining of biopsy specimens for the Epstein-Barr nuclear antigen, and EBV DNA molecular hybridization studies implicated EBV as the cause of both PDBH and PBL. Acyclovir, an antiviral agent that blocks EBV replication in vitro, inhibited oropharyngeal shedding of EBV and caused complete remission in four patients with polyclonal B-cell proliferations. The monoclonal tumors were acyclovir resistant. We suggest that surgical treatment, radiotherapy, or chemotherapy may be more appropriate therapy in selected patients with acyclovir resistant tumors. Therapeutic decisions require not only documentation of the viral etiology of these tumors, but also immunologic and cytogenetic analysis to determine the stage of tumor evolution in individual patients.
Hanto, D W; Gajl-Peczalska, K J; Frizzera, G; Arthur, D C; Balfour, H H; McClain, K; Simmons, R L; Najarian, J S
CD30+ lymphoproliferative disorders are the most common group of cutaneous T-cell lymphomas after mycosis fungoides and its subtypes. This group includes lymphomatoid papulosis and CD30+ anaplastic large-cell lymphoma; these 2 entities are the extremes of a spectrum with numerous intermediate varieties in which it is not possible to establish a clear diagnosis based on clinical and histopathologic criteria. CD30+ lymphoproliferative disorders must be differentiated from other lymphoproliferative diseases with CD30+ cells in the tumor infiltrates, such as mycosis fungoides or Hodgkin disease, and also from other inflammatory conditions or nonhematological neoplasms that can include this cell type, such as pityriasis lichenoides et varioliformis acuta or certain mesenchymal tumors (CD30+ pseudolymphomas). In contrast to their systemic homologues, which arise in the lymph nodes, CD30+ lymphoproliferative disorders generally have a good prognosis. It is very important to exclude the presence of a lymphoma of systemic origin with extralymphatic spread, as the prognosis and treatment are different. PMID:20223154
Calzado-Villarreal, L; Polo-Rodríguez, I; Ortiz-Romero, P L
X-linked lymphoproliferative disease (XLP) is an often-fatal immunodeficiency characterized by hypogammaglobulinemia, fulminant infectious mononucleosis, and/or lymphoma. The genetic lesion in XLP, SH2D1A, encodes the adaptor protein SAP (signaling lymphocytic activation molecule–associated [SLAM-associated] protein); however, the mechanism(s) by which mutations in SH2D1A causes hypogammaglobulinemia is unknown. Our analysis of 14 XLP patients revealed normal B cell development but a marked reduction in the number of memory B cells. The few memory cells detected were IgM+, revealing deficient isotype switching in vivo. However, XLP B cells underwent proliferation and differentiation in vitro as efficiently as control B cells, which indicates that the block in differentiation in vivo is B cell extrinsic. This possibility is supported by the finding that XLP CD4+ T cells did not efficiently differentiate into IL-10+ effector cells or provide optimal B cell help in vitro. Importantly, the B cell help provided by SAP-deficient CD4+ T cells was improved by provision of exogenous IL-10 or ectopic expression of SAP, which resulted in increased IL-10 production by T cells. XLP CD4+ T cells also failed to efficiently upregulate expression of inducible costimulator (ICOS), a potent inducer of IL-10 production by CD4+ T cells. Thus, insufficient IL-10 production may contribute to hypogammaglobulinemia in XLP. This finding suggests new strategies for treating this immunodeficiency.
Ma, Cindy S.; Hare, Nathan J.; Nichols, Kim E.; Dupre, Loic; Andolfi, Grazia; Roncarolo, Maria-Grazia; Adelstein, Stephen; Hodgkin, Philip D.; Tangye, Stuart G.
Intestinal T-cell and natural killer (NK)–cell lymphomas are clinically aggressive and can be challenging to diagnose in small endoscopic biopsies. We describe 8 patients in whom atypical NK-cell lymphoproliferative lesions mimicked NK- or T-cell lymphoma. The patients (2 men; 6 women; ages 27-68 years) presented with vague gastrointestinal symptoms with lesions involving stomach, duodenum, small intestine, and colon. At endoscopy, the lesions exhibited superficial ulceration, edema, and hemorrhage. Biopsies revealed a mucosal infiltrate of atypical cells with an NK-cell phenotype (CD56+/TIA-1+/Granzyme B+/cCD3+), which displaced but did not invade the glandular epithelium. Epstein-Barr virus–encoded RNA in situ hybridization was negative, and T-cell receptor-? gene rearrangement showed no evidence of a clonal process. Based on an original diagnosis of lymphoma, 3 patients received aggressive chemotherapy followed by autologous bone marrow transplantation in 2. Five patients were followed without treatment. However, no patient developed progressive disease or died of lymphoma (median follow-up, 30 months). Repeat endoscopies in 6 of 8 patients showed persistence or recurrence of superficial gastrointestinal lesions. This unique entity mimics intestinal and NK-/T-cell lymphomas on endoscopic biopsies and can result in erroneous diagnosis, leading to aggressive chemotherapy. We propose the term “NK-cell enteropathy” for this syndrome of as yet unknown etiology.
Mansoor, Adnan; Pittaluga, Stefania; Beck, Paul L.; Wilson, Wyndham H.; Ferry, Judith A.
X-linked inhibitor of apoptosis (XIAP) deficiency, caused by BIRC4 mutations, is described to cause X-linked lymphoproliferative disease (XLP) phenotypes. However, compared with XLP caused by SLAM-Associated Protein deficiency (SH2D1A mutation), XIAP deficiency was originally observed to be associated with a high incidence of hemophagocytic lymphohistiocytosis (HLH) and a lack of lymphoma, suggesting that classification of XIAP deficiency as a cause of XLP may not be entirely accurate. To further characterize XIAP deficiency, we reviewed our experience with 10 patients from 8 unrelated families with BIRC4 mutations. Nine of 10 patients developed HLH by 8 years of age. Most patients presented in infancy, and recurrent HLH was common. There were no cases of lymphoma. Lymphocyte defects thought to contribute to HLH development in SLAM-Associated Protein deficiency were not observed in XIAP deficiency. We conclude that XIAP deficiency is a unique primary immunodeficiency that is more appropriately classified as X-linked familial hemophagocytic lymphohistiocytosis.
Madden, Lisa; Kitchen, Brenda J.; Mody, Rajen; McClimon, Brad; Jordan, Michael B.; Bleesing, Jack J.; Zhang, Kejian; Filipovich, Alexandra H.
X-linked inhibitor of apoptosis (XIAP) deficiency, caused by BIRC4 mutations, is described to cause X-linked lymphoproliferative disease (XLP) phenotypes. However, compared with XLP caused by SLAM-Associated Protein deficiency (SH2D1A mutation), XIAP deficiency was originally observed to be associated with a high incidence of hemophagocytic lymphohistiocytosis (HLH) and a lack of lymphoma, suggesting that classification of XIAP deficiency as a cause of XLP may not be entirely accurate. To further characterize XIAP deficiency, we reviewed our experience with 10 patients from 8 unrelated families with BIRC4 mutations. Nine of 10 patients developed HLH by 8 years of age. Most patients presented in infancy, and recurrent HLH was common. There were no cases of lymphoma. Lymphocyte defects thought to contribute to HLH development in SLAM-Associated Protein deficiency were not observed in XIAP deficiency. We conclude that XIAP deficiency is a unique primary immunodeficiency that is more appropriately classified as X-linked familial hemophagocytic lymphohistiocytosis. PMID:20489057
Marsh, Rebecca A; Madden, Lisa; Kitchen, Brenda J; Mody, Rajen; McClimon, Brad; Jordan, Michael B; Bleesing, Jack J; Zhang, Kejian; Filipovich, Alexandra H
Patients with the primary immunodeficiency X-linked lymphoproliferative disease (XLP), which is caused by mutations in SH2D1A, are highly susceptible to Epstein-Barr virus (EBV) infection. Nonetheless, some XLP patients demonstrate less severe clinical manifestations after primary infection. SH2D1A encodes the adaptor molecule SLAM-associated protein (SAP), which is expressed in T and natural killer cells and is required for cytotoxicity against B cells, the reservoir for EBV. It is not known why the clinical presentation of XLP is so variable. In this study, we report for the first time the occurrence of somatic reversion in XLP. Reverted SAP-expressing cells resided exclusively within the CD8+ T cell subset, displayed a CD45RA?CCR7? effector memory phenotype, and were maintained at a stable level over time. Importantly, revertant CD8+ SAP+ T cells, but not SAP? cells, proliferated in response to EBV and killed EBV-infected B cells. As somatic reversion correlated with EBV infection, we propose that the virus exerts a selective pressure on the reverted cells, resulting in their expansion in vivo and host protection against ongoing infection.
Low, Carol; Bell, Andrew I.; Abbott, Rachel J.M.; Phan, Tri Giang; Riminton, D. Sean; Choo, Sharon; Smart, Joanne M.; Lougaris, Vassilios; Giliani, Silvia; Buckley, Rebecca H.; Grimbacher, Bodo; Alvaro, Frank; Klion, Amy D.; Nichols, Kim E.; Adelstein, Stephen; Rickinson, Alan B.
X-linked lymphoproliferative disease (XLP) is a congenital immunodeficiency that is characterized by an abnormal immune response to primary Epstein-Barr virus (EBV) infection. After EBV exposure, affected patients often develop fulminant infectious mononucleosis (FIM), a life-threatening condition marked by the uncontrolled expansion and activation of T and B lymphocytes and macrophages. We hypothesized that the rapid elimination of B cells immediately following EBV exposure might reduce the severity of primary EBV infection in patients with XLP. To test this possibility, we administered the anti-CD20 antibody rituximab to 2 patients who presented with acute infection. Following treatment, both patients exhibited a complete resolution of symptoms and no longer demonstrated detectable EBV DNA within circulating lymphocytes. Moreover, neither patient has developed FIM or lymphoma in more than 2 years of follow-up. These data suggest that the pre-emptive use of B-cell-directed therapy may reduce the morbidity and mortality of primary EBV infection in XLP-affected individuals. PMID:15494422
Milone, Michael C; Tsai, Donald E; Hodinka, Richard L; Silverman, Lewis B; Malbran, Alejandro; Wasik, Mariusz A; Nichols, Kim E
Aplastic anemia (AA) may precede, co-occur, or follow a lymphoproliferative neoplasm. The best molecularly clarified scenario is that of concurrent AA and unsuspected (occult) T-cell large granular lymphocyte leukemia. Several reported cases of AA and concurrent small B-cell lymphomas/leukemias and Hodgkin lymphomas suggest also a possible link to simultaneous or preceding AA that might be sought in an antineoplastic immunological attempt to 'eradicate' the underlying malignant clone. The 'immuno-deregulatory' potential and the direct cytotoxicity of regimens used for lymphoma therapy might be able to trigger AA in cases evolving after lymphoma treatment too. Alternative explanations of AA associated with lymphoproliferative disorders might be particular (immuno-)genetic patient backgrounds predisposing to both AA and lymphoid neoplasms or exposures to environmental factors, increasing the risk for both diseases. Finally, the most common causal relationship of AA and lymphoma is that of immunosuppression- or allogeneous hematopoietic stem cell transplantation-associated posttransplantational lymphoproliferative disorders in AA patients, who are treated in the respective manner. As all above scenarios are differently (specifically) therapeutically approachable and accompanied by diverse outcomes, they should be actively sought for and diagnosed as precisely as possible. This review summarizes the current knowledge on associations between AA and lymphoproliferative neoplasms. PMID:24750685
Tzankov, A; Medinger, M
Post-transplant malignancies, which occur either de novo or as cancer recurrences, are due to chronic exposure to immunosuppressive agents and are often more aggressive than those that develop in the non-transplant setting. Mammalian target of rapamycin (mTOR) inhibitors have antitumor and immunosuppressive effects. The dual effects of this class of agents may provide adequate immunosuppression to prevent organ rejection while simultaneously reducing the risk of post-transplant malignancy. mTOR inhibitors have become established approved agents for treating renal cell carcinoma and other cancers and, as reviewed herein, accumulating experience among organ transplant recipients collectively points toward a potential to prevent the development of de novo malignancies of various types in the post-transplant period. To date, most research efforts surrounding mTOR inhibitors and cancer control in the transplant population have been in the area of skin cancer prevention, but there have also been interesting observations regarding regression of post-transplant Kaposi's sarcoma and post-transplantation lymphoproliferative disorder that warrant further study. PMID:24628264
Klintmalm, Goran B; Saab, Sammy; Hong, Johnny C; Nashan, Björn
The lack of functional SAP protein, a consequence of mutation or deletion of the SH2D1A gene is the cause of X-linked lymphoproliferative disease (XLP). Others and we have shown that SAP can be involved in apoptosis. Activation induced apoptosis plays a pivotal role in the termination of the lymphocyte proliferation in infectious mononucleosis IM. This mechanism is inefficient in the XLP patients. Primary EBV infection of boys with XLP leads therefore to fulminant, often even fatal disease. In addition, the condition predisposes to considerably elevated incidence of lymphomas. Chromosomal translocation that juxtaposes one of the three immunoglobulin loci to the c-myc proto-oncogene is the hallmark of Burkitt lymphomas (BL), whether they carry the Epstein-Barr Virus (EBV) or not. Ig/myc translocations occur as rare accidents of normal B lymphocyte differentiation. The activated myc would drive the cells to proliferate, however unless protected, the cells become prone to apoptosis. Our results with BL derived cell lines suggest that the fate of the precursor cells is decided by the expression of the proapototic SAP and EBV infection. We found SAP expression in eight of ten EBV carrying, but none of nine EBV negative BL lines. Therefore it seems that the apoptosis prone Ig/myc translocation carrying EBV negative precursors of BL can grow into lymphomas only if they do not express the proapoptotic SAP while SAP expressor, but EBV positive cells can survive and proliferate. This is probably due to the antiapoptotic function of EBNA-1 and the proliferation induced by activated myc. PMID:20080127
Nagy, Noemi; Klein, Eva
Background Evaluation of a transplanted liver by Imaging techniques and enzyme changes is sensitive to hepatocellular or biliary problems, but in most instances liver allograft biopsies are performed in order to find out the final reason for these changes. Objectives It’s been about 17 years (with more than 1326 cases) since the first liver transplantation in the Namazi Hospital of Shiraz University of Medical Sciences while during the last five years the number of post liver transplant biopsies have increased. Until now there has been no report of the pathological results of post liver transplant needle biopsies from Iran. Materials and Methods During the last 5 years, there have been 382 post liver transplant biopsies. We studied the clinical charts and pathological results of all needle biopsies. Results A total of 382 needle biopsies were performed on 287 patients aged between 1 and 64 years old. The earliest specimen was obtained within the first few hours following transplantation, and the last was gathered 3209 days (261 ± 523) post-transplantation. Acute rejection was the most common diagnosis, which occurred in 180 (47%) of specimens. Among other complications were vascular problems (8.6%), preservation/reperfusion (I/R) injury (7%), chronic rejection (5.2%), biliary injury/obstruction (3.4%), recurrence of primary disease (2.6%), drug-induced hepatic injury (1.8%), cirrhosis (1.6%), sepsis (1.4%), cytomegalovirus hepatitis (1.4%), post-transplantation lymphoproliferative disease (1%) and Venous outflow obstruction (0.5%). Conclusions The most common pathological diagnosis of post-transplant liver needle biopsies has been acute rejection, followed by ischemia due to hepatic artery thrombosis, preservation/reperfusion injury, and chronic rejection.
Geramizadeh, Bita; Motevalli, Dorna; Nikeghbalian, Saman; Malek Hosseini, Seyed Ali
Information regarding the development of diverse diseases associated with EBV virus in immune deficient patients has been gained by studying males with XLP, and their families. Multiple immune defenses normally protect against the ubiquitous EBV. Depending on the type and degree of inherited or acquired immunodeficiency, EBV may more or less be capable of inducing a variety of diseases. Multiple methods may be needed to document EBV in the immune deficient individual. Rational approaches to prevention and intervention in EBV-induced diseases in immune compromised individuals are being developed. PMID:2990590
Purtilo, D T
The purposes of this study were to determine the frequency of mutations in SH2D1A in X-linked lymphoproliferative disease (XLP) and the role of SH2D1A mutations and Epstein-Barr virus (EBV) infection in determining the phenotype and outcome of patients with XLP. Analysis of 35 families from the XLP Registry revealed 28 different mutations in 34 families-large genomic deletions (n = 3), small intragenic deletions (n = 10), splice-site (n = 3), nonsense (n = 3), and missense (n = 9) mutations. No mutations were found in 25 males, so-called sporadic XLP (males with an XLP phenotype after EBV infection but no family history of XLP) or in 9 patients with chronic active EBV syndrome. Of 304 symptomatic males in the XLP Registry, 38 had no evidence of EBV infection at first clinical manifestation. When fulminant infectious mononucleosis (FIM) was excluded, there was no statistical difference in the frequency of EBV infectivity in the other XLP phenotypes. Furthermore, there was no difference at age of first clinical manifestation between EBV(+) and EBV(-) males or in survival when patients with FIM were excluded. In conclusion, it was found that mutations in the SH2D1A gene are responsible for XLP but that there is no correlation between genotype and phenotype or outcome. It was also found that though EBV infection often results in FIM, it is unnecessary for the expression of other manifestations of XLP, and it correlates poorly with outcome. These results suggest that unidentified factors, either environmental or genetic (eg, modifier genes), contribute to the pathogenesis of XLP. PMID:11049992
Sumegi, J; Huang, D; Lanyi, A; Davis, J D; Seemayer, T A; Maeda, A; Klein, G; Seri, M; Wakiguchi, H; Purtilo, D T; Gross, T G
X-linked lymphoproliferative disease (XLP) is an inherited immunodeficiency characterized by extreme vulnerability to Epstein-Barr virus (EBV) infection, resulting in fatal infectious mononucleosis, dysgammaglobulinemia and malignant lymphoma. Recently, mutations in the SH2D1A gene, which encodes SLAM-associated protein (SAP), have been found to cause XLP. Although the molecular events behind XLP are largely unknown, there is evidence that affected males exhibited some immunohematological abnormalities, such as hypogammaglobulinemia or lymphoma, even prior to EBV infection. Because of the poor prognosis in XLP, an early diagnosis to patients and families is clinically of great importance. A glutathione-S-transferase-SAP fusion protein was used to immunize rats and generate mAb against human SAP to investigate its pathogenic role in XLP and develop a flow cytometric assay for detection of XLP. By flow cytometric and Western immunoblot analyses using an established anti-SAP mAb, termed KST-3, we determined that SAP was expressed intensely in thymocytes, but at lower levels in peripheral T cells and NK cells. In contrast, expression of SAP was negligible in B cells, monocytes or granulocytes. We found that SAP expression in T cells increased upon in vivo as well as in vitro activation. In two XLP survivors with SH2D1A mutations, a flow cytometric evaluation of activated T cells using KST-3 could demonstrate SAP deficiency as a diagnostic indicator of XLP. Through this approach, we identified three novel XLP families with SH2D1A mutations in Japan. A flow cytometric assessment of SAP expressed in activated T cells would lead to easy detection of XLP patients. PMID:12356686
Shinozaki, Kentaro; Kanegane, Hirokazu; Matsukura, Hiroyoshi; Sumazaki, Ryo; Tsuchida, Masahiro; Makita, Mika; Kimoto, Yasuo; Kanai, Rie; Tsumura, Kumi; Kondoh, Tatsuro; Moriuchi, Hiroyuki; Miyawaki, Toshio
SLAM (signaling lymphocyte activation molecule)-associated protein (SAP) is a Src homology 2 (SH2) domain-containing adaptor expressed in T cells and natural killer cells. Its essential role in immune responses is underscored by the recent finding that mutations in SAP result in a rare but fatal X-linked lymphoproliferative disease (XLP). Although SAP is known to associate with SLAM-family receptors, the exact molecular mechanism by which SAP regulates lymphocyte signaling remains elusive. We here report that in T cells, SAP associates with the PAK-interacting exchange factor (PIX), a guanine nucleotide exchange factor (GEF) specific for Rac/Cdc42 GTPases. Moreover, SAP, PIX, and an activated form of Cdc42 form a complex in mammalian cells. We demonstrate that the SAP-PIX interaction is specific and is mediated by the C-terminal region of the SAP SH2 domain and the PIX SH3 domain. We further show that SAP is required for the recruitment of PIX to the SLAM-family receptors. Interestingly, overexpression of SAP, but not its homolog EAT-2, leads to a synergistic activation of nuclear factor of activating T cells (NFAT) in combination with a calcium signal in T cells. This SAP-mediated activation appears to be receptor-dependent and can be blocked by a dominant negative form of PIX. Taken together, our data strongly suggest that, in addition to the known SAP-interacting kinase Fyn, PIX may be another key player in SAP-mediated T cell activation. PMID:16983070
Gu, Cuiping; Tangye, Stuart G; Sun, Xiaoqing; Luo, Ying; Lin, Zhixin; Wu, Jun
We review monoclonal B-cell lymphocytosis (MBL) as a precursor to chronic lymphocytic leukemia and monoclonal gammopathy of undetermined significance (MGUS) as a precursor to plasma cell disorders. These conditions are present in the general population and increase with age. These precursors aggregate with lymphoproliferative malignancies in families suggesting shared inheritance. MBL and MGUS may share some of the same risk factors as their related malignancies but data are limited. While these conditions are characterized by enhanced risk for the associated malignancy, the majority of individuals with these conditions do not progress to malignancy. A key focus for current work is to identify markers that predict progression to malignancy.
Goldin, Lynn R.; McMaster, Mary L.; Caporaso, Neil E.
A number of risk factors for the occurrence of neutropaenic fever after haematopoietic stem cell transplantation (HSCT) have been proposed. We were interested in whether these factors remain valid for several early infection-related outcomes when applied to a homogeneous group of patients in uni- and multivariate analyses. Therefore, we analysed 144 consecutive patients with lymphoproliferative disorders receiving autologous peripheral blood
H. W. Auner; A. Zebisch; P. Ofner; H. Sill; W. Linkesch; R. Krause
There is a growing interest in the evaluation of non-myeloablative conditioning therapy for allogeneic stem cell transplantation. Such regimens are expected to produce less toxicity while allowing both engraftment and a graft-versus-disease effect from the large number of donor-derived immunocompetent T lymphocytes given with the stem cells. Heavy immunosuppression used in recipients may have unexpected consequences. We describe the occurrence
N Milpied; M Coste-Burel; F Accard; A Moreau; P Moreau; R Garand; J-L Harousseau
The Autoimmune Lymphoproliferative Syndrome (ALPS) is an impairment of lymphocyte apoptosis expressed by generalized non-malignant lymphoproliferation, lymphadenopathy and/or splenomegaly. This article describes a seven and 14 year old males. The first one was admitted at 3 years of age with fever, bicytopenia and generalized lymphadenopathy. Hystopathological analysis of lymph nodes showed reactive follicular hyperplasia and marked paracortical expansion. He was readmitted three years later presenting herpes zoster and similar clinical features. High levels of IL-10 and increasing tendency of Fas-L in plasma and serum. The second child was admitted at 13 years of age presenting thigh and gluteus cellulitis, anemia and neutropenia. T lymphocytes aß+CD4-CD8- 3,1%. Hystopathological analysis of lymph nodes showed marked paracortical hyperplasia. Both children are treated with mycophenolate mofetil with good response. ALPS is an underestimated entity that must be considered in non malign lymphoproliferation, autoimmunity and expansion of an unusual population of a/ßCD3+CD4-CD8-(double-negative T cells>1%). PMID:22525637
Rodrigues, Vera; Conde, Marta; Figueiredo, António; Vasconcelos, Júlia; Dias, Alexandra
Autologous stem cell transplantation (SCT) has become standard therapy in high risk stage IV neuroblastoma (NB) patients. Residual NB cells in the bone marrow (BM) shortly before SCT may shape the overall survival.Thus, we sought to thoroughly investigate minimal residual disease (MRD) in BM prior to SCT using conventional and real time RT-PCR for tyrosine hydroxylase (TH) as well as morphology. To avoid influence of residual NB cells in the stem cell harvest, 17 patients transplanted with MRD negative grafts (n=11 CD34-selected and n=6 unmanipulated) are included in the final analysis, only.35% of these patients are alive with a median follow up of 8.6 years. In the BM of 9/17 patients residual NB cells could be detected < 40 d before SCT. These patients had a significant lower overall survival compared to patients without BM involvement based on combined RT-PCR and morphology results (11% vs. 62%, p=0.026) or using RT-PCR, only (p=0.01). In contrast morphology on its own did not lead to a significant discrimination between both groups.Our results obtained in a small cohort of stage IV NB patients suggest that MRD diagnostic in the BM shortly before SCT might be a valuable predictive tool for these patients but requires conformation in a multicenter study. PMID:22377741
Bochennek, K; Esser, R; Lehrnbecher, T; Glienke, W; Wehner, S; Erben, S; Soerensen, J; Schwabe, D; Bader, P; Klingebiel, T; Koehl, U
De novo malignancies represent an increasing concern in the transplant population, particularly as long-term graft and patient survival improves. EBV-associated B-cell lymphoma in the setting of PTLD is the leading malignancy in children following solid organ transplantation. Therapeutic strategies can be categorized as pharmacologic, biologic, and cell-based but the variable efficacy of these approaches and the complexity of PTLD suggest that new treatment options are warranted. Here, we review current therapeutic strategies for treatment of PTLD. We also describe the life cycle of EBV, addressing the viral mechanisms that contribute to the genesis and persistence of EBV+ B-cell lymphomas. Specifically, we focus on the oncogenic signaling pathways activated by the EBV LMP1 and LMP2a to understand the underlying mechanisms and mediators of lymphomagenesis with the goal of identifying novel, rational therapeutic targets for the treatment of EBV-associated malignancies.
Hatton, Olivia; Martinez, Olivia M.; Esquivel, Carlos O.
It is not clear whether pretransplantation MELD (model for End-Stage Liver Disease) score can foresee posttransplant outcome. We retrospectively evaluated 80 adult patients (55 men, 25 women) who underwent living donor liver transplantation between September 1998 and March 2003. Five other patients with fulminant hepatitis were excluded. The UNOS-modified MELD scores were calculated to stratify patients into three groups: group
M Akyildiz; Z Karasu; C Arikan; M Kilic; M Zeytunlu; F Gunsar; G Ersoz; U Akarca; Y Batur; Y Tokat
Factors predictive of post-transplant erythrocytosis. Ninety-three patients with PTE (that is, hematocrit 51% or greater) were identified among 431 renal transplant recipients, an incidence of 21.6%. Thirty-eight patients underwent blood volume measurements, and 22 of these had high red cell volume and therefore were considered to have true PTE. To analyze factors predictive of erythrocytosis, a control group with normal
Wajeh Y Qunibi; Yousri Barri; E Devol; Othman Al-Furayh; Kirtikant Sheth; Saadi Taher
Umbilical cord blood as an alternative source of reduced-intensity hematopoietic stem cell transplantation for chronic Epstein-Barr virus-associated T or natural killer cell lymphoproliferative diseases.
Chronic Epstein-Barr virus-associated T/natural killer cell lymphoproliferative diseases represented by chronic active Epstein-Barr virus infection are lethal but are curable with several courses of chemotherapy and allogeneic hematopoietic stem cell transplantation (HSCT). Recently, we reported that reduced-intensity conditioning (RIC) provided better outcomes than myeloablative conditioning because RIC was less toxic. However, it was unclear whether cord blood transplantation (CBT) works in the context of RIC. We retrospectively analyzed 17 patients who underwent RIC followed by bone marrow transplantation (RIC-BMT) and 15 patients who underwent RIC followed by CBT (RIC-CBT). The representative regimen was fludarabine and melphalan based. The overall survival rates with RIC-BMT and RIC-CBT were 92.9% ± 6.9% and 93.3% ± 6.4%, respectively (P = .87). One patient died of lung graft-versus-host disease after RIC-BMT, and 1 patient died of multiple viral infections after RIC-CBT. Although cytotoxic chemotherapy was also immunosuppressive and might contribute to better donor cell engraftment after RIC-HSCT, the rate of engraftment failure after RIC-CBT was still higher than that after RIC-BMT (not significant); however, patients who had experienced graft failure were successfully rescued with a second HSCT. Unrelated cord blood can be an alternative source for RIC-HSCT if a patient has no family donor. PMID:24188918
Sawada, Akihisa; Inoue, Masami; Koyama-Sato, Maho; Kondo, Osamu; Yamada, Kayo; Shimizu, Mariko; Isaka, Kanako; Kimoto, Tomiko; Kikuchi, Hiroaki; Tokimasa, Sadao; Yasui, Masahiro; Kawa, Keisei
Background Several interventions can cure posttransplant lymphoproliferative disease (PTLD); a sequential approach is usual, starting with reduction in immunosuppressives (RI). The efficacy of RI remains poorly defined, particularly in adults. We assessed an algorithm starting with a defined course of RI in all patients, escalating to interferon (IFN) alpha2b, and finally to chemotherapy, in a prospective multicenter phase II study of adult solid organ transplant recipients. The design predated rituximab. Methods Reduction in immunosuppressives: cyclosporine or tacrolimus reduction by 50% for 2 weeks; a further 50% reduction for 1 week if not in complete remission (CR). Intravenous acyclovir was given for the duration of all RI. Patients with less than CR, or any rejection, resumed immunosuppressives and proceeded to IFN 3 MIU/m2/day for up to 3 months; if less than CR, ProMACE-CytaBOM chemotherapy. Results Twenty patients were registered over 60 months; 16 patients with biopsy-proven PTLD were eligible (13 heart, 3 kidney recipients). Median age was 47 (24–75) years. Reduction in immunosuppressives resulted in only 1 of 16 partial responses (12.5%), no CR. Progressive disease occurred in 8 of 16 (50%) and 6 of 16 (38%) experienced rejection. Only 1 of 13 (7%) patients achieved durable CR with IFN. Seven eligible patients received ProMACE-CytaBOM chemotherapy, five of seven (67%) achieving CR, four of five durable beyond 2 years. Conclusions Reduction in immunosuppressives produced no CR, progressive disease and rejection were frequent; response to IFN was rare. A strong case can be made for adding rituximab to RI as initial therapy. Chemotherapy resulted in 57% durable CR, data that are relevant for the up to two thirds of PTLD patients who are refractory to rituximab.
Swinnen, Lode J.; LeBlanc, Michael; Grogan, Thomas M.; Gordon, Leo I.; Stiff, Patrick J.; Miller, Alan M.; Kasamon, Yvette; Miller, Thomas P.; Fisher, Richard I.
X-linked lymphoproliferative disease (XLP) is a condition associated with mutations in the signaling lymphocytic activation molecule (SLAM)-associated protein (SAP; SH2D1A). SAP functions as an adaptor, binding to and recruiting signaling molecules to SLAM family receptors expressed on T and natural killer cells. XLP is associated with extreme sensitivity to primary Epstein-Barr virus (EBV) infection, often leading to a lethal infectious mononucleosis. To investigate EBV-specific immunity in XLP patients, we studied 5 individuals who had survived EBV infection and found CD8(+) T-cell responses numerically comparable with healthy donors. However, further investigation of in vitro-derived CD8(+) T-cell clones established from 2 of these donors showed they efficiently recognized SLAM ligand-negative target cells expressing EBV antigens, but showed impaired recognition of EBV-transformed, SLAM ligand-positive, lymphoblastoid cell lines (LCLs). Importantly, LCL recognition was restored when interactions between the SLAM receptors CD244 and natural killer-, T-, and B-cell antigen (NTBA) and their ligands on LCLs were blocked. We propose that XLP patients' particular sensitivity to EBV, and not to other viruses, reflects at least in part EBV's strict tropism for B lymphocytes and the often inability of the CD8(+) T-cell response to contain the primary infection of SLAM ligand-expressing target cells. PMID:20644117
Hislop, Andrew D; Palendira, Umaimainthan; Leese, Alison M; Arkwright, Peter D; Rohrlich, Pierre S; Tangye, Stuart G; Gaspar, H Bobby; Lankester, Arjan C; Moretta, Alessandro; Rickinson, Alan B
X-linked lymphoproliferative disease (XLP) is a primary immunodeficiency, which most often manifests itself after Epstein-Barr virus (EBV) infection. The main clinical phenotypes include fulminant or fatal infectious mononucleosis, dysgammaglobulinaemia and malignant lymphoma. We have recently cloned the SH2D1A gene, which has been shown to be mutated in approximately 70% of XLP patients. Now we report five novel SH2D1A mutations in patients from five unrelated XLP families. No mutations were found in another three XLP families. In three boys with early onset non-Hodgkin lymphoma (NHL) from two unrelated families a deletion of SH2D1A exon 1 and a splice site mutation were found, respectively. These patients did not show any laboratory or clinical signs of a previous EBV infection. A fourth EBV-uninfected and unrelated boy with a stop mutation in the SH2D1A gene shows only signs of dysgammaglobulinaemia. Development of dysgamma-globulinaemia and lymphoma without evidence of prior EBV infection in four of our patients suggests that EBV is unrelated to these phenotypes, in contrast to fulminant or fatal infectious mononucleosis. The role of SH2D1A as a putative tumour suppressor gene remains to be investigated. PMID:10556288
Brandau, O; Schuster, V; Weiss, M; Hellebrand, H; Fink, F M; Kreczy, A; Friedrich, W; Strahm, B; Niemeyer, C; Belohradsky, B H; Meindl, A
Risk factors for post-transplant tuberculosis.BackgroundPost-transplant tuberculosis (post-TxTB) occurs in 12 to 20% of patients in India and results in the death of 20 to 25% of those patients. Prospective studies on post-TxTB are few.MethodsRenal allograft recipients were studied prospectively for 3.1 (0 to 13.9) median (range) years for incidence, manifestations, risk factors, and prognosis for post-TxTB. Kaplan-Meier analysis was used
George Tharayil John; Viswanathan Shankar; Abi Mookanottle Abraham; Uma Mukundan; Paulose Punnakuzhathil Thomas; Chakko Korula Jacob
Similarly to Epstein-Barr virus (EBV), the human herpesvirus-8 (HHV-8) is a ?-herpesvirus, recently recognized to be associated with the occurrence of rare B cell lymphomas and atypical lymphoproliferations, especially in the human immunodeficiency virus (HIV) infected subjects. Moreover, the human herpesvirus-6 (HHV-6), a ?-herpesvirus, has been shown to be implicated in some non-malignant lymph node proliferations, such as the Rosai Dorfman disease, and in a proportion of Hodgkin’s lymphoma cases. HHV-6 has a wide cellular tropism and it might play a role in the pathogenesis of a wide variety of human diseases, but given its ubiquity, disease associations are difficult to prove and its role in hematological malignancies is still controversial. The involvement of another ?-herpesvirus, the human cytomegalovirus (HCMV), has not yet been proven in human cancer, even though recent findings have suggested its potential role in the development of CD4+ large granular lymphocyte (LGL) lymphocytosis. Here, we review the current knowledge on the pathogenetic role of HHV-8 and human ?-herpesviruses in human lymphoproliferative disorders.
Quadrelli, C.; Barozzi, P.; Riva, G.; Vallerini, D.; Zanetti, E.; Potenza, L.; Forghieri, F.; Luppi, M.
Hepatitis C virus (HCV) is a global health problem affecting 3% of the world's population (about 180 million) and a cause of both hepatic and extrahepatic diseases. B-cell lymphoproliferative disorders, whose prototype is mixed cryoglobulinemia, represent the most closely related as well as the most investigated HCV-related extrahepatic disorder. The association between extrahepatic (lymphoma) as well as hepatic malignancies (hepatocellular carcinoma) has justified the inclusion of HCV among human cancer viruses. HCV-associated manifestations also include porphyria cutanea tarda, lichen planus, nephropathies, thyreopathies, sicca syndrome, idiopathic pulmonary fibrosis, diabetes, chronic polyarthritis, sexual dysfunctions, cardiopathy/atherosclerosis, and psychopathological disorders. A pathogenetic link between HCV virus and some lymphoproliferative disorders was confirmed by their responsiveness to antiviral therapy, which is now considered the first choice treatment. The aim of the present paper is to provide an overview of extrahepatic manifestations of HCV infection with particular attention to B-cell lymphoproliferative disorders. Available pathogenetic hypotheses and suggestions about the most appropriate, currently available, therapeutic approaches will also be discussed. PMID:17552031
Zignego, Anna-Linda; Giannini, Carlo; Ferri, Clodoveo
The X-linked lymphoproliferative syndrome (XLP), also known as Duncan's disease, is an X-linked recessive disorder that is characterized by the inability of affected individuals to mount a sufficient immune response to Epstein-Barr virus (EBV). After EBV primary infection, male family members suffer from severe infectious mononucleosis (IM), aplastic anemia, hypogammaglobulinemia, and a spectrum of lymphoproliferative diseases. Autosomal mode of inheritance with similar symptoms as in XLP has been reported. We have studied two families with EBV-associated syndromes and an X-linked and an autosomal mode of inheritance, respectively. Affected family members presented with severe IM, hemophagocytosis, aplastic anemia, acquired hypogammaglobulinemia, and B-cell lymphoproliferative diseases. PMID:1646073
Schuster, V; Dohrmann, E; Kreth, H W
Mutations in the SH2D1A gene have been described in most patients with the clinical syndrome of X-linked lym- phoproliferative disease (XLP). The diag- nosis of XLP is still difficult given its clinical heterogeneity and the lack of a readily available rapid diagnostic labora- tory test, particularly in patients without a family history of XLP. XLP should always be a consideration
Yasuhiro Tabata; Joyce Villanueva; Susan Molleran Lee; Kejian Zhang; Hirokazu Kanegane; Toshio Miyawaki; Janos Sumegi; Alexandra H. Filipovich
We describe 2 cases of autoimmune lymphoproliferative syndrome (ALPS), which is a rare disorder of auto-immunity, chronic persistent or recurrent lymphadenopathy, splenomegaly, hepatomegaly and hyper gamma globulinemia (1gG, 1gA). Both cases presented in neonatal period which is a rare age of presentation in this disease. A 20 days old female neonate presented with respiratory symptoms which rapidly progressed needing ventilatory support. There was hepatomegaly and no auscultatory findings in the chest. Serial CBCs (complete blood counts) showed persistent leucocytosis with predominant lymphocytosis. Her chest X-ray showed left sided consolidation which responded poorly to antibiotics. Her prompt clinical response to steroids raised the suspicion of autoimmunity and the diagnosis was established after a negative bone marrow examination for leukemia and a positive result for ALPS on flow cytometry. The second case presented with anemia, thrombocytopenia starting in neonatal period followed by persistent lymphadenopathy, hepatosplenomegaly and recurrent infections which responded poorly to antibiotics. Diagnosis was delayed due to low index of suspicion, and finally achieved with multiple radiological studies, histopathology and flow cytometry. PMID:24906264
Naveed, Muhammad; Khamis Butt, Umar Bin; Mannan, Jovaria
Objective and Importance Post-transplant lymphoproliferative disorder (PTLD) is a severe complication after allogeneic hematopoietic stem cell transplantation (allo-HSCT) associated with Epstein-Barr virus (EBV). Clinical presentations Among 263 individuals treated with allo-HSCT for severe aplastic anemia, pure white cell aplasia, T-prolymphocytic leukemia, and relapsed Hodgkin lymphoma, we diagnosed EBV-PTLD in 5 patients. Median age was 29 years (range 19-70 years) and four of five patients were EBV-seropositive prior to HSCT. All five had unrelated EBV-positive donors. In all cases, PTLD occurred within the first year post-transplant (median 4 months). Intervention There were two rapidly fatal courses with extensive organ involvement. Both patients showed lymphopenia and thrombocytopenia. In contrast, the three surviving patients had higher lymphocytes and normal platelet counts, while PTLD was restricted to one site and resolved after 2-4 cycles of rituximab. Conclusion In this case series courses of PTLD showed substantial diversity. PMID:24074746
Meyer, Sara C; Medinger, Michael; Halter, Jörg P; Baldomero, Helen; Hirsch, Hans H; Tzankov, Alexandar; Dirnhofer, Stephan; Passweg, Jakob R; Tichelli, André
The X-linked lymphoproliferative (XLP) syndrome is characterized by a selective immunodeficiency to Epstein-Barr virus (EBV) manifested by severe or fatal infectious mononucleosis and acquired immunodeficiency. Prospective studies in males prior to EBV infection have demonstrate vigorous cytotoxic cellular responses, which are predominantly polyclonally activated alloreactive cytotoxic T cells. Cytotoxic T cells that recognize EBV-infected autologous B cells have been demonstrated. Fatal EBV infections in males with XLP usually result from extensive liver necrosis. Males who survive acute EBV infection demonstrate global cellular immune defects with deficient T-, B- and NK-cell responses. It is hypothesized that uncontrolled alloreactive T-cell responses triggered by EBV-transformed B cells result in the immunopathy of XLP. Genetic studies have demonstrated XLP to be genetically linked to restriction fragment length polymorphisms detected with the DXS42 and DXS37 probes (from Xq26-q27). These probes make detection of carrier females and presymptomatic (EBV-seronegative) XLP males possible. Treatment of males with XLP experiencing acute EBV infection has not been successful, and current efforts are directed at prophylaxis with intravenous gammaglobulin. PMID:2561059
Sullivan, J L; Woda, B A
A total of 398 cases of B cell lymphoproliferative disease were phenotypically characterised by membrane mouse red blood cell (MRBC) receptor, surface immunoglobulin, common acute lymphoblastic leukaemia (CALLA), and FMC7 and T1 monoclonal antibody studies. Relations between chronic lymphocytic leukaemia (CLL), prolymphocytic leukaemia (PLL), and "prolymphocytoid" CLL variants were examined with particular reference to the expression of FMC7. In addition, the reactivity of TU1 monoclonal antibody with B cell disorders was established. The results suggest that despite some heterogeneity most cases may be characterised by their phenotypic patterns and that these investigations provide a reproducible basis for classification.
Scott, C S; Limbert, H J; MacKarill, I D; Roberts, B E
Background Although cardiovascular disease is thouht to be common in cirrhosis, there are no systematic investigations on the prevalence of electrocardiographic (ECG) abnormalities in these patients and data on the occurrence of post-transplant cardiac events in comparison with the general population are lacking. We aimed to study the prevalence and predictors of ECG abnormalities in patients with cirrhosis undergoing liver transplantation and to define the risk of cardiac events post-transplant compared to the general population. Methods Cirrhotic patients undergoing first-time liver transplantation between 1999–2007 were retrospectively enrolled. ECGs at pre-transplant evaluation were reviewed using the Minnesota classification and compared to healthy controls. Standardized incidence ratios for post-transplant cardiac events were calculated. Results 234 patients with cirrhosis were included, 186 with an available ECG (36% with alcoholic and 24% with viral cirrhosis; mean follow-up 4 years). Cirrhotics had a prolonged QTc interval, a Q wave, abnormal QRS axis deviation, ST segment depression and a pathologic T wave more frequently compared to controls (p?0.05 for all). Arterial hypertension, older age, cirrhosis severity and etiology were related to ECG abnormalities. Compared to the general Swedish population, patients were 14 times more likely to suffer a cardiac event post-transplant (p?0.001). A prolonged QTc interval and Q wave were related to post-transplant cardiac events (p?0.05 for all). Conclusions Pre-transplant ECG abnormalities are common in cirrhosis and are associated with cardiovascular risk factors and cirrhosis severity and etiology. Post-transplant cardiac events are more common than in the general population.
Signaling lymphocyte activation molecule (SLAM)-associated protein (SAP) is a short intracellular molecule that is mutated in humans with X-linked lymphoproliferative (XLP) disease. Although the exact role and mechanism of action of SAP are not known, it has the capacity to interact with the cytoplasmic region of SLAM and other related immune cell receptors. As SAP is composed almost exclusively of
Sylvain Latour; Gerald Gish; Cheryl D. Helgason; R. Keith Humphries; Tony Pawson; André Veillette
Abstract Invasive fungal infections (IFIs) seem to be a relevant cause of morbidity and mortality in patients with chronic lymphoproliferative disorders. We studied retrospectively the epidemiology, clinical manifestations and outcome of invasive fungal infections in 42 patients with lymphoproliferative diseases, treated between January 2004 and February 2012 for probable or proven IFI. In our entire population (1355 patients) of chronic lymphoproliferative malignancies, the incidence of probable/proven IFI was 3% (molds 2.3%, yeasts 0.5%, mixed infections 0.2%). Eight patients developed a yeast infection documented by blood cultures in seven cases and by the microscopic observation of Candida spp. in the vitreum after vitrectomy in one case. Among molds we diagnosed three proven infections by histologic evidence of Aspergillus spp. (n = 2) and Mucor (n = 1) in the lung and 28 probable mycoses. Three mixed infections from both molds and yeasts were also observed. Twenty-two cases showed positivity of galactomannan antigen in the serum (n = 16), in bronchoalveolar lavage (BAL) fluid (n = 4) or in both (n = 2). Cultures were positive in 11 cases. The overall rate of response to therapy was 64%. Fungal-attributable mortality rate was 17%, with a significant difference between molds and yeasts (16% vs. 25%, p = 0.03). At univariate analysis, the only risk factors related to mortality were severe and prolonged neutropenia (p = 0.003) and age (p = 0.03). Among molds, the rapid start of antifungals was probably partially responsible, together with new drugs, for the reduction of mortality, despite the severe immunosuppression of these patients. PMID:24138328
Nosari, Anna Maria; Pioltelli, Maria Luisa; Riva, Marta; Marbello, Laura; Nichelatti, Michele; Greco, Antonino; Molteni, Alfredo; Vismara, Eleonora; Gabutti, Cristina; Volonterio, Alberto; Lombardi, Pierluigi; Morra, Enrica
The results of the analysis of suspected lymphoproliferative disorders using flow cytometry (FACS II) over the past 12 months have been evaluated and assessed with respect to “conventional” microscopical examination. The major advantages in using these methods is the speed, the number of parameters which are capable of measurement, the sensitivity, and the ability to quantitate large numbers of cells
Ian G. Barr; Ban-Hock Toh
Although cardiac transplantation is life-saving, morbidities from immunosuppression are significant. EoE is a complication of calcineurin inhibitors following liver transplant causing feeding intolerance, weight loss, vomiting, and dysphagia. There are limited reports of EoE following heart transplantation. We performed a retrospective single-center review of pediatric cardiac transplant patients from 2000 to 2010. A case-control analysis of patients with and without EoE was performed evaluating heart transplantation outcomes such as rates of rejection, CAV, PTLD, and graft loss. Eighty-six transplants were performed in 84 patients; 34 (40%) underwent diagnostic endoscopy, and 10 (12%) had EoE. Median time to diagnosis of EoE was 3.7 yr (IQR: 2.0-5.2). There were no differences in demographics or use of induction medications between patients with or without EoE. Patients with EoE had fewer episodes of treated rejection (1.0 vs. 2.5; p = 0.04). Four of 10 (40%) EoE patients had PTLD compared with only 2/24 (8%) of those without EoE (p = 0.048; OR 7.33 [95% CI: 1.1-50.2]). There were no differences in CAV or graft loss between groups. EoE should be considered as a cause of GI symptoms in children after cardiac transplantation and may be associated with fewer rejection episodes and increased rates of PTLD, thus representing a marker of over-immunosuppression. PMID:24931365
Kindel, Steven J; Joy, Brian F; Pahl, Elfriede; Wald, Eric L
PTLDs are a well-recognized and potentially fatal complication after intestinal transplantation. We analyzed the incidence, clinical features, and outcome in a 63 intestinal transplantation series performed in our unit between October 1999 and July 2011. Types of graft included ISB (n = 23), LSB (n = 20), and MV (n = 20). Patients were categorized into three groups of immunosuppression: I (n = 43) received basiliximab, tacrolimus, and steroids; II (n = 11) thymoglobulin and tacrolimus, and III (n = 9) alemtuzumab and tacrolimus. EBV status was serially assessed. All PTLD cases were biopsied to establish histopathological diagnosis. The incidence of PTLD was 14.2% (9/63). Median onset of PTLD after transplant was four months (range: 0.5-28), within first postoperative year in 6 (66.6%) patients. Fever was the most common symptom. Graft removal was needed in four patients (44%). The patient survival rate was 66.6% (6/9). We have not found any association between PTLD and immunosuppression regimen or transplant type. However, there was a statistical association with EBV active infection. PMID:23730927
Ramos, Esther; Hernández, Francisco; Andres, Ane; Martínez-Ojinaga, Eva; Molina, Manuel; Sarría, Jesús; Lopez-Santamaria, Manuel; Prieto, Gerardo
X-linked lymphoproliferative syndrome (XLP) is a rare, often fatal, primary immunodeficiency disease characterized by an abnormal response to Epstein-Barr virus (EBV) infection. The gene responsible for XLP has been identified as SH2D1A/DSHP/SLAM-associated protein (SAP). The major clinical manifestations include fulminant infectious mononucleosis, lymphoproliferative disorder, and dysgammaglobulinemia. Affected males uncommonly present with lymphocytic vasculitis in addition to aplastic anemia. In this study, we describe a Japanese XLP patient who presented with hypogammaglobulinemia following acute EBV-induced infectious mononucleosis in the infancy and later had systemic lymphocytic vasculitis and hemophagocytic lymphohistiocytosis in the adulthood, which resolved by steroid pulse therapy. The patient's SAP gene was found to harbor a missense mutation (His8Asp), presumably resulting in defective expression of SAP in T cells. Biopsy specimens of lung and skin disclosed that CD8+ T cells predominantly infiltrated vascular vessels. However, immunohistochemical examination showed that EBV-infected cells were not identifiable in the vessels. We propose that T-cell-mediated immune dysregulation in XLP can cause vasculitis by EBV infection-unrelated mechanism. PMID:15682426
Kanegane, Hirokazu; Ito, Yoshikiyo; Ohshima, Koichi; Shichijo, Takeshi; Tomimasu, Kunio; Nomura, Keiko; Futatani, Takeshi; Sumazaki, Ryo; Miyawaki, Toshio
Salivary gland lymphoproliferative disorders (SGLD) are very rare tumors and clinicopathological data is sparse. In a Canadian series of 30 cases, extracted from the surgical pathology files of The Ottawa Hospital between 1990 and 2010, a clinical, histopathological, and immunophenotypic analysis was conducted. Tumors were staged using the Ann Arbor staging and classified using the World Health Organization 2008 classification. There were 15 salivary gland (SG) primary lymphomas with localized disease, predominantly mucosa associated lymphoid tissue type marginal zone lymphoma (MALT-L), but with a significant incidence of low grade follicular lymphoma (FL) and diffuse large B cell phenotype as well. There were 7 systemic SG lymphomas and 5 patients were diagnosed with lymphoproliferative disorders originating from intra-parotid lymph nodes. Finally, the remaining 3 cases represented reactive sialadenitis. A literature review was conducted and our primary lymphoma group was compared to those from other countries. SGLDs are predominantly B cell lymphomas that develop in older adults. Primary tumors, which have MALT-L and low grade FL characteristics, have a favorable survival, however MALT-L have a high rate of relapse. A minority of SG lesions are excised secondary to lymphomas that definitely arose from intra-parotid lymph nodes. PMID:23821219
Paliga, A; Farmer, J; Bence-Bruckler, I; Lamba, M
Pre- and posttransplant risk estimation in kidney transplantation is important for the selection of appropriate treatment strategies. Recently, using new immunologic tests, we made observations within the framework of the Collaborative Transplant Study that may influence clinical practice. Complement-dependent lymphocytotoxic panel reactivity as a measure of anti-HLA sensitization, although criticized for its low sensitivity, is a useful indicator of an
C Süsal; S Pelzl; T Simon; G Opelz
ObjectiveLymphoproliferative lesions of the ocular adnexa were analyzed to examine (1) the suitability of the Revised European-American Lymphoma (REAL) classification for the subtyping of the lymphomas in these sites; (2) the predictive value of the REAL classification for the evolution of these tumors; and (3) the frequency and prognostic impact of tumor type, location, proliferation rate (Ki-67 index), p53, and
Sarah E Coupland; Lothar Krause; Henri-Jacques Delecluse; Ioannis Anagnostopoulos; Hans-Dieter Foss; Michael Hummel; Norbert Bornfeld; William R Lee; Harald Stein
Familial aggregation of lymphoproliferative disorders from the Scandinavian family cancer database Print This Page Familial Aggregation of Lymphoproliferative Disorders from the Scandinavian Family Cancer Database Our Research
Liver transplantation (LT) is a standard treatment for children with end-stage liver disease, standing at more than 90% survival rate after one yr, and at over a 70% survival rate after five yr. The majority of transplanted children enjoy an excellent quality of life but complications can occur in the long term, and can develop subclinically in otherwise well children; there are various underestimated nutritional and metabolic aspects, including the so-called post-transplant metabolic syndrome (PTMS). During the post-transplant period, the use of immunosuppressants, corticosteroids, calcineurin inhibitors, and the presence of risk factors, including non-alcoholic fatty liver disease (NAFLD), and kidney and bone complications have been largely implicated in PTMS development. Strategies to reduce the progression of PMTS should include careful screening of patients for diabetes, dyslipidemia, and obesity, and to support weight reduction with a carefully constructed program, particularly based on diet modification and exercise. With early identification and appropriate and aggressive management, excellent long-term health outcomes and acceptable graft survival can be achieved. PMID:23496113
Nobili, Valerio; de Ville de Goyet, Jean
Anti-hepatitis C virus (HCV) antibody prevalence was investigated in 228 patients with lymphoproliferative disorders (LPDs). Twenty-six of 228 (11.40%) patients with LPDs were positive for anti-HCV which was higher than the donor population (P = 0.0007). Nine of 98 cases with non-Hodgkin’s lymphoma, five of 47 cases with multiple myeloma, seven of 36 cases with Hodgkin’s disease, four of 38
S Paydas; B Kiliç; B Sahin
The immunopathogenesis of 25 kindreds affecting 100 males with the X-linked lymphoproliferative syndrome (XLP) is being studied comprehensively by our registry and laboratory group. XLP is a combined variable immune deficiency with Epstein-Barr virus (EBV) induced phenotypes of: (1) fatal infectious mononucleosis (IM), (2) chronic IM progressive to malignant lymphoma, (3) acute IM progressive to acquired agammaglobulinemia or (4) malignant lymphoma. Cytogenetic studies of peripheral blood lymphocytes from 15 surviving males and 21 carrier females reveal random karyotype errors in several kindreds. Often polyclonal Ig or selective IgM increases and lymphocytosis with plasmacytoid forms typifies the IM phenotypes. Weakly reactive EBV-specific antibodies are found and anti-EB nuclear antigen is lacking. Antibodies to EBV are paradoxically elevated in female carriers. Initially all lymphoid tissues show immunoblastic proliferation with plasma cell differentiation and focal to extensive necrosis. Thymus gland and other lymphoid organs become depleted in T cell regions and Hassall's corpuscles may become destroyed. Multinucleated giant cells may be seen destroying the corpuscles or calcified corpuscles are found. The lymphoid infiltrates and lesions resemble graft-versus-host response in the fatal IM phenotype. Extensive necrosis in lymph nodes and deficient Ig secretion of B-cells characterize acquired agammaglobulinemia phenotypes. The malignant lymphomas span the spectrum of B cell differentiation with most being immunoblastic sarcomas. One case probably was monoclonal thus far, others are being studied. EBV DNA hybridization of tissues from 7 patients with fatal IM revealed 1 to 20 EBV genome equivalents per cell. The patients lacked appropriate EBV antibody responses. Our studies of XLP support the hypothesis that immune deficiency the EBV permits chronic and fatal lymphoproliferative diseases in XLP following EBV infections. Owing to this knowledge, rational bases for prevention by genetic counseling and by providing high titer gammaglobulin and antiviral therapy is being attempted. PMID:6274747
Purtilo, D T
Primary graft dysfunction (PGD) and bronchiolitis obliterans (BO) are the leading causes of morbidity and mortality after lung transplantation. Reports from clinical and rodent models suggest the implication of IL-17A in either PGD or BO. We took advantage of the heterotopic trachea transplantation model in mice to study the direct role of IL-17A in post-transplant airway lesions. Across full MHC barrier, early lesions were controlled in IL-17A-/- or anti-IL17 treated recipients. In contrast, IL-17A deficiency did not prevent subsequent obliterative airway disease (OAD). Interestingly, this early protection occurred also in syngeneic grafts and was accompanied by a decrease in cellular stress, as attested by lower HSP70 mRNA levels, suggesting the involvement of IL-17A in ischemia-reperfusion injury (IRI). Furthermore, persistence of multipotent CK14+ epithelial stem cells underlined allograft protection afforded by IL-17A deficiency or neutralisation. Recipient-derived ??+ and CD4+ T cells were the major source of IL-17A. However, lesions still occurred in the absence of each subset, suggesting a high redundancy between the innate and adaptive IL-17A producing cells. Notably, a double depletion significantly diminished lesions. In conclusion, this work implicated IL-17A as mediator of early post-transplant airway lesions and could be considered as a potential therapeutic target in clinical transplantation.
Lemaitre, Philippe H.; Vokaer, Benoit; Charbonnier, Louis-Marie; Iwakura, Yoichiro; Estenne, Marc; Goldman, Michel; Leo, Oberdan; Remmelink, Myriam; Le Moine, Alain
Primary graft dysfunction (PGD) and bronchiolitis obliterans (BO) are the leading causes of morbidity and mortality after lung transplantation. Reports from clinical and rodent models suggest the implication of IL-17A in either PGD or BO. We took advantage of the heterotopic trachea transplantation model in mice to study the direct role of IL-17A in post-transplant airway lesions. Across full MHC barrier, early lesions were controlled in IL-17A(-/-) or anti-IL17 treated recipients. In contrast, IL-17A deficiency did not prevent subsequent obliterative airway disease (OAD). Interestingly, this early protection occurred also in syngeneic grafts and was accompanied by a decrease in cellular stress, as attested by lower HSP70 mRNA levels, suggesting the involvement of IL-17A in ischemia-reperfusion injury (IRI). Furthermore, persistence of multipotent CK14(+) epithelial stem cells underlined allograft protection afforded by IL-17A deficiency or neutralisation. Recipient-derived ??(+) and CD4(+) T cells were the major source of IL-17A. However, lesions still occurred in the absence of each subset, suggesting a high redundancy between the innate and adaptive IL-17A producing cells. Notably, a double depletion significantly diminished lesions. In conclusion, this work implicated IL-17A as mediator of early post-transplant airway lesions and could be considered as a potential therapeutic target in clinical transplantation. PMID:23936171
Lemaître, Philippe H; Vokaer, Benoît; Charbonnier, Louis-Marie; Iwakura, Yoichiro; Estenne, Marc; Goldman, Michel; Leo, Oberdan; Remmelink, Myriam; Le Moine, Alain
Background: Chronic hepatitis C virus (HCV) infection is associated with a variety of extrahepatic disorders that may relate to direct or indirect effects of virus infection. Increased levels of soluble forms of tumor necrosis factor (TNF) receptors I and II, found in lymphoproliferative and infectious diseases, can interfere with TNF induced apoptotic cell death. The aim of the present study
Stefano Realdon; Patrizia Pontisso; Fausto Adami; Livio Trentin; Franco Noventa; Alessia Ferrari; Irene Migliorato; Angelo Gatta; Alfredo Alberti
Posterior reversible encephalopathy syndrome (PRES) is characterized by headache, nausea, vomiting, seizures and visual disturbances. PRES has been usually associated with hypertension, chronic renal disease, malignancy and chemotherapeutic agents. We report the association of PRES with Autoimmune lymphoproliferative syndrome, which to our best knowledge has not been reported before.
Chandramohan, Vaishnavi; Nagarajan, Vinoth Ponnurangam; Sathyamoorthi, Muthamil Selvan; Kumar, Sathish; Shanmugasundaram, Chitrambalam; Periakaruppan, Gokulakrishnan; Scott, Julius Xavier
Transplantation is considered definitive therapy for acute or chronic irreversible pathologies of the liver, and the increased survival rates are mainly due to improved immunosuppressive therapies and surgical techniques. However, early diagnosis of possible graft dysfunction is crucial to liver graft survival. Diagnostic imaging plays an important role in the evaluation of the liver before and after transplant and in the detection of complications such as vascular and biliary diseases, acute and chronic rejection and neoplastic recurrence. Integrated imaging using color-Doppler, CT, MRI and traditional x-ray reach a high level of sensitivity and specificity in the management of transplanted patients.
Drudi, F.M.; Pagliara, E.; Cantisani, V.; Arduini, F.; D'Ambrosio, U.; Alfano, G.
Autoimmune Pancytopenia; Autoimmune Lymphoproliferative Syndrome (ALPS); Evans Syndrome; Idiopathic Thrombocytopenic Purpura; Anemia, Hemolytic, Autoimmune; Autoimmune Neutropenia; Lupus Erythematosus, Systemic; Inflammatory Bowel Disease; Rheumatoid Arthritis
BACKGROUND Primary central nervous system (CNS) post-transplantation lymphoproliferative disorder (PCNS-PTLD) is a rare complication of solid organ transplantation. The objectives of this study were to define the clinical, radiologic, and pathologic features of this disease and to explore the impact of treatment on patient outcomes. METHODS The authors reviewed the databases of participating institutions of the International Primary CNS Lymphoma Collaborative Group for cases of PCNS-PTLD. Thirty-four patients who had pathologically confirmed PCNS-PTLD without evidence of systemic PTLD were investigated retrospectively. RESULTS The median time from transplantation to diagnosis of PCNS-PTLD was 4.4 years. Disease usually was multifocal and involved any location of the brain but was most common in the cerebral hemispheres, usually in the subcortical white matter or basal ganglia. Radiographically, all lesions enhanced either homogenously or in a ring-enhancing pattern. Cerebral biopsy was required to establish diagnosis in most patients. Most patients had monomorphic, Epstein-Barr virus (EBV)-positive disease of B-cell origin. Response rates were high regardless of treatment type, and the median survival was 47 months. Age was the only factor predictive of survival. CONCLUSIONS The current study demonstrated that PCNS-PTLD is typically an EBV-induced B-cell lymphoma that is responsive to treatment with favorable survival in many patients. An aggressive approach to tissue confirmation of diagnosis and treatment with chemotherapy or radiotherapy should be strongly considered.
Cavaliere, Robert; Petroni, Gina; Lopes, Maria B.; Schiff, David
Experiments were performed to examine expression of proto-oncogenes and other related genes in ten cases of chronic T-cell lymphoproliferative disorders. The helper vs. suppressor nature of the T-cells was determined using monoclonal antibodies. RNA was isolated from peripheral blood mononuclear cells and/or lymph node sections and 5'-end labelled with ..gamma..-/sub 32/P-ATP. RNA preparations were hybridized under stringent conditions to an excess of nitrocellulose-bound specific cloned DNA; autoradiographs were analyzed by microdensitometry. Hybridizations of PHA-activated T-cells to various probes as well as hybridizations of RNA samples to parent plasmid were negative in all experiments. Results revealed increased expression of K-ras, B-lym, transferrin receptor, ..cap alpha..-tubulin and ..cap alpha..-interferon in 5/5 helper T-cell lymphoproliferative disorders, while 5/5 suppressor T-cell disorders demonstrated levels of hybridization to these clones no higher than background. However, studies of T-suppressor disorders demonstrated enhanced levels of ..beta..-interferon-specific RNA in 5/5 patients, an increase not apparent in T-helper chronic lymphoproliferative disorders. There was no correlation of this pattern of gene expression with the aggressive nature of the disease since T-cells from 2/5 suppressor disorders were actively proliferating.
Doerge, M.J.; Hooper, W.C.; Phyliky, R.L.; Witzig, T.E.; Banks, P.M.; Li, C.Y.; Woloschak, G.E.
Lymphomatoid papulosis (LyP) and cutaneous anaplastic large cell lymphoma (ALCL) belong to the spectrum of cutaneous CD30+ lymphoproliferative disorders, an indolent form of T-cell lymphoproliferative disease. We reviewed 21 cases of CD30+ lymphoproliferative lesions expressing cytotoxic profile (CD8+). Seven cases of cutaneous ALCL, 2 cases of systemic ALCL involving the skin, and 12 cases of LyP. The cases of LyP were predominated by small lymphocytes exhibiting a prominent epidermotropic pattern consistent with either type B or type D LyP. Four cases showed co-expression of CD56. The ALCL cases included myxoid features, pseudoepitheliomatous change, and an intravascular component. In all cases that were primary in the skin an indolent clinical course was seen while one patient with systemic myxoid ALCL is in remission following systemic multiagent chemotherapy. The paucity of other neutrophils and eosinophils and concomitant granulomatous inflammation were distinctive features in cases of type B and type D LyP. CD30 and CD45 Ro positivity and a clinical course typical of LyP were useful differentiating features from an aggressive cytotoxic CD8+ T cell lymphoma. In all cases that were primary in the skin an indolent clinical course was observed. CD30 and CD45 Ro positivity and a clinical course typical of LyP were useful in preventing a misdiagnosis of an aggressive cytotoxic CD8+ T cell lymphoma. PMID:23189966
Plaza, Jose A; Feldman, Andrew L; Magro, Cynthia
X-linked lymphoproliferative disease (XLP1), described in the mid-1970s and molecularly defined in 1998, and XLP2, reported in 2006, are prematurely lethal genetic immunodeficiencies that share susceptibility to overwhelming inflammatory responses to certain infectious triggers. Signaling lymphocytic activation molecule-associated protein (SAP; encoded by SH2D1A) is mutated in XLP1, and X-linked inhibitor of apoptosis (XIAP; encoded by BIRC4) is mutated in XLP2. XLP1 is a disease with multiple and variable clinical consequences, including fatal hemophagocytic lymphohistiocytosis (HLH) triggered predominantly by Epstein-Barr virus, lymphomas, antibody deficiency, and rarer consequences of immune dysregulation. To date, XLP2 has been found to cause HLH with and without exposure to Epstein-Barr virus, and HLH is commonly recurrent in these patients. For both forms of XLP, the only curative therapy at present is allogeneic hematopoietic cell transplantation. Beyond their common X-linked locus and their requirement for normal immune responses to certain viral infections, SAP and XIAP demonstrate no obvious structural or functional similarity, are not coordinately regulated with respect to their expression, and do not appear to directly interact. In this review, we describe the genetic, clinical, and immunopathologic features of these 2 disorders and discuss current diagnostic and therapeutic strategies. PMID:20660790
Filipovich, Alexandra H; Zhang, Kejian; Snow, Andrew L; Marsh, Rebecca A
X-linked lymphoproliferative syndrome (XLP, also known as Duncan's disease) is characterised by an extreme sensitivity to Epstein Barr virus (EBV), resulting in a complex phenotype manifested by severe or fatal mononucleosis, acquired hyogammaglobulinemia and malignant lymphoma. The gene responsible for XLP has recently been identified by a positional cloning and a functional cloning approach and encodes a small cytoplasmic protein involved in signal transduction of T and NK cells. The identification of the XLP gene will permit direct diagnosis of XLP in families with a single affected male. Recent progress in immunobiology and genetics of this primary immunodeficiency disease are presented. PMID:11109949
Stéphan, J L
Immunosuppression management in post-transplant malignancy is challenging because of a lack of objective immunologic assessment tools. The ImmuKnow assay measures the ATP level from CD4 T cells, quantifying cell-mediated immunity and providing an insight into the immune status of transplant recipients. Its potential use in patients with post-transplant de novo malignancy was evaluated. Thirteen adult transplant patients with de novo malignancy were divided into survivors (n = 9) and non-survivors (n = 4) after malignancy treatment. Tacrolimus and the ImmuKnow levels were monitored before, during, and after malignancy treatment. The ImmuKnow level in non-survivors group was significantly lower before and after malignancy treatment compared to survivors group (p = 0.013 and 0.0014 respectively). In survivor group, the ImmuKnow level was significantly decreased during malignancy treatment (p = 0.019) but recovered to the initial level after the treatment. However, in non-survivor group, the ImmuKnow level remained suppressed throughout the observed period despite a reduction in immunosuppressive drug levels. The ImmuKnow assay can be an objective means evaluating immune status of patients with de novo malignancy. The ImmuKnow assay can express the degree of immune suppression induced by chemotherapeutic or radiation therapy and may be a useful tool in optimizing the timing of re-introduction of immunosuppression after malignancy treatment.
Uemura, Tadahiro; Riley, Thomas R.; Khan, Akhtar; Hollenbeak, Christopher; Schreibman, Ian; Ghahramani, Nasrollah; Reeves, Brian; Domen, Ronald E.; Zander, Dani S.; Kadry, Zakiyah
To clarify the significance of post-transplant serum ferritin (SF), we retrospectively assessed pre- and post-transplant SF. Among 256 patients undergoing allogeneic stem cell transplant (SCT) for hematologic malignancies between 2000 and 2011, those who had relapsed within 1 year were excluded, and 110 patients surviving for more than 1 year were included in the analysis. The cut-off value of SF was 1000 ng/mL, and four pre- and post-SF groups were defined: low-low (n = 62), low-high (n = 12), high-low (n = 13) and high-high (n = 23). Outcomes at 5 years for each group were as follows: overall survival (OS) 88.2, 38.1, 92.3 and 76.7%, respectively, p = 0.004, and non-relapse mortality (NRM) 11.3, 53.6, 7.7 and 18.9%, respectively, p = 0.037. Patients receiving larger transfusion volumes or developing chronic graft-versus-host disease (GVHD) demonstrated higher 1-year SF values. In multivariate analysis for OS and NRM, low-high SF remained a significant predictor of OS (hazard ratio [HR] = 3.49, 95% confidence interval [CI]: 1.10-11.0, p = 0.032) and NRM (HR = 2.95, 95%CI: 1.04-8.36, p = 0.041). These results suggest that the elevation of SF at 1 year after SCT, which may reflect transfusion and the development of chronic GVHD, may have an aggravating influence on outcomes after SCT. This study provides a clue to clarifying the clinical significance of SF in a transplant setting. PMID:24024470
Tachibana, Takayoshi; Tanaka, Masatsugu; Numata, Ayumi; Matsumoto, Kenji; Tomita, Naoto; Fujimaki, Katsumichi; Taguchi, Jun; Sakai, Rika; Fujita, Hiroyuki; Fujisawa, Shin; Maruta, Atsuo; Ishigatsubo, Yoshiaki; Kanamori, Heiwa
Accumulating evidence indicates that bone marrow microenvironment plays an important role in the pathogenesis of some myeloid and lymphoid hematological malignancies (HM). Among different environmental associated parameters, those related to functional, cytogenetic and immunological integrity of mesenchymal stromal cells (MSC) are particularly relevant. Functional alterations and immunophenotypic abnormalities have been described in MSC obtained from HM patients. These data seem to confirm the defective biological pattern of MSC especially in myeloid diseases, while MSC cytogenetic profile in HM is still an open question, because it is not clear whether BM stromal cells are "culprit or bystander" displaying or not an abnormal karyotype. Contradictory findings were reported in different HM but the functional implications of altered MSC karyotype need to be further addressed also in light of a clinical use of MSC. A "pathological" in vivo supportive function of endogenous MSC, which provide important survival and drug resistance signals to leukemic cells especially in lymphoproliferative disorders, is suggested. Thus, the mechanisms underlying these protective versus cytotoxic effects exerted by MSC on leukemic cells need further investigations. PMID:24389177
Campioni, Diana; Voltan, Rebecca; Tisato, Veronica; Zauli, Giorgio
Background: Myeloproliferative neoplasms likely involve both myeloid and lymphoid lineages. Nevertheless, the coincidence of chronic myeloproliferative and lymphoproliferative diseases in the same patient is a rare phenomenon. Methods: We report a case of a patient having essential thrombocythemia (ET) and B-chronic lymphocytic leukemia (B-CLL). In this patient and in 2 relatives with lymphoproliferative disorders, we searched for JAK2V617F mutation in
Caterina Musolino; Alessandro Allegra; Giuseppa Penna; Raffaella Centorrino; Maria Cuzzola; Arianna D’Angelo; Pasquale Iacopino; Andrea Alonci
We report the case of a 68-year-old woman who underwent heart transplantation for hypertrophic cardiomyopathy. Two months after the transplant she developed mild fever and dyspnea with a marked drop in left ventricle ejection fraction of 31%. Coronary angiography was negative for cardiac allograft vasculopathy. Endomyocardial biopsy revealed ischemic damage with no evidence of acute cellular rejection, antibody-mediated rejection or viral myocarditis. A neoplastic process was suspected even though full-body computerized tomography was negative for malignancy. The patient died 4 months after transplantation. The autopsy showed acute antero-septal myocardial infarction due to a nodular epicardial EBV-related posttransplant lymphoproliferative disorder (PTLD) infiltrating the left anterior descending coronary artery with occlusive neoplastic thrombosis. We highlight two major aspects of this case: (1) the unusual occurrence of early PTLD involving the cardiac allograft and causing a fatal outcome, (2) the application of an immunological technique for HLA-DRB1 typing to posttransplant paraffin-embedded autopsy material to identify the recipient origin of this early malignancy, thus excluding a possible donor-transmitted neoplasm. PMID:23331771
Fedrigo, M; Poli, F; Esposito, G; Feltrin, G; Toscano, G; d'Agostino, C; Schiavon, B; Gerosa, G; Amadori, A; Valente, M; Thiene, G; Angelini, A
AIMS: To determine whether the proliferation rates of tumour cells may relate to prognosis and reflect disease activity. METHODS: Blood mononuclear cells from 155 patients with B cell (n = 120) or T cell (n = 35) chronic lymphoproliferative disorders were tested with the monoclonal antibody Ki-67 by indirect immunoperoxidase or immunoalkaline phosphatase techniques. B cell diseases included chronic lymphocytic leukaemia (CLL), CLL in prolymphocytic transformation (CLL/PL), prolymphocytic leukaemia (B-PLL) and non-Hodgkin's lymphoma (B-NHL) in leukaemic phase. The T cell diseases comprised large granular lymphocyte (LGL) leukaemia, T-PLL, and T-NHL. RESULTS: These showed significantly higher proportions of Ki-67 positive cells in T cell (11.2%) than in B cell (2.9%) disorders (p < 0.001). The highest values were found in NHL of both B and T cell types, particularly when low grade disease transformed to high grade. The lowest percentages of Ki-67 positive cells were found in CLL (1.4%) and LGL leukaemia (1.7%); intermediate values were seen in B PLL (3.3%) and T PLL (5.8%). CONCLUSIONS: There is a positive correlation between prognosis and proliferation rates in chronic B and T cell lymphoproliferative disorders. Estimation of Ki-67 in circulating leukaemic cells could be used to determine prognosis in low grade malignancies. Images
de Melo, N.; Matutes, E.; Cordone, I.; Morilla, R.; Catovksy, D.
X-linked lymphoproliferative disease (XLP) and IL-2-inducible T cell kinase (ITK) deficiency are rare immunodeficiencies with a spectrum of clinical manifestations. Although there are no official guidelines for allogeneic hematopoietic stem cell transplantation (HSCT) in these patients, previous reports have shown that reduced intensity conditioning regimens provide successful engraftment with limited toxicity. Here, we report on three children with XLP and one with ITK deficiency, who underwent successful HSCT using a rituximab containing conditioning regimen, and review the current literature. PMID:24584040
Shamriz, Oded; Vilk, Shoshana Revel; Wolf, Dana G; Ta-Shma, Asaf; Averbuch, Diana; Weintraub, Michael; Stepensky, Polina
Chronic hepatitis C (HCV) infection in patients with primary immunodeficiency increases the risk of an accelerated progression\\u000a of HCV-related liver disease. Here, we report a patient with X-linked lymphoproliferative syndrome infected with HCV and Epstein-Barr\\u000a virus (EBV). After combination treatment with interferon ?-2b and ribavirin, clearance of HCV-RNA was achieved, and noteworthily,\\u000a EBV DNA also became undetectable.
Nicola Strnad-Trojan; Richard Linde; Janine Reichenbach; Jörg Trojan; Stefan Zeuzem; Stefan Zielen
Mixed cryoglobulinaemia (MC) is a systemic vasculitis involving small vessels (arterioles, capillaries, venules). The histological hallmark of the disease is the leukocytoclastic vasculitis secondary to the vascular deposition of circulating immune-complexes (CIC), mainly cryoglobulins and complement. The immune-mediated vasculitic lesions are responsible for different MC clinical features, including cutaneous and visceral organ involvement. Hepatitis C virus (HCV) represents the triggering factor in the large majority of MC patients (>90%). Moreover, several epidemiological, clinico-pathological and laboratory investigations suggested a possible role for HCV in a wide spectrum of immuno-lymphoproliferative disorders; namely, porphyria cutanea tarda, diabetes, polyarthritis, lung fibrosis, poly-dermatomyositis, thyroiditis, thyroid cancer, B-cell non-Hodgkin's lymphomas (B-NHL), etc. Renal involvement with or without MC syndrome can be observed in HCV-infected individuals. There is great geographical etherogeneity in the prevalence of HCV-related disorders. This epidemiological observation suggests a multifactorial and multistep process in the pathogenesis of these conditions, involving other unknown genetic and/or environmental factors. HCV lymphotropism may explain the mono-oligoclonal B-lymphocyte expansion observed in HCV-infected individuals, particularly in MC patients. The 'benign' lymphoproliferative disorder, classified as monotypic lymphoproliferative disorders of undetermined significance (MLDUS), may be responsible for the wide production of CIC, including cryoglobulins, rheumatoid factor and different organ and non-organ specific autoantibodies. The consequence is the appearance of various HCV-related autoimmune diseases, including MC syndrome. This latter may be complicated by B-NHL in 10% of the cases; moreover, HCV infection has been confirmed in a significant percentage of 'idiopathic B-NHL. For a correct therapeutic approach to cryoglobulinaemic vasculitis, as well as to other HCV-related disorders, we should deal with concomitant, conflicting conditions: HCV infection, autoimmune and lymphoproliferative alterations. In this scenario, we can treat the diseases at three different levels by means of etiologic, pathogenetic and/or symptomatic therapies. The eradication of HCV by combined interferon and ribavirin therapy can be achieved in only a minority of cases. On the contrary, severe complications such as glomerulonephritis, sensory-motor neuropathy or diffuse vasculitis can be effectively treated by a combination of corticosteroids, plasma exchange and cyclophosphamide. More recently, a pathogenetic treatment with rituximab, a monoclonal chimeric antibody that binds to the B-cell surface antigen CD20 with selective B-cell blockade, was proposed in patients with HCV-related MC syndrome. PMID:15285001
Ghinoi, A; Mascia, M T; Puccini, R; Ferri, C
Autoimmune lymphoproliferative syndrome (ALPS) is caused by genetic defects decreasing Fas function and is characterized by lymphadenopathy/splenomegaly and expansion of CD4/CD8 double-negative T cells. This latter expansion is absent in the ALPS variant named Dianzani Autoimmune/lymphoproliferative Disease (DALD). In addition to the causative mutations, the genetic background influences ALPS and DALD development. We previously suggested a disease-modifying role for the perforin gene involved in familial hemophagocytic lymphohistiocytosis (FHL). The UNC13D gene codes for Munc13-4, which is involved in perforin secretion and FHL development, and thus, another candidate for a disease-modifying role in ALPS and DALD. In this work, we sequenced UNC13D in 21 ALPS and 20 DALD patients and compared these results with sequences obtained from 61 healthy subjects and 38 multiple sclerosis (MS) patients. We detected four rare missense variations in three heterozygous ALPS patients carrying p.Cys112Ser, p.Val781Ile, and a haplotype comprising both p.Ile848Leu and p.Ala995Pro. Transfection of the mutant cDNAs into HMC-1 cells showed that they decreased granule exocytosis, compared to the wild-type construct. An additional rare missense variation, p.Pro271Ser, was detected in a healthy subject, but this variation did not decrease Munc13-4 function. These data suggest that rare loss-of-function variations of UND13D are risk factors for ALPS development.
Arico, Maurizio; Boggio, Elena; Cetica, Valentina; Melensi, Matteo; Orilieri, Elisabetta; Clemente, Nausicaa; Cappellano, Giuseppe; Buttini, Sara; Soluri, Maria Felicia; Comi, Cristoforo; Dufour, Carlo; Pende, Daniela; Dianzani, Irma; Ellis, Steven R.; Pagliano, Sara; Marcenaro, Stefania; Ramenghi, Ugo; Chiocchetti, Annalisa; Dianzani, Umberto
Describing the evolution of medication nonadherence from pretransplant until 3 years post-transplant and determining pretransplant medication nonadherence as risk factor for post-transplant nonadherence to immunosuppressives: The Swiss Transplant Cohort Study.
Although medication nonadherence (MNA) is a major risk factor for poor outcomes, the evolution of MNA from pre- to 3 years post-transplant among the four major organ transplant groups remains unknown. Therefore, this study described this evolution and investigated whether pretransplant MNA predicts post-transplant immunosuppressive medication nonadherence (IMNA). Adult participants (single transplant, pretransplant and ?1 post-transplant assessment, using medications pretransplant) in the Swiss Transplant Cohort Study (a prospective nation-wide cohort study) were included. Nonadherence, defined as any deviation from dosing schedule, was assessed using two self-report questions pretransplant and at 6, 12, 24 and 36 months post-transplant. Nonadherence patterns were modelled using generalized estimating equations. The sample included 1505 patients (average age: 52.5 years (SD: 13.1); 36.3% females; 924 renal, 274 liver, 181 lung, 126 heart). The magnitude and variability of self-reported MNA decreased significantly from pretransplant to 6 months post-transplant (OR = 0.21; 95% CI: 0.16-0.27). Post-transplant IMNA increased continuously from 6 months to 3 years post-transplant (OR = 2.75; 95% CI: 1.97-3.85). Pretransplant MNA was associated with threefold higher odds of post-transplant IMNA (OR = 3.10; 95% CI: 2.29-4.21). As pretransplant MNA predicted post-transplant IMNA and a continuous increase in post-transplant IMNA was observed, early adherence-supporting interventions are indispensible. PMID:24628915
De Geest, Sabina; Burkhalter, Hanna; Bogert, Laura; Berben, Lut; Glass, Tracy R; Denhaerynck, Kris
We evaluated 26?901 patients who underwent allogeneic hematopoietic cell transplantation (HCT) at 271 centers worldwide to define patterns of posttransplantation lymphoproliferative disorders (PTLDs). PTLDs developed in 127 recipients, with 105 (83%) cases occurring within 1 year after transplantation. In multivariate analyses, we confirmed that PTLD risks were strongly associated (P < .001) with T-cell depletion of the donor marrow, antithymocyte globulin (ATG) use, and unrelated or HLA-mismatched grafts (URD/HLA mismatch). Significant associations were also confirmed for acute and chronic graft-versus-host disease. The increased risk associated with URD/HLA-mismatched donors (RR = 3.8) was limited to patients with T-cell depletion or ATG use (P = .004). New findings were elevated risks for age 50 years or older at transplantation (RR = 5.1; P < .001) and second transplantation (RR = 3.5; P < .001). Lower risks were found for T-cell depletion methods that remove both T and B cells (alemtuzumab and elutriation, RR = 3.1; P = .025) compared with other methods (RR = 9.4; P = .005 for difference). The cumulative incidence of PTLDs was low (0.2%) among 21?686 patients with no major risk factors, but increased to 1.1%, 3.6%, and 8.1% with 1, 2, and more than 3 major risk factors, respectively. Our findings identify subgroups of patients who underwent allogeneic HCT at elevated risk of PTLDs for whom prospective monitoring of Epstein-Barr virus activation and early treatment intervention may be particularly beneficial.
Gilbert, Ethel S.; Rizzo, J. Douglas; Socie, Gerard; Banks, Peter M.; Sobocinski, Kathleen A.; Horowitz, Mary M.; Jaffe, Elaine S.; Kingma, Douglas W.; Travis, Lois B.; Flowers, Mary E.; Martin, Paul J.; Deeg, H. Joachim; Curtis, Rochelle E.
Posttransplant erythrocytosis (PTE) poses a potential risk of thrombosis in kidney transplantation. Clinical observation of our systemically drained simultaneous kidney pancreas transplant (S-SPK) patients showed a higher incidence of PTE and need for phlebotomies. To evaluate the incidence of PTE we analyzed hematocrit (Hct) levels and frequency of phlebotomies in 94 SPK as compared to 174 living donor (LD) recipients and 53 type-I diabetic with kidney transplant only. For study purposes we defined PTE as Hct >50% or the necessity for phlebotomies. Kaplan-Meier plots and Cox proportional hazard models were used to examine the association between the transplant type and PTE. We found an increased incidence of PTE in SPK compared to LD (p < 0.001). In the multivariate model, SPK had a 5-fold risk for the development of PTE (AHR 5.3, 95% CI 1.8, 15.9). The incidence of therapeutic phlebotomy was 13% among SPK patients and 4% in LD kidney recipients; 19 patients altogether. A total of 64 units were phlebotomized (48-SPK and 16-LD). Type I diabetic patients with a kidney transplant showed a 0% incidence of PTE. We observed a greater incidence of PTE and phlebotomies in S-SPK compared to LD with kidney only transplant recipients. PMID:20148815
Guerra, G; Indahyung, R; Bucci, C M; Schold, J D; Magliocca, J F; Meier-Kriesche, H-U
Fas (also known as Apo1 and CD95) is a cell surface receptor involved in apoptotic cell death. Fas expression and function were analyzed in three children (including two siblings) with a lymphoproliferative syndrome, two of whom also had autoimmune disorders. A large deletion in the gene encoding Fas and no detectable cell surface expression characterized the most affected patient. Clinical
F. Rieux-Laucat; F. Le Deist; C. Hivroz; I. A. G. Roberts; K. M. Debatin; A. Fischer; J. P. de Villartay
Male patients with the X-linked lymphoproliferative syndrome (XLP) have an inherited immune deficiency to Epstein-Barr virus (EBV) infection that results in fatal infectious mononucleosis (IM), acquired hypogammaglobulinemia- or agammaglobulinemia, virus-associated hemophagocytic syndrome, and non-Hodgkin's malignant lymphoma (ML). A clinicopathologic analysis of 17 patients with XLP who developed ML was performed. The median age of the patients at the time of diagnosis was 4.0 years (range, 2-19 years). The median overall survival was 12 months (range, 1-216 months). Eight patients had maternally related male relatives with ML. Other phenotypes of XLP were documented in male relatives of the remaining nine patients. Common presenting symptoms were fever, nausea, vomiting, and abdominal pain. Nine patients had "B" symptoms. All ML occurred at extranodal sites. The intestines, most commonly ileocecal, were involved in 76.5% of the cases. Thirteen patients had localized disease (Stages I and II) and four patients had advanced disease (Stages III and IV). A diffuse histologic pattern of growth was observed in all cases. The distribution of histologic subtypes included small noncleaved (41.2%), large noncleaved (17.6%), immunoblastic (17.6%), small cleaved or mixed cell (11.8%), and unclassifiable (5.9%) ML. Surgical resection, radiation therapy, and chemotherapy resulted in disease-free survivals of up to 192 months in eight patients (median 114 months; range, 12-192 months). Eight of 17 patients (47%) are still alive. A median survival of only 6.0 months (range, 1-12 months) was observed in the nine patients who died. No residual ML was found at autopsy. The small noncleaved subtype had an adverse prognosis (seven of nine deaths versus one of eight survivors; P less than 0.05). Bacterial infection was the major cause of death (seven of nine patients). Characteristics that distinguish ML in XLP from other ML include a maternal family history of XLP, early age of onset, acquired hypogammaglobulinemia, post-EBV infection, and ileocecal involvement. PMID:3815312
Harrington, D S; Weisenburger, D D; Purtilo, D T
We present a series of 15 cases of cutaneous lymphoma and pseudolymphoma with dual lineage rearrangement identified among approximately 1200 cases of cutaneous lymphoproliferative disorders assessed in our 4 institutions during the last 8 years in which the results of both T-cell receptor and immunoglobulin heavy chain rearrangement investigations were available. On the basis of the clinicopathologic information, the cases were retrospectively subdivided into 2 categories: (1) cases with definite features of cutaneous lymphoma or pseudolymphoma (n = 11) and (2) cases with unclassifiable disease (n = 4). The detection of dual genotype in the first group did not influence the final diagnosis; 7 cases represented cutaneous B-cell lymphomas, 3 pseudolymphomas, and 1 case lymphomatoid papulosis. The presence of monoclonal T-cell receptor-gene rearrangements in these cases may be explained either by monoclonal or oligoclonal expansion of exuberant T cells (or B cells in case of lymphomatoid papulosis) or by lineage infidelity. Three patients with unclassifiable disease had several clinical and histopathologic features in common. They were elderly, presented with solitary lesions, were in good general health and histopathologically demonstrated a dense multinodular infiltrate containing approximately an equal number of T and B cells and a high number of histiocytes forming granulomas, with prominent granulomatous features in 2 cases. B cells were either scattered with the infiltrate or formed collections vaguely resembling follicles; Reed-Sternberg-like cells were seen in 2 cases. B cells showed expression neither of immunoglobulin light chain. The T-cell component was represented mainly by small, well-differentiated lymphocytes or slightly pleomorphic cells, with some medium-sized convoluted cells. Epstein-Barr virus was not detected by polymerase chain reaction. The exact classification of these cases is unknown; they differ histopathologically from previously published cases of bigenotypic cutaneous lymphomas. They may merely represent a growth or reactive pattern, but, on the other hand, may be low-grade lymphomas. If so, they may be histopathologically related to cutaneous Hodgkin disease, T-cell/histiocyte-rich large B-cell lymphoma, or composite lymphomas. Further reports are needed to identify these lesions to clarify their nature and biologic potential. PMID:17012914
Kazakov, Dmitry V; Kutzner, Heinz; Palmedo, Gabriele; Boudova, Ludmila; Michaelis, Sonja; Michal, Michal; Vanecek, Tomas; Magro, Cynthia M; Mukensnabl, Petr; Dummer, Reinhard; Burg, Günter; Kempf, Werner
BKV is known to cause allograft failure in kidney transplant recipients. It has been recently recognized to cause native kidney nephropathy in non-kidney transplant recipients. This is a case report BKVN in a 15-yr-old HTx recipient who had PTLD and a review of pediatric cases in the literature. The patient was diagnosed with BKVN +189 months after transplantation and died thirty days after diagnosis of BKVN. We identified five other cases of BKVN in pediatric non-kidney solid organ transplantation, of which all were HTx recipients. Overall, outcome was poor and BKV clearance was not achieved with reduction of immunosuppression and with current therapies. We strongly recommend that pediatric HTx recipients be tested for BKV infection if there is evidence of kidney dysfunction. We also recommend that they have an annual screening for BKV viruria and viremia with the assessment of kidney function. PMID:23230886
Lorica, C; Bueno, T G; Garcia-Buitrago, M T; Rusconi, P; Gonzalez, I A
We retrospectively analyzed the p.V158F polymorphism of Fc?-receptor IIIA (FCGR3A, CD16) in patients with PTLD treated with rituximab monotherapy. Previous reports had indicated that the lower affinity F allele affects rituximab-mediated antibody-dependent cellular cytotoxicity (ADCC) and is linked to inferior outcome of rituximab monotherapy in B cell malignancies. 25 patients with PTLD after solid organ transplantation were included in this analysis. They had received 4 weekly doses of rituximab as part of two clinical trials, which had a rituximab monotherapy induction regimen in common. 16/25 patients received further treatment with CHOP-21 after rituximab monotherapy (PTLD-1, NCT01458548). The FCGR3A status was correlated to the response after 4 cycles of rituximab monotherapy. Response to rituximab monotherapy was not affected by F carrier status. This is in contrast to previous findings in B cell malignancies where investigators found a predictive impact of FCGR3A status on outcome to rituximab monotherapy. One explanation for this finding could be that ADCC is impaired in transplant recipients receiving immunosuppression. These results suggest that carrying a FCRG3A F allele does not negatively affect rituximab therapy in immunosuppressed patients. PMID:24741582
Zimmermann, Heiner; Weiland, Theresa; Nourse, Jamie P; Gandhi, Maher K; Reinke, Petra; Neuhaus, Ruth; Karbasiyan, Mohsen; Gärtner, Barbara; Anagnostopoulos, Ioannis; Riess, Hanno; Trappe, Ralf U; Oertel, Stephan
X-linked lymphoproliferative syndrome (XLP; Duncan's disease) is a primary immunodeficiency disease that manifests as an inability to regulate the immune response to Epstein–Barr virus (EBV) infection. Here we examine the ability of the product of the gene defective in XLP, SAP (DSHP\\/SH2D1A), to associate with the cytoplasmic domains of several members of the CD2 subfamily of cell surface receptors, including
Jennifer Lewis; Lisa J. Eiben; David L. Nelson; Jeffrey I. Cohen; Kim E. Nichols; Hans D. Ochs; Luigi D. Notarangelo; Colin S. Duckett
... called signaling lymphocyte activation molecule (SLAM) associated protein (SAP). This protein is involved in the functioning of ... T cells called natural killer T cells. The SAP protein also helps control immune reactions by triggering ...
Background Sjögren’s syndrome is characterized by lymphocytic infiltration of the exocrine glands, together with polyclonal B-cell activation, and lung diseases are well-known complications of the disease. Therefore, in most cases associated with Sjögren’s syndrome, infiltrating lymphocytes in the lung specimen exhibit the features of B-cells. We herein report an atypical case of lymphoproliferative pulmonary involvement in a patient with Sjögren’s syndrome. Case presentation A 46-year-old female was admitted to our hospital because of an abnormal chest roentgenogram finding on a medical checkup. Chest computed tomography showed randomly-distributed micronodules and patchy ground-glass opacities. A surgical biopsied specimen showed an atypical pattern of interstitial pneumonia with numerous lymphoid follicles. Among the infiltrating lymphocytes in the lung, only the monoclonality of the T-cells was proven by a gene rearrangement analysis, but there was no cytological atypicality or genetic disorder revealed by testing the bone marrow aspirate. A diagnosis of Sjögren’s syndrome was made based on the patient’s other symptoms and these negative findings. The patient’s pulmonary lesions have been successfully treated and remission has been maintained for over three years with corticosteroid treatment alone. Conclusion The present patient was an atypical case of lymphoproliferative pulmonary involvement in a patient with Sjögren’s syndrome. Although monoclonality of the infiltrating T-cells was proven, the clinical course and the findings of the imaging and laboratory examinations were inconsistent with the previously-reported cases of primary pulmonary T-cell lymphoma. This suggests that the monoclonality of lymphocytes does not always define malignancy. The diagnosis of malignant lymphoma or lymphoproliferative diseases should be made clinically, pathologically and cytogenetically to rule out other similar diseases.
We describe the case of a 59-year-old HIV-negative male who developed multicentric Castleman's disease (MCD) 1 year postliver transplantation due to recrudescence of a pretransplant human herpesvirus-8 (HHV-8) infection. He presented with fevers, dry cough, weight loss and drenching night sweats. Routine investigations were all unremarkable. Computerized axial tomography (CT) scans showed splenomegaly and intra-abdominal lymphadenopathy, confirmed by positron emission tomography. Cervical lymph node biopsies were consistent with MCD. The presence of HHV-8 was confirmed on immunohistochemistry. Peripheral blood HHV-8 quantitative polymerase chain reaction (qPCR) monitoring showed a threefold decrease in viremia in the first week of treatment with ganciclovir but had little impact on clinical symptoms. Reducing immunosuppression and switching to rituximab resolved clinical symptoms and produced a negative HHV-8 qPCR result. Retrospective molecular testing of sera collected pre- and immediately posttransplantation confirmed preexisting HHV-8 in the host. This is the first reported case of an HIV-negative postliver transplant patient developing MCD that manifested as posttransplant lymphoproliferative disorder due to recrudescence of HHV-8. We propose (1) the introduction of the term iatrogenic Castleman's disease (CD) for this and similar cases, (2) rituximab should be considered as a treatment option for CD and (3) consideration be given to a change to the World Health Organization classification of CD to incorporate such cases. PMID:24674650
Speicher, D J; Sehu, M M; Mollee, P; Shen, L; Johnson, N W; Faoagali, J L
SAP is an adaptor mutated in X-linked lymphoproliferative disease. It plays a critical role in T helper 2 (TH2) cytokine production. This function was suggested to reflect the capacity of SAP to associate with SLAM family receptors and enable tyrosine phosphorylation signaling by these receptors through SAP-mediated recruitment of Src-related kinase FynT. Here, we addressed by genetic means the importance
Dominique Davidson; Xiaochu Shi; Shaohua Zhang; Hao Wang; Mona Nemer; Nobuyuki Ono; Shinji Ohno; Yusuke Yanagi; André Veillette
Fulminant Epstein-Barr virus (EBV)-driven clonal T-cell lymphoproliferative disorder (T-LPD) is rare and most patients are of Asian origin. The disease usually develops shortly after primary acute EBV infection and the mechanism remains poorly understood. Here we report such a rare case in a 28-year-old Caucasian female with systemic lupus erythematosus (SLE). Immunophenotypic and molecular studies revealed that the proliferating lymphoid
Ken H. Young; Dahua Zhang; Jeffery T. Malik; Eliot C. Williams
X-linked lymphoproliferative disease (XLP) is characterized by a marked vulnerability in Epstein-Barr virus (EBV) infection. Infection of XLP patients with EBV invariably results in fatal mononucleosis, agammaglobulinemia or B-cell lymphoma. The XLP gene lies within a 10 cM region in Xq25 between DXS42 and DXS10. Initial chromosome studies revealed an interstitial, cytogenetically visible deletion in Xq25 in one XLP family
A. Lanyi; B. F. Li; S. Li
We have performed, in a large Swiss family, a study of linkage between various DNA markers in the Xq24-27 region and the locus for the X-linked lymphoproliferative syndrome (XLP). Our results indicated that the marker DXS37 in Xq25-q26 is genetically linked to the XLP syndrome. The multipoint linkage analysis showed that the disease locus is distal to DXS11, but proximal to the hypoxanthine phosphoribosyl-transferase gene (HPRT). PMID:2574086
Sylla, B S; Wang, Q; Hayoz, D; Lathrop, G M; Lenoir, G M
The X-linked lymphoproliferative syndrome is characterized by immunodeficiency to Epstein-Barr virus (EBV) manifested by severe or fatal infectious mononucleosis and acquired immunodeficiency. We studied immune responses in six males of a well-characterized kindred with the X-linked lymphoproliferative syndrome. Two males were studied before and during acute fatal EBV infection. Both individuals demonstrated normal cellular and humoral immunity before EBV infection. During acute EBV infection, both individuals developed vigorous cytotoxic cellular responses against EBV-infected and -uninfected target cells. Anomalous killer and natural killer T cell activity was demonstrated against a variety of lymphoid cell lines, autologous fibroblasts and autologous hepatocytes. Effector cells responsible for anomalous killing reacted with a pan-T cell monoclonal antibody, and belonged to the OKT.8 T cell subset. Death in each case was caused by liver failure, but one patient developed extensive liver necrosis, whereas the other developed a massive infiltration of the liver with EBV-infected immunoblasts after aggressive immunosuppressive therapy. Immunological studies were performed on four males who had survived EBV infection years previously. They demonstrated global cellular immune defects with deficiencies of lymphocyte proliferative responses to mitogens and antigens, humoral immune deficiencies, abnormalities of regulatory T cell subsets and deficient natural killer cell activity. We propose that an aberrant immune response triggered by acute EBV infection results in unregulated anomalous killer and natural killer cell activity against EBV infected and uninfected cells. These studies suggest that global immune defects appearing in males with X-linked lymphoproliferative syndrome who survive EBV infection are epiphenomenon. Images
Sullivan, J L; Byron, K S; Brewster, F E; Baker, S M; Ochs, H D
Background Vitamin D does not only regulate calcium homeostasis but also plays an important role as an immune modulator. It influences the immune system through the induction of immune shifts and regulatory cells resulting in immunologic tolerance. As such, vitamin D is thought to exert beneficial effects within the transplant setting, especially in kidney transplant recipients, considering the high prevalence of vitamin D deficiency in kidney transplant recipients. Methods/Design The VITA-D study, a randomized, placebo-controlled, double-blind study with two parallel groups including a total of 200 kidney transplant recipients, is designed to investigate the immunomodulatory and renoprotective effects of cholecalciferol (vitamin D3) within the transplant setting. Kidney transplant recipients found to have vitamin D deficiency defined as 25-hydroxyvitamin D3 < 50 nmol per liter will be randomly assigned to receive either oral cholecalciferol therapy or placebo and will be followed for one year. Cholecalciferol will be administered at a dose of 6800 International Units daily over a time period of one year. The objective is to evaluate the influence of vitamin D3 substitution in vitamin D deficient kidney transplant recipients on the post-transplant outcome. As a primary endpoint glomerular filtration rate calculated with the MDRD formula (modification of diet in renal disease) one year after kidney transplantation will be evaluated. Incidence of acute rejection episodes, and the number and severity of infections (analyzed by means of C-reactive protein) within the first year after transplantation will be monitored as well. As a secondary endpoint the influence of vitamin D3 on bone mineral density within the first year post-transplant will be assessed. Three DXA analyses will be performed, one within the first four weeks post-transplant, one five months and one twelve months after kidney transplantation. Trial Registration ClinicalTrials.gov NCT00752401
Thiem, Ursula; Heinze, Georg; Segel, Rudolf; Perkmann, Thomas; Kainberger, Franz; Muhlbacher, Ferdinand; Horl, Walter; Borchhardt, Kyra
Leukemia, i.e., the neoplasia of one or more cell lines of the bone marrow, although less common than in other species, it is also reported in horses. Leukemia can be classified according to the affected cells (myeloproliferative or lymphoproliferative disorders), evolution of clinical signs (acute or chronic) and the presence or lack of abnormal cells in peripheral blood (leukemic, subleukemic and aleukemic leukemia). The main myeloproliferative disorders in horses are malignant histiocytosis and myeloid leukemia, the latter being classified as monocytic and myelomonocytic, granulocytic, primary erythrocytosis or polycythemia vera and megakaryocytic leukemia. The most common lymphoproliferative disorders in horses are lymphoid leukemia, plasma cell or multiple myeloma and lymphoma. Lymphoma is the most common hematopoietic neoplasia in horses and usually involves lymphoid organs, without leukemia, although bone marrow may be affected after metastasis. Lymphoma could be classified according to the organs involved and four main clinical categories have been established: generalized-multicentric, alimentary-gastrointestinal, mediastinal-thymic-thoracic and cutaneous. The clinical signs, hematological and clinical pathological findings, results of bone marrow aspirates, involvement of other organs, prognosis and treatment, if applicable, are presented for each type of neoplasia. This paper aims to provide a guide for equine practitioners when approaching to clinical cases with suspicion of hematopoietic neoplasia.
MUNOZ, Ana; RIBER, Cristina; TRIGO, Pablo; CASTEJON, Francisco
Hydroa vacciniforme-like lymphoma (HVLL) is an Epstein-Barr virus (EBV)-positive T-cell lymphoproliferative disorder of childhood that occurs mainly in Central and South America and Asia. We present the clinicopathological features of 20 Mexican children with HVLL with a median age of 8 years at diagnosis (range, 1-15). All patients presented with skin lesions involving sun-exposed areas, but not exclusively. Fever, lymphadenopathy, and hepatosplenomegaly were often observed. Most patients were treated with immunomodulators and/or immunosuppressive agents, resulting in temporary remission. For 13 patients follow-up was available for a median of 3 years (range, 1 month-13 years). Three patients with long follow-up (9-13 years) are alive with disease. Four patients died, 2 after developing systemic lymphoma. Histologically, the skin showed a predominantly angiocentric and periadnexal Epstein-Barr early RNA+ lymphoid infiltrate with variable atypia and subcutaneous involvement. Fifteen patients showed a T-cell phenotype (12, ??; 2, ??; 1, silent phenotype) and monoclonal T-cell receptor-? rearrangements, whereas 6 exhibited a natural killer (NK)-cell phenotype. Four patients had hypersensitivity to mosquito bites. One patient showed both phenotypes. HVLL is an EBV-associated lymphoproliferative disorder of ??-, ??-, or NK-cell phenotype with a broad clinical spectrum, usually prolonged clinical course, and risk for progression to systemic disease. PMID:23982171
Quintanilla-Martinez, Leticia; Ridaura, Cecilia; Nagl, Florian; Sáez-de-Ocariz, Marimar; Durán-McKinster, Carola; Ruiz-Maldonado, Ramon; Alderete, Georgia; Grube, Peter; Lome-Maldonado, Carmen; Bonzheim, Irina; Fend, Falko
Introduction Myeloma following kidney transplantation is a rare entity. It can be divided into two groups: relapse of a previous myeloma and de novo myeloma. Some of these myelomas can be complicated by a monoclonal immunoglobulin deposition disease, which is even less common. Less than ten cases of monoclonal immunoglobulin deposition disease after renal graft have been reported in the literature. The treatment of these patients is not well codified. Case presentation We report the case of a 43-year-old white European man who received a renal transplant for a nephropathy of unknown etiology and developed a nephrotic syndrome with kidney failure at 2-years follow-up. We diagnosed a de novo monoclonal immunoglobulin deposition disease associated with a kappa light chain multiple myeloma, which is a very uncommon presentation for this disease. Three risk factors were identified in this patient: Epstein–Barr virus reactivation with cytomegalovirus co-infection; intensified immunosuppressive therapy during two previous rejection episodes; and human leukocyte antigen-B mismatches. Chemotherapy treatment and decrease in the immunosuppressive therapy were followed by remission and slight improvement of renal function. A relapse occurred 8 months later and his renal function worsened rapidly requiring hemodialysis. He died from septic shock 4 years after the diagnosis of monoclonal immunoglobulin deposition disease. Conclusions This rare case of post-transplant lymphoproliferative disorder with an uncommon presentation illustrates the fact that treatment in such a situation is very difficult to manage because of a small number of patients reported and a lack of information on this disease. There are no guidelines, especially concerning the immunosuppressive therapy management.
The incidence of lymphoproliferative disorders (LD) is increasing in developed countries. Patients with inflammatory bowel disease (IBD) exposed to thiopurines are at additional risk of three specific forms of LD: Epstein-Barr-Virus-related post-transplant like LD, hepato-splenic T-cell lymphoma and post-mononucleosis lymphoproliferation. The risk of the two latter forms of LD can be reduced when considering specific immunosuppressive strategies in young males. It is still unclear whether the risk of uterine cervix abnormalities is increased in IBD women, irrespective of the use of immunosuppressants. Given the excess risk demonstrated in various other contexts of immunosuppression, it is currently recommended that all women with IBD, particularly those receiving immunosuppressants, strictly adhere to a screening program of cervical surveillance and undergo vaccination against HPV, when appropriate. Patients with IBD receiving immunosuppressants are at increased risk of skin cancers. The risk of non-melanoma skin cancer is notably increased in patients receiving thiopurines. Recent data suggest that the risk of melanoma is mildly increased in patients exposed to anti-TNF therapy. All IBD patients should adhere to a program of sun protection and dermatological surveillance, whose details should take into account the other non-IBD-related risk factors. PMID:23721759
Magro, Fernando; Peyrin-Biroulet, Laurent; Sokol, Harry; Aldeger, Xavier; Costa, Antonia; Higgins, Peter D; Joyce, Joel C; Katsanos, Konstantinos H; Lopez, Anthony; de Xaxars, Teresa Mas; Toader, Elena; Beaugerie, Laurent
Purpose of Review Autoimmune Lymphoproliferative Syndrome (ALPS) is a disorder of disrupted lymphocyte homeostasis, resulting from mutations in the Fas apoptotic pathway. Clinical manifestations include lymphadenopathy, splenomegaly, and autoimmune cytopenias. A number of new insights have improved the understanding of the genetics and biology of ALPS. These will be discussed in this review. Recent Findings A number of key observations have been made recently that better define the pathophysiology of ALPS, including the characterization of somatic FAS variant ALPS, the identification of haploinsufficiency as a mechanism of decreased Fas expression, and the description of multiple genetic hits in FAS in some families that may explain the variable penetrance of the disease. In addition, ALPS has been shown to be a more common condition, as patients diagnosed with other disorders, including Evans syndrome and common variable immune deficiency have been found to have ALPS. Finally, the treatment of the disease has changed as splenectomy and rituximab have been shown to have unexpected ALPS specific toxicities, and mycophenolate mofetil and sirolimus have been demonstrated to have marked activity against the disease. Summary Based on novel advances the diagnostic algorithm and recommended treatment for ALPS have changed significantly, improving quality of life for many patients.
Teachey, David T.
Although glucocorticoid therapy is considered to be the main pathogenic factor, a consistent body of evidence suggests that other immunosuppressants might also play an important role in the development of the post-transplant renal osteopathy (PRO) through their pleiotropic pharmacological effects. Glucocorticoids seem to induce osteoclasts' activity suppressing the osteoblasts while data regarding other immunosuppressive drugs are still controversial. Mycophenolate mofetil and azathioprine appear to be neutral regarding the bone metabolism. However, the study analyzing any independent effect of antimetabolites on bone turnover has not been conducted yet. Calcineurin inhibitors (CNIs) induce trabecular bone loss in rodent, with contradictory results in renal transplant recipients. Suppression of vitamin D receptor is probably the underlying mechanism of renal calcium wasting in renal transplant recipients receiving CNI. In spite of an increased 1,25(OH)2 vitamin D level, the kidney is not able to reserve calcium, suggesting a role of vitamin D resistance that may be related to bone loss. More efforts should be invested to determine the role of CNI in PRO. In particular, data regarding the role of mammalian target of rapamycin inhibitors (mTORi), such as sirolimus and everolimus, in the PRO development are still controversial. Rapamycin markedly decreases bone longitudinal growth as well as callus formation in experimental models, but also lowers the rate of bone resorption markers and glomerular filtration in clinical studies. Everolimus potently inhibits primary mouse and human osteoclast activity as well as the osteoclast differentiation. It also prevents the ovariectomy-induced loss of cancellous bone by 60 %, an effect predominantly associated with a decreased osteoclast-mediated bone resorption, resulting in a partial preservation of the cancellous bone. At present, there is no clinical study analyzing the effect of everolimus on bone turnover in renal transplant recipients or comparing sirolimus versus everolimus impact on bone, so only general conclusions could be drawn. Hence, the use of mTORi might be useful in patients with PRO due to their possible potential to inhibit osteoclast activity which might lead to a decreased rate of bone resorption. In addition, it should be also emphasized that they might inhibit osteoblast activity which may lead to a decreased bone formation and adynamic bone disease. Further studies are urgently needed to solve these important clinical dilemmas. PMID:24217803
Blaslov, Kristina; Katalinic, Lea; Kes, Petar; Spasovski, Goce; Smalcelj, Ruzica; Basic-Jukic, Nikolina
Treatment of multiple myeloma (MM) has evolved significantly over the past two decades with high-dose chemotherapy and autologous stem cell transplant (ASCT), incorporating novel therapies such as proteasome inhibitors (PIs) and immunomodulatory drugs (IMiDs) during induction and post-transplant maintenance therapies. We reviewed the evolution of maintenance therapy from traditional chemotherapy, interferon (IFN), and prednisone to the current use of thalidomide, lenalidomide, and bortezomib in the post-transplant maintenance setting. Based on existing literature, either thalidomide or lenalidomide can be recommended for maintenance therapy post-transplant resulting in improved progression- free survival (PFS) and overall survival (OS). Thalidomide is less tolerated than lenalidomide and does not improve survival in patient subgroups who had achieved at least a very good partial response (VGPR) or who had chromosome 13 deletion. Thalidomide maintenance may be even detrimental in patients with high-risk cytogenetics. Alternatively, lenalidomide maintenance improves PFS in all subgroups of patients including those achieving at least a VGPR and those with high-risk cytogenetics, and improves OS in one other study. Bortezomib maintenance improves PFS and OS as part of induction and maintenance when compared to thalidomide maintenance and it is uncertain as to whether this improvement was due to bortezomib used during induction. The future research in maintenance therapy may include incorporation of current novel agents and testing new oral agents such as pomalidomide, or ixazomib or antibody therapy with elotuzumab. PMID:24135405
Liu, Hong; McCarthy, Philip
Gastric antral vascular ectasia (GAVE) is an angiodysplastic disorder that causes gastric bleeding. GAVE can develop as a complication of hematopoietic stem cell transplantation (HSCT-GAVE), and it has been suggested that it may be associated with oral administration of busulfan. We report two cases of HSCT-GAVE after a conditioning regimen containing intra-venous busulfan (ivBu), not oral busulfan. The first case, a 42-year-old woman with blastic plasmacytoid dendritic cell neoplasm, underwent second allogeneic HSCT with conditioning regimen consisting of cyclophosphamide (120 mg/kg) and ivBu (12.8 mg/kg). HSCT-GAVE developed on day 84 post-transplant, and argon plasma coagulation (APC) was performed successfully. The second case, a 60-year-old woman with acute myelogenous leukemia, underwent allogeneic HSCT with the conditioning regimen consisting of ivBu (12.8 mg/kg) and fludarabine (150 mg/kg). She developed melena and was diagnosed with GAVE by endoscopy on day 145 post-transplant. Although complete hemostasis was not achieved despite four administrations of APCs, the melena spontaneously terminated on day 235 post-transplant. To our knowledge, this is the first report describing HSCT-GAVE after ivBU-based HSCT. Although there is no established therapy for HSCT-GAVE, APC may be an option for HSCT-GAVE. PMID:23632949
Fukuda, Kuniyoshi; Kurita, Naoki; Sakamoto, Tatsuhiro; Nishikii, Hidekazu; Okoshi, Yasushi; Sugano, Masato; Chiba, Shigeru
Background The use of high-dose chemotherapy and autologous stem-cell transplantation in patients with relapsed Hodgkin’s lymphoma is supported by two randomized clinical trials but its benefit in patients with primary refractory disease is less clear. Aiming to shed light on this issue, we analyzed and compared the outcomes of patients with relapsed or refractory Hodgkin’s lymphoma treated with second-line chemotherapy and planned autologous stem-cell transplantation. Design and Methods We retrospectively analyzed data on 157 consecutive patients with Hodgkin’s lymphoma referred to our institution for consideration of autologous stem-cell transplantation between 1999 and 2006. Of those, 73 met the definition of having primary refractory disease, ie. progressive disease during first line chemotherapy or within 3 months of completion of the treatment. Those patients achieving complete remission, partial remission and stable disease with symptomatic improvement after two or three cycles of salvage chemotherapy proceeded to stem cell mobilization and autologous transplantation. Results From first relapse/progression, the 3-year overall survival was 76% (95% CI: 66%?89%) for the refractory cohort and 91% (95% CI: 84%?98%) for the relapsed cohort (P=0.034); the overall response rate to second-line chemotherapy was 51% and 83% (P<0.0001), respectively. Three-year progression-free survival post-transplant was 49% in refractory patients and 67% in relapsed patients (P=0.21); overall survival was 75% and 91% (P=0.097), respectively. Conclusions Using the group with relapsed disease as a reference, we can conclude that the subset of patients with chemosensitive primary refractory Hodgkin’s lymphoma do benefit from autologous stem-cell transplantation.
Puig, Noemi; Pintilie, Melania; Seshadri, Tara; al-Farsi, Khalil; Nagy, Tracy; Franke, Norman; Tsang, Richard; Keating, Armand; Crump, Michael; Kuruvilla, John
Abstract Background. Hepatitis B and C viruses’ infections are often associated with hematological disorders in evolution, suggesting that these viruses have a tropism for peripheral blood and/or bone marrow cells. Aim. To analyze the hematological parameters and bone marrow findings in a group of patients diagnosed with chronic lymphoproliferative disorders (CLD) and hepatitis viruses B, C, D infections, which were included in the research grant (acronym LIMFO-VIR) between December 2007 and May 2010 in the Hematology Department of the Emergency University Hospital of Bucharest. Methods and results. Patients were diagnosed by using immunopathology according to the WHO criteria. The analyzed group included 42 patients (both sexes), with the mean age of 60,35 years. The most frequent hematologic disease was non-Hodgkin’s lymphoma 30/42 (71,42%), followed by chronic lymphocytic leukemia (16,66%) and Hodgkin’s lymphoma (7,14%). Hepatitis viruses were distributed: 17/42 (40,47%) patients with HBV, 22/42 (52,38%) with HCV and 3/42 (7,14%) had a double/triple association of viruses. Most of the patients had an indolent type of disease - 27/42 (64,28%), whereas 15/42 (35,71%) had an aggressive one, pattern found both in the HBV and HCV infected groups. An abnormal bone marrow result was revealed in 32/42 (76,19%) patients, 19 (59,37%) of them being HCV infected. Myelodysplasia was found in 6/42(14,28%) patients, the majority being HCV infected, all having an indolent form of CLD. The antiviral therapy did not influence the hematological parameters (no significant differences were found between the groups with/without an antiviral therapy). Discussions. Patients with hepatitis virus infections may associate neutropenia and thrombocytopenia; the mechanisms are thought to involve hypersplenism, autoimmune processes and antiviral therapy. We excluded the influence of chemotherapy, as the study was performed before the treatment. In our group, patients whether HBV or HCV infected, presented an isolated cytopenia. The abnormal bone marrow cellularity (increased or decreased) and dysplasia were found especially in the HCV group. There are studies showing no association between myelodysplasia and hepatitis viruses; others found a strong relation of these. One of the mechanisms of myelodysplasia could be a dysregulation of the immune system. Conclusions. Bone marrow/peripheral blood features correlate with the type of viral infection and HCV is more prone to develop additional hematological changes than HBV. The degree of bone marrow involvement by CLDs influences these features. We considered mandatory to perform a bone marrow analysis at the diagnosis of CLDs to stage and to establish if other bone marrow changes were present, a crucial aspect for therapy and outcome of the disease. The association between the hepatitis viruses – myelodysplasia- autoimmunity seems to have a role in the lymphoproliferative disorders etiology. Abbreviations: CLD – chronic lymphoproliferative disorders; NHL- non-Hodgkin’s lymphoma, CLL- chronic lymphocytic leukemia, HL- Hodgkin’s lymphoma, MDS – myelodysplastic syndrome, AML – acute myeloid leukemia
Ciufu, C; Arama, V; Bumbea, H; Dobrea, C; Ion, I; Vladareanu, AM
Next-generation sequencing techniques are powerful high-throughput methods that have enabled the comprehensive documentation of genetic lesions in numerous hematological malignancies. In recent times, the genomes of multiple different B-cell lymphoproliferative disorders including chronic lymphocytic leukemia, diffuse large B-cell lymphoma, Burkitt lymphoma, splenic marginal zone lymphoma, mantle cell lymphoma, hairy cell leukemia and Waldenström macroglobulinemia have been documented. Between them, these studies have reinforced and provided insight into the mechanisms for the dysregulation of known pathways (e.g. nuclear factor-?B [NF-?B]), uncovered the importance of new pathways for oncogenesis (e.g. mRNA processing), identified disease-defining mutations and provided meaningful new targets which are already being translated into therapeutic interventions. This review summarizes the molecular lesions that have been discovered in B-cell lymphoproliferative disorders thus far by studies utilizing high-throughput sequencing techniques and the aberrations in the numerous intracellular pathways that have been shown to be involved. PMID:23550993
Blombery, Piers A; Dickinson, Michael; Westerman, David A
This article presents a case report for a child presenting with mixed clinical features of autoimmune lymphoproliferative syndrome (ALPS), familial hemophagocytic lymphohistiocytosis (FHL), and X-linked lymphoproliferative (XLP) disease. From 6 months, he exhibited splenomegaly and lymphoadenopathy and from 4 years, he showed recurrent severe autoimmune hemocytopenia and sepsislike bouts of fever, from which he eventually died at the age of 12. Intriguingly, the patient carried mutations in FAS, XIAP, and UNC13D genes, which are involved in ALPS, XLP disease, and FHL, respectively. These mutations were inherited from the mother, who had rheumatoid arthritis but no signs of ALPS. A role for other modifying genes was suggested by the finding that the healthy father exhibited defective Fas function, without mutation of the FAS gene, and had transmitted to the patient an osteopontin (OPN) gene variant previously associated with ALPS. Therefore, several genes might influence the disease outcome in this family. In vitro analyses revealed that the FAS and the XIAP mutations decreased expression of the corresponding proteins, and the UNC13D mutation decreased granule secretion and Munc interaction with Rab-27a. These findings suggest that overlap may exist between ALPS, FHL, and XLP disease, in accordance with the notion that FHL and XLP disease are due to defective natural killer (NK)/NK T-cell function, which involves Fas. Therefore, we propose that NK cell defects should be evaluated in patients with ALPS-like characteristics, and hematopoietic stem cell transplantation should be considered in individuals with severe refractory cytopenia and FHL-like manifestations. PMID:24043286
Boggio, Elena; Aricò, Maurizio; Melensi, Matteo; Dianzani, Irma; Ramenghi, Ugo; Dianzani, Umberto; Chiocchetti, Annalisa
Age-related EBV-associated B-cell lymphoproliferative disorder is a highly aggressive lymphoma, and a standard therapy for this disease has not yet been established. A 58-year-old male was admitted to our hospital because of fever and lymphadenopathy across the whole body. Neck lymph node biopsy showed hemorrhagic and geographic necrosis with Hodgkin-like large cells against a background of small lymphocytes. The large cells were positive for CD30 and EBER. The patient was diagnosed as having age-related EBV-associated B-cell lymphoproliferative disorder. Although there was no response to CHOP therapy, he obtained partial response after 3 courses of DeVIC therapy. Because his lymphoma was highly aggressive and chemotherapy-resistant, he underwent autologous stem cell transplantation with a conditioning regimen including ranimustine, etoposide, cytarabine, and melphalan. After stem cell transplantation and subsequent radiotherapy to the residual lesion, the patient achieved complete remission. This is the first report of successful autologous stem cell transplantation for a patient with age-related EBV-associated B-cell lymphoproliferative disorder. PMID:21471700
Sugino, Noriko; Nakamura, Chishiho; Fujii, Sumie; Matsui, Yusuke; Kaneko, Hitomi; Watanabe, Mitsumasa; Miura, Yasuo; Wakasa, Tomoko; Tsudo, Mitsuru
Orthotopic and living related liver transplantation is an established mode of treatment of end-stage liver disease. One of the major causes of postoperative complications is vascular anastomotic stenosis. One such set of such complications relates to hepatic vein, inferior vena cava (IVC), or portal vein stenosis, with a reported incidence of 1-3%. The incidence of vascular complications is reported to be higher in living donor versus cadaveric liver transplants. We encountered a patient with hepatic venous outflow tract obstruction, where the hepatic vein had been previously stented, but the patient continued to have symptoms due to additional IVC obstruction. The patient required double-balloon dilatation of the IVC simultaneously from the internal jugular vein and IVC.
Kohli, Vikas, E-mail: email@example.com [Indraprastha Apollo Hospital, Pediatric Cardiology and Congenital Cardiac Surgery Unit (India); Wadhawan, Manav [Indraprastha Apollo Hospital, Department of Gastroenterology and Hepatology (India); Gupta, Subhash [Indraprastha Apollo Hospital, Department of Liver Transplant (India); Roy, Vipul [Indraprastha Apollo Hospital, Department of Cardiology (India)
We report a case of Epstein Barr virus-associated large B cell lymphoproliferative disorder, with an abdominal cutaneous localization, in an adult treated for 10 years with immunosuppressive agents for a dermatomyositis. This is the third case of immunosuppressive induced lymphoproliferative disorder localized to skin in a patient with dermatomyositis. Diagnosis was unexpectedly obtained by the histologic examination of surgical samples of skin necrosis possibly induced by edetate calcium disodium subcutaneous injections in calcinosis cutis. PMID:19027995
Steff, M; Le Corre, Y; Penisson-Besnier, I; Michalak, S; Drossard, G; Lebrun-Vignes, B; Le Clec'h, C
Twenty-two Epstein-Barr virus-associated B-cell lymphoproliferative disorders (LPDs) without predisposing immunodeficiencies were evaluated clinically and pathologically. All patients were Japanese and negative for anti-human immunodeficiency virus antibody. They were all more than 60 years old with a median age of 75.5 years. Eighteen (82%) patients showed extranodal involvement. Biopsied specimens contained variable numbers of centroblasts, immunoblasts, and Reed-Sternberg-like giant cells often with necrosis and an angiocentric pattern. The 13 cases showing polymorphous composition and inflammatory background were categorized as polymorphic LPD subtype. The other nine cases contained diffuse proliferative lesions of large lymphoid cells and were categorized as large cell lymphoma subtype. Tumor cells expressed CD20 and/or CD79a, and in situ hybridization showed them to be associated with Epstein-Barr virus. LMP1 was detected in all cases and EBNA2 in seven. Eighteen patients initially received combination chemotherapy, and 12 achieved complete remission. However, six patients were refractory to chemotherapy and four patients with complete remission later relapsed. Eight of the 18 patients who received chemotherapy showed an aggressive disease course within a year after the diagnosis. There was a significant difference in prognosis between the group with polymorphic LPDs and the one with large cell lymphomas (p = 0.003). Although the disease profile of the 22 cases was analogous to that of immunodeficiency-associated B-cell LPDs, none of the patients showed evidence of underlying immunodeficiency-related diseases. These findings suggest that Epstein-Barr virus-associated LPD without immunodeficiency mainly occurs in elderly patients. Further investigations are needed to clarify the pathogenesis of this disease and to determine the optimal treatment strategy. PMID:12502924
Oyama, Takashi; Ichimura, Koichi; Suzuki, Ritsuro; Suzumiya, Junji; Ohshima, Koichi; Yatabe, Yasushi; Yokoi, Takio; Kojima, Masaru; Kamiya, Yoshikazu; Taji, Hirofumi; Kagami, Yoshitoyo; Ogura, Michinori; Saito, Hidehiko; Morishima, Yasuo; Nakamura, Shigeo
Sirolimus is an antiproliferative immunosuppressive agent that inhibits the mammalian target of rapamycin. It is highly effective in preventing acute renal allograft rejection and can be used with either calcineurin inhibitors, antimetabolites or corticosteroids. Early studies in renal transplantation have provided insight into optimal dosing strategies of sirolimus and of concomitant immunosuppressive agents. Familiarity with the adverse effect profile of sirolimus and pharmacokinetic and dynamic interactions with other immunosuppressive agents allows for earlier recognition and better management of sirolimus-related complications. The role of sirolimus in preserving long-term renal function, post-transplant malignancies and in prevention of atherosclerosis is currently being considered. PMID:19522662
Patel, Samir J; Elliott, Erin N; Knight, Richard J; Gaber, Lillian W; Gaber, A Osama
We report a case of posttransplant distal limb syndrome (PTDLS) representing a rare complication in kidney transplant recipients characterized by a pain syndrome of the distal extremities. A 68-year-old man with a history of kidney transplantation presented with symmetrical and incapacitating pain in the feet and knees and underwent whole-body Tc-methylene diphosphonate (MDP) scintigraphy for further evaluation. Planar scintigraphy demonstrated marked tracer uptake in the distal femoral and tibial epiphyses, and magnetic resonance imaging showed corresponding osteoedema. Tc-MDP scintigraphy is a valuable tool for evaluation of the etiology of musculoskeletal pain and may demonstrate typical findings in case of PTDLS. PMID:24873782
Derlin, Thorsten; Busch, Jasmin D; Bannas, Peter
Nodular lymphoid hyperplasia (NLH) belongs to a very rare, mild, lymphoproliferative disease of unestablished aetiology historically included in the group of pseudolymphomas. Its existence was controversial for many years, until modern techniques of pathomorphological diagnosis approved it as a separate entity of lung disease. It manifests in the form of well limited nodules localized in the lungs, which are mostly identified accidentally. Clinical symptoms are rare and nonspecific; the disease usually occupies only one lung. Pathomorphological diagnosis requires immunohistochemical designation of expressions of numerous antigens in order to exclude malignant lymphoma of the lungs. Surgical resection is used in cases of larger nodules; the smaller ones require periodic observation, and the prognosis is good. The authors describe the case of 65-year-old woman with pulmonary nodules which were detected accidentally in the right lung. The patient was qualified for right-sided videothoracoscopy and removal of the lung nodule. In classic HE staining of the histological material, the presence of lymphoid infiltration of the lungs was revealed, which formed lymph follicles with reactive germinal centres. In order to differentiate from the malignant lymphatic expansion, immunohistochemical designations were made, which showed positive expression of CD20 antigen in the B cell zone, positive expression of the CD3 antigen in the T cells zone, positive expression of CD23 antigen in the lymph follicles, negative expression of bcl-2 in the lymph follicles, and positive expression of MIB-1 in the germinal centres of lymph follicles. Such a histopathological and immunohistochemical picture provided the basis for diagnosis of nodular lymphoid hyperplasia of the lung. PMID:23258474
Rogozi?ski, Pawe?; Bruli?ski, Krzysztof; Malinowski, Eugeniusz; Wandzel, Piotr; Kucharzewski, Marek
The purpose of this study was to evaluate the association of post-transplant soluble CD30 (sCD30) levels, isolated or in combination with of anti-HLA class II antibodies and of serum creatinine levels, with kidney graft loss due to chronic allograft nephropathy (CAN), and type of lesions in graft biopsies for cause. The study comprised 511 first kidney graft recipients, transplanted at a single center, with a graft functioning for at least 2.8 years. A single blood sample was collected from each patient. sCD30 levels were determined by ELISA, and HLA antibodies by Luminex assay. The minimum follow-up after testing was 9.3 years. High sCD30 levels, set at sCD30 ? 34.15 ng/mL, the presence of HLA class II antibodies, and serum creatinine ? 1.9 mg/dL were independently associated with CAN-graft loss (P values <0.0001, 0.05, <0.0001, respectively), and the combined hazard ratio for CAN-graft loss was 20.2. Analyses of 166 biopsies for cause showed that high sCD30 levels and creatinine were independently associated with interstitial lesions. Post-transplant sCD30 serum levels, especially in conjunction with information regarding HLA class II antibodies and serum creatinine levels, provide valuable information regarding graft outcome and could be useful for the management of kidney transplant recipients. PMID:23928467
Grenzi, Patricia C; Campos, Érika F; Tedesco-Silva, Hélio; Felipe, Claudia R; Franco, Marcello F; Soares, Maria Fernanda; Medina-Pestana, José Osmar; Gerbase-Delima, Maria
The authors examined pretransplant assessment in order to predict posttransplant occurrence of psychiatric disorders in living-related transplantation (LRT). Before LRT, the authors administered the Integrated House-Tree-Person Drawing Test (I-HTP) and 20-item Toronto Alexithymia Scale (TAS-20) to 31 donor-recipient pairs undergoing living-related liver transplantation (LRLT) and 65 pairs undergoing living-related kidney transplantation (LRKT). After LRT, the authors examined the occurrence of psychiatric disorders for the recipients and donors. Pretransplant, two psychological indicators,-alexithymia, a lack of verbalized emotion and abnormal projective drawings such as truncated tree representation-were significantly related to the manifestation of paradoxical psychiatric syndrome (PPS) in LRLT and LRKT. The occurrence of PPS was significantly related to recipients' guilt feelings toward living donors, but these were strongly superseded by recipients' desires to escape from approaching death just before LRT. These results suggest that pretransplant psychological assessment is useful for predicting posttransplant occurrence of psychiatric disorders. PMID:11927758
Fukunishi, Isao; Sugawara, Yasutoshi; Takayama, Tadatoshi; Makuuchi, Masatoshi; Kawarasaki, Hideo; Surman, Owen S
Immunosuppression management in post-transplant malignancy is challenging because of a lack of objective immunologic assessment tools. The ImmuKnow assay measures the ATP level from CD4 T cells, quantifying cell-mediated immunity and providing an insight into the immune status of transplant recipients. Its potential use in patients with post-transplant de novo malignancy was evaluated. Thirteen adult transplant patients with de novo malignancy were divided into survivors (n = 9) and non-survivors (n = 4) after malignancy treatment. Tacrolimus and the ImmuKnow levels were monitored before, during, and after malignancy treatment. The ImmuKnow level in non-survivors group was significantly lower before and after malignancy treatment compared to survivors group (p = 0.013 and 0.0014 respectively). In survivor group, the ImmuKnow level was significantly decreased during malignancy treatment (p = 0.019) but recovered to the initial level after the treatment. However, in non-survivor group, the ImmuKnow level remained suppressed throughout the observed period despite a reduction in immunosuppressive drug levels. The ImmuKnow assay can be an objective means evaluating immune status of patients with de novo malignancy. The ImmuKnow assay can express the degree of immune suppression induced by chemotherapeutic or radiation therapy and may be a useful tool in optimizing the timing of re-introduction of immunosuppression after malignancy treatment. PMID:20636411
Uemura, Tadahiro; Riley, Thomas R; Khan, Akhtar; Hollenbeak, Christopher; Schreibman, Ian; Ghahramani, Nasrollah; Reeves, Brian; Domen, Ronald E; Zander, Dani S; Kadry, Zakiyah
Erythropoiesis-stimulating agents (ESAs) are approved to treat anemia in patients with non-myeloid malignancies receiving myelosuppressive chemotherapy. ESAs reduce transfusion rates, but some clinical studies suggest that ESAs may reduce survival or increase disease progression. This study-level meta-analysis examined the effects of darbepoetin alfa, epoetin alfa or epoetin beta on mortality, disease progression and transfusion incidence in patients with lymphoproliferative malignancies, using randomized, controlled trials of patients receiving chemotherapy and ESAs or standard of care. The odds ratio (OR) for mortality was 1.04 (95% confidence interval [CI], 0.81–1.34, random-effects model, 10 studies); the risk difference was ? 0.01 (95% CI, ? 0.03–0.02). The OR for disease progression was 1.02 (95% CI 0.81–1.30, random-effects model, five studies). A lower proportion of ESA-treated patients than controls received transfusions (seven studies). In this meta-analysis, ESAs reduced transfusions with no clear effect on mortality or disease progression in patients with lymphoproliferative malignancies receiving chemotherapy.
CD30+ lymphoproliferative disorders represent a spectrum of diseases with distinct clinical phenotypes ranging from reactive conditions to aggressive systemic anaplastic lymphoma kinase (ALK)? anaplastic large cell lymphoma (ALCL). In January 2011, the U.S. Food and Drug Administration (FDA) announced a possible association between breast implants and ALCL, which was likened to systemic ALCL and treated accordingly. We analyzed existing data to see if implant-associated ALCL (iALCL) may represent a distinct entity, different from aggressive ALCL. We conducted a systematic review of publications regarding ALCL and breast implantation for 1990–2012 and contacted corresponding authors to obtain long-term follow-up where available. We identified 44 unique cases of iALCL, the majority of which were associated with seroma, had an ALK? phenotype (97%), and had a good prognosis, different from the expected 40% 5-year survival rate of patients with ALK? nodal ALCL (one case remitted spontaneously following implant removal; only two deaths have been reported to the FDA or in the scientific literature since 1990). The majority of these patients received cyclophosphamide, doxorubicin, vincristine, and prednisolone with or without radiation, but radiation alone also resulted in complete clinical responses. It appears that iALCL demonstrates a strong association with breast implants, a waxing and waning course, and an overall good prognosis, with morphology, cytokine profile, and biological behavior similar to those of primary cutaneous ALCL. Taken together, these data are suggestive that iALCL may start as a reactive process with the potential to progress and acquire an aggressive phenotype typical of its systemic counterpart. A larger analysis and prospective evaluation and follow-up of iALCL patients are necessary to definitively resolve the issue of the natural course of the disease and best therapeutic approaches for these patients.
Story, Sara K.; Schowalter, Michael K.
We elaborate on the diagnosis of CD30 positive cutaneous lymphoproliferative conditions including the various clinical and pathological presentations, our understanding of its pathomechanisms and prognostic implications. The most common reactive conditions that can simulate CD30 lymphoproliferative conditions, including arthropod bite reactions, various viral infections, pityriasis lichenoides and lymphocytic papules in myelodysplastic syndrome, are discussed in detail. PMID:20043512
Guitart, Joan; Querfeld, Christiane
We report on posttransplant relapsed pediatric patients with B-precursor acute lymphoblastic leukemia with no further standard of care therapy who were treated with the T-cell engaging CD19/CD3-bispecific single-chain antibody construct blinatumomab on a compassionate use basis. Blast load was assessed prior to, during and after blinatumomab cycle using flow cytometry to detect minimal residual disease, quantitative polymerase chain reaction for rearrangements of the immunoglobulin or T-cell receptor genes, and bcr/abl mutation detection in one patient with Philadelphia chromosome-positive acute lymphoblastic leukemia. Blinatumomab was administered as a 4-week continuous intravenous infusion at a dosage of 5 or 15 ?g/m(2)/day. Nine patients received a total of 18 cycles. Four patients achieved complete remission after the first cycle of treatment; 2 patients showed a complete remission from the second cycle after previous reduction of blast load by chemotherapy. Three patients did not respond, of whom one patient proceeded to a second cycle without additional chemotherapy and again did not respond. Four patients were successfully retransplanted in molecular remission from haploidentical donors. After a median follow up of 398 days, the probability of hematologic event-free survival is 30%. Major toxicities were grade 3 seizures in one patient and grade 3 cytokine release syndrome in 2 patients. Blinatumomab can induce molecular remission in pediatric patients with posttransplant relapsed B-precursor acute lymphoblastic leukemia and facilitate subsequent allogeneic hematopoietic stem cell transplantation from haploidentical donor with subsequent long-term leukemia-free survival. PMID:24727818
Schlegel, Patrick; Lang, Peter; Zugmaier, Gerhard; Ebinger, Martin; Kreyenberg, Hermann; Witte, Kai-Erik; Feucht, Judith; Pfeiffer, Matthias; Teltschik, Heiko-Manuel; Kyzirakos, Christina; Feuchtinger, Tobias; Handgretinger, Rupert
We report on posttransplant relapsed pediatric patients with B-precursor acute lymphoblastic leukemia with no further standard of care therapy who were treated with the T-cell engaging CD19/CD3-bispecific single-chain antibody construct blinatumomab on a compassionate use basis. Blast load was assessed prior to, during and after blinatumomab cycle using flow cytometry to detect minimal residual disease, quantitative polymerase chain reaction for rearrangements of the immunoglobulin or T-cell receptor genes, and bcr/abl mutation detection in one patient with Philadelphia chromosome-positive acute lymphoblastic leukemia. Blinatumomab was administered as a 4-week continuous intravenous infusion at a dosage of 5 or 15 ?g/m2/day. Nine patients received a total of 18 cycles. Four patients achieved complete remission after the first cycle of treatment; 2 patients showed a complete remission from the second cycle after previous reduction of blast load by chemotherapy. Three patients did not respond, of whom one patient proceeded to a second cycle without additional chemotherapy and again did not respond. Four patients were successfully retransplanted in molecular remission from haploidentical donors. After a median follow up of 398 days, the probability of hematologic event-free survival is 30%. Major toxicities were grade 3 seizures in one patient and grade 3 cytokine release syndrome in 2 patients. Blinatumomab can induce molecular remission in pediatric patients with posttransplant relapsed B-precursor acute lymphoblastic leukemia and facilitate subsequent allogeneic hematopoietic stem cell transplantation from haploidentical donor with subsequent long-term leukemia-free survival.
Schlegel, Patrick; Lang, Peter; Zugmaier, Gerhard; Ebinger, Martin; Kreyenberg, Hermann; Witte, Kai-Erik; Feucht, Judith; Pfeiffer, Matthias; Teltschik, Heiko-Manuel; Kyzirakos, Christina; Feuchtinger, Tobias; Handgretinger, Rupert
Objectives Acute and chronic rejection remain unresolved problems after lung transplantation, despite heavy multidrug immunosuppression. In turn, the strong immunosuppression has been responsible for mortality and pervasive morbidity. It also has been postulated to interdict potential mechanisms of alloengraftment. Methods In 48 lung recipients we applied 2 therapeutic principles: (1) recipient pretreatment with antilymphoid antibody preparations (Thymoglobulin [SangStat, Fremont, Calif] or Campath [alemtuzumab; manufactured by ILEX Pharmaceuticals, LP, San Antonio, Tex; distributed by Berlex Laboratories, Richmond, Calif]) and (2) minimal posttransplant immunosuppression with tacrolimus monotherapy or near-monotherapy. Our principal analysis was of the events during the critical first 6 posttransplant months of highest immunologic and infectious disease risk. Results were compared with those of 28 historical lung recipients treated with daclizumab induction and triple immunosuppression (tacrolimus-prednisone-azathioprine). Results Recipient pretreatment with both antilymphoid preparations allowed the use of postoperative tacrolimus monotherapy with prevention or control of acute rejection. Freedom from rejection was significantly greater with Campath than with Thymoglobulin (P = .03) or daclizumab (P = .05). After lymphoid depletion with Thymoglobulin or Campath, patient and graft survival at 6 months was 90% or greater. Patient and graft survival after 9 to 24 months is 84.2% in the Thymoglobulin cohort, and after 10 to 12 months, it is 90% in the Campath cohort. There has been a subjective improvement in quality of life relative to our historical experience. Conclusion Our results suggest that improvements in lung transplantation can be accomplished by altering the timing, dosage, and approach to immunosuppression in ways that might allow natural mechanisms of alloengraftment and diminish the magnitude of required maintenance immunosuppression.
McCurry, Kenneth R.; lacono, Aldo; Zeevi, Adrianna; Yousem, Samuel; Girnita, Alin; Husain, Shahid; Zaldonis, Diana; Johnson, Bruce; Hattler, Brack G.; Starzl, Thomas E.
Chronic antigen-stimulation has been recurrently involved in the earlier stages of monoclonal B-cell lymphocytosis, chronic lymphocytic leukemia and other B-cell chronic lymphoproliferative disorders. The expansion of two or more B-cell clones has frequently been reported in individuals with these conditions; potentially, such coexisting clones have a greater probability of interaction with common immunological determinants. Here, we analyzed the B-cell receptor repertoire and molecular profile, as well as the phenotypic, cytogenetic and hematologic features, of 228 chronic lymphocytic leukemia-like and non-chronic lymphocytic leukemia-like clones comparing multiclonal (n=85 clones from 41 cases) versus monoclonal (n=143 clones) monoclonal B-cell lymphocytosis, chronic lymphocytic leukemia and other B-cell chronic lymphoproliferative disorders. The B-cell receptor of B-cell clones from multiclonal cases showed a slightly higher degree of HCDR3 homology than B-cell clones from mono clonal cases, in association with unique hematologic (e.g. lower B-lymphocyte counts) and cytogenetic (e.g. lower frequency of cytogenetically altered clones) features usually related to earlier stages of the disease. Moreover, a subgroup of coexisting B-cell clones from individual multiclonal cases which were found to be phylogenetically related showed unique molecular and cytogenetic features: they more frequently shared IGHV3 gene usage, shorter HCDR3 sequences with a greater proportion of IGHV mutations and del(13q14.3), than other unrelated B-cell clones. These results would support the antigen-driven nature of such multiclonal B-cell expansions, with potential involvement of multiple antigens/epitopes.
Henriques, Ana; Rodriguez-Caballero, Arancha; Criado, Ignacio; Langerak, Anton W.; Nieto, Wendy G.; Lecrevisse, Quentin; Gonzalez, Marcos; Cortesao, Emilia; Paiva, Artur; Almeida, Julia; Orfao, Alberto
Chronic antigen-stimulation has been recurrently involved in the earlier stages of monoclonal B-cell lymphocytosis, chronic lymphocytic leukemia and other B-cell chronic lymphoproliferative disorders. The expansion of two or more B-cell clones has frequently been reported in individuals with these conditions; potentially, such coexisting clones have a greater probability of interaction with common immunological determinants. Here, we analyzed the B-cell receptor repertoire and molecular profile, as well as the phenotypic, cytogenetic and hematologic features, of 228 chronic lymphocytic leukemia-like and non-chronic lymphocytic leukemia-like clones comparing multiclonal (n=85 clones from 41 cases) versus monoclonal (n=143 clones) monoclonal B-cell lymphocytosis, chronic lymphocytic leukemia and other B-cell chronic lymphoproliferative disorders. The B-cell receptor of B-cell clones from multiclonal cases showed a slightly higher degree of HCDR3 homology than B-cell clones from mono clonal cases, in association with unique hematologic (e.g. lower B-lymphocyte counts) and cytogenetic (e.g. lower frequency of cytogenetically altered clones) features usually related to earlier stages of the disease. Moreover, a subgroup of coexisting B-cell clones from individual multiclonal cases which were found to be phylogenetically related showed unique molecular and cytogenetic features: they more frequently shared IGHV3 gene usage, shorter HCDR3 sequences with a greater proportion of IGHV mutations and del(13q14.3), than other unrelated B-cell clones. These results would support the antigen-driven nature of such multiclonal B-cell expansions, with potential involvement of multiple antigens/epitopes. PMID:24488564
Henriques, Ana; Rodríguez-Caballero, Arancha; Criado, Ignacio; Langerak, Anton W; Nieto, Wendy G; Lécrevisse, Quentin; González, Marcos; Cortesão, Emília; Paiva, Artur; Almeida, Julia; Orfao, Alberto
Although herbs and botanicals have been available for thousands of years, detailed scientific research regarding the potential health benefits and risks of dietary supplements has been conducted only for the past 15-20 years. Millions of Americans use herbal supplements regularly, but many are not aware of the possible hidden dangers. Organ transplant recipients and patients with end-stage organ failure awaiting transplantation are at particularly high risk for potential complications due to herbal supplement use. This review provides background information regarding complementary and alternative medicine (CAM) use in the United States, regulatory history of dietary supplements in the United States, and concerns and special considerations regarding the risks associated with dietary/herbal supplement use in pretransplant and posttransplant patients. PMID:24710858
Corey, Rebecca L; Rakela, Jorge
This study was purpose to investigate the clinical characteristics of B-cell chronic lymphoproliferative disorders (B-CLPD) complicated by autoimmune hemolytic anemia (AIHA) so as to improve the understanding of this disease. The clinical characteristics, laboratory data, therapy and outcome of 14 patients suffering from B-CLPD complicated by AIHA were retrospectively analyzed in Wuxi People Hospital and the First Affiliated Hospital of Nanjing Medical University from 2000 to 2012. The results showed that 9 cases of the 14 patients were patients with chronic lymphocytic leukemia (CLL), 5 cases were patients with lymphoma, at time of hemolysis the median level of hemoglobin was 61 (33 - 84)g/L, the median ratio of reticulocytes was 12.0 (3.1 - 35.0)%, the positive rate of Coombs test was 100%. 1 case received corticosteroid alone, 5 cases were treated with chemotherapy combined with corticosteroid, 8 cases were treated with immunochemotherapy rituximab combined with corticosteroid. Overall response rate was 100%, in which CR was 78.6% (11/14), PR was 21.4% (3/14). The follow-up for these patients were performed to now, 35.7% (5/14) patients relapsed with hemolysis again, but they showed therapeutic response to treatment with above-mentioned therapy. From patients treated with rituximab alone, only 1 patient relapsed. Among 14 patients, 6 cases died, 1 case was lost, the other cases are still alive. It is concluded that the AIHA is the commonest complication of B-CLPD, it can be observed at different stages of B-CLPD, the treatment with corticosteroids can give well therapeutic effect for these patients, but the long time CR is lower, the rituximab has been confirmed to be effective for B-CLPD complicated by AIHA. PMID:23815912
Zhuang, Yun; Fan, Lei; Shen, Yun-Feng; Xu, Wei; Li, Jian-Yong
Chronic lymphoproliferative disorders of natural killer cells (CLPD-NKs) and T-cell large granular lymphocytic leukemias (T-LGLs) are clonal lymphoproliferations arising from either natural killer cells or cytotoxic T lymphocytes (CTLs). We have investigated for distribution and functional significance of mutations in 50 CLPD-NKs and 120 T-LGL patients by direct sequencing, allele-specific PCR, and microarray analysis. STAT3 gene mutations are present in both T and NK diseases: approximately one-third of patients with each type of disorder convey these mutations. Mutations were found in exons 21 and 20, encoding the Src homology 2 domain. Patients with mutations are characterized by symptomatic disease (75%), history of multiple treatments, and a specific pattern of STAT3 activation and gene deregulation, including increased expression of genes activated by STAT3. Many of these features are also found in patients with wild-type STAT3, indicating that other mechanisms of STAT3 activation can be operative in these chronic lymphoproliferative disorders. Treatment with STAT3 inhibitors, both in wild-type and mutant cases, resulted in accelerated apoptosis. STAT3 mutations are frequent in large granular lymphocytes suggesting a similar molecular dysregulation in malignant chronic expansions of NK and CTL origin. STAT3 mutations may distinguish truly malignant lymphoproliferations involving T and NK cells from reactive expansions.
Jerez, Andres; Clemente, Michael J.; Makishima, Hideki; Koskela, Hanna; LeBlanc, Francis; Peng Ng, Kwok; Olson, Thomas; Przychodzen, Bartlomiej; Afable, Manuel; Gomez-Segui, Ines; Guinta, Kathryn; Durkin, Lisa; Hsi, Eric D.; McGraw, Kathy; Zhang, Dan; Wlodarski, Marcin W.; Porkka, Kimmo; Sekeres, Mikkael A.; List, Alan; Mustjoki, Satu; Loughran, Thomas P.
This review summarizes relevant published data on transplant recipients with Chagas' disease and of naïve recipients transplanted with organs from infected donors. Unpublished experience from some of the largest transplant centers in Argentina is also included. The review outlines the guidelines for pretransplant evaluation and for posttransplant management formulated by the Chagas Disease Argentine Collaborative Transplant Consortium. PMID:21094779
In view of the widespread use of pesticides in Egypt and the increasing incidence of leukaemia and lymphoma we aimed to assess pesticide exposure and other selected variables as risk factors for lymphoproliferative disorders (leukaemia and non-Hodgkin lymphoma). In a hospital-based, retrospective, case-control study in 2011-2012, adult cases of lymphoproliferative disorders (n = 130) were recruited from outpatient clinics in Menoufia, Egypt, while controls (n = 130) were age- and sex-matched fracture patients. Family history of cancer, exposure to X-rays, smoking and use of hair dyes were not risk factors for lymphoproliferative disorders in univariate analysis. History of exposure to pesticides and HCV infection were significant risk factors for lymphoproliferative disorders in multivariate analysis (OR = 2.24; 95% CI: 1.22-4.11 and OR = 2.67; 95% CI: 1.50-4.80 respectively). The risk was significant for cases of non-Hodgkin lymphoma but not chronic lymphocytic leukaemia. PMID:24960512
Salem, E A; Hegazy, M M; El Khouley, E A
The homeostasis of the immune response requires tight regulation of the proliferation and apoptosis of activated lymphocytes. In humans, defects in immune homeostasis result in lymphoproliferation disorders including autoimmunity, haemophagocytic lymphohystiocytosis and lymphomas. The X-linked lymphoproliferative syndrome (XLP) is a rare, inherited immunodeficiency that is characterized by lymphohystiocytosis, hypogammaglobulinaemia and lymphomas, and that usually develops in response to infection with
Stéphanie Rigaud; Marie-Claude Fondanèche; Nathalie Lambert; Benoit Pasquier; Véronique Mateo; Pauline Soulas; Lionel Galicier; Françoise Le Deist; Frédéric Rieux-Laucat; Patrick Revy; Alain Fischer; Geneviève de Saint Basile; Sylvain Latour
Latent Epstein-Barr virus (EBV) infection is associ- ated with several malignancies, including Burkitt's lym- phoma, Hodgkin's disease, nasopharyngeal carcinoma, and post-transplant lymphoproliferative disease (LPD). The presence of EBV antigens in these tumors provides a target for immunotherapy approaches, and immunother- apy with EBV-specific cytotoxic T cells (CTLs) has proved effective in post-transplant LPDs, which are highly immunogenic tumors expressing type
KARIN C. M. STRAATHOF; CATHERINE M. BOLLARD; CLIONA M. ROONEY; HELEN E. HESLOP
Purpose To study the pattern of ocular adnexal lymphoproliferative disorders (OALD) in an ophthalmic referral center in Saudi Arabia and to review their, histopathological characteristics with clinical correlation. Methods Retrospective chart review of 40 cases of patients who underwent incisional biopsy with the suspected diagnosis of periocular and/or adnexal lymphoid lesions over the period: 2000–2012 at the King Khaled Eye Specialist Hospital (KKESH), Riyadh, Saudi Arabia. The routine histopathologic slides are reviewed by a single pathologist to identify cases of Benign Reactive Lymphoid Hyperplasia (RLH), Atypical Lymphoid Hyperplasia and probable lymphoma. The identification of the specific types of lymphoma is performed at a tertiary general hospital: King Faisal Specialist Hospital and Research Centre (KFSH&RC). Results Forty patients are included with an age range of 11–91 years and a median of 36 years. The males constitute 70% and females 30% of the cases. The right eye and/or orbit are involved in 48%. The left eye is involved in 45% while a bilateral disease is found in 7.5%. The median duration of symptoms is 5 months. The site distribution is conjunctiva (42.5%), orbit (25%), lacrimal gland (12.5%), eyelid (10%), lacrimal sac (7.5%) and caruncle (2.5%). One case is excluded after histopathologic diagnosis of malignant melanoma. Diagnosis in the remaining 39 cases includes: RLH in 14 cases (35%), atypical lymphoid hyperplasia in three cases (9%), and lymphoma in 22 cases (56%). Classification of the lymphoma group is: extranodal marginal zone lymphoma (EMZL) in 9/22 cases (41%), diffuse large B cell lymphoma (DLBCL) in 4/22 cases (18%), Castelman’s disease in 3/22 cases (14%), Burkitt’s lymphoma in 2/22 cases (9%), follicular lymphoma and T cell-rich B cell lymphoma: one case each (4.5%).Two cases remain unclassified. Conclusion We have a wide age range which is comparable to other studies. Our results show male predominance and the commonest site of involvement is conjunctival, however if RLH cases are excluded, the commonest site for lymphoma is orbit/lacrimal gland in 45% followed by conjunctival in 23%. The commonest type of lymphoma is: EMZL in 41% followed by DLBCL in 18% then other types of lymphoma including follicular lymphoma.
Alkatan, Hind M.; Alaraj, Ahmad; El-khani, Albarah; Al-Sheikh, Osama
Defective lymphocyte apoptosis results in chronic lymphadenopathy and/or splenomegaly associated with autoimmune phenomena. The prototype for human apoptosis disorders is the autoimmune lymphoproliferative syndrome (ALPS), which is caused by mutations in the FAS apoptotic pathway. Recently, patients with an ALPS-like disease called RAS-associated autoimmune leukoproliferative disorder, in which somatic mutations in NRAS or KRAS are found, also were described. Despite this progress, many patients with ALPS-like disease remain undefined genetically. We identified a homozygous, loss-of-function mutation in PRKCD (PKC?) in a patient who presented with chronic lymphadenopathy, splenomegaly, autoantibodies, elevated immunoglobulins and natural killer dysfunction associated with chronic, low-grade Epstein-Barr virus infection. This mutation markedly decreased protein expression and resulted in ex vivo B-cell hyperproliferation, a phenotype similar to that of the PKC? knockout mouse. Lymph nodes showed intense follicular hyperplasia, also mirroring the mouse model. Immunophenotyping of circulating lymphocytes demonstrated expansion of CD5+CD20+ B cells. Knockdown of PKC? in normal mononuclear cells recapitulated the B-cell hyperproliferative phenotype in vitro. Reconstitution of PKC? in patient-derived EBV-transformed B-cell lines partially restored phorbol-12-myristate-13-acetate–induced cell death. In summary, homozygous PRKCD mutation results in B-cell hyperproliferation and defective apoptosis with consequent lymphocyte accumulation and autoantibody production in humans, and disrupts natural killer cell function.
Kuehn, Hye Sun; Niemela, Julie E.; Rangel-Santos, Andreia; Zhang, Mingchang; Pittaluga, Stefania; Stoddard, Jennifer L.; Hussey, Ashleigh A.; Evbuomwan, Moses O.; Priel, Debra A. Long; Kuhns, Douglas B.; Park, C. Lucy; Fleisher, Thomas A.; Uzel, Gulbu
Despite advances in islet transplantation, challenges remain in monitoring for anti-islet immune responses. Soluble CD30 (sCD30) has been investigated as a predictor of acute rejection in kidney, lung, and heart transplantation as well as in a single study in human islet cell recipients. In this study, sCD30 levels were retrospectively assessed in 19 allograft recipients treated with three different immunosuppression induction therapies. Soluble CD30 levels were assessed at pre-transplant; early post-transplant (day 4-day 7); one-month post-transplant; and late post-transplant (day 90-day 120) and then correlated with eventual graft outcomes at 1-year follow-up. Results showed no correlation between mean serum sCD30 levels at any point in time pre- or post-transplant and graft function at 1-year follow-up. However, analysis demonstrated that mean sCD30 levels at day 28 or day 90-day 120 decreased from pre-transplant levels in recipients with long-term islet allograft function compared to recipients with partial or non-graft function (a decrease of 43.6+/-25.6% compared to 16.7+/-35.2%, p<0.05). In another finding, immunosuppression with the ATG protocol led to a greater reduction in sCD30 levels post-transplant overall. A larger reduction post-transplant correlated with full graft function. The results demonstrate that a relative reduction in sCD30 levels post-transplant may be applicable as a biomarker to monitor graft function in islet allograft recipients. Additionally, knowledge of the impact of various immunosuppression protocols on the timing and extent of changes in post-transplant sCD30 levels could aid in patient-specific tailoring of immunosuppression. PMID:20600901
Hire, Kelly; Hering, Bernhard; Bansal-Pakala, Pratima
Post-transplant diabetes among renal transplant recipients is more prevalent in the African-American population. However, it is unknown if methylprednisolone (a commonly prescribed glucocorticoid in transplant patients) pharmacokinetics is altered among African-American renal allograft recipients compared to Caucasian counterparts. Therefore, the objectives of this study were to identify the occurrence of post-transplant diabetes in our clinic population and to characterize the pharmacokinetics of methylprednisolone among our African-American and Caucasian renal transplant recipients. A retrospective chart survey was done on African-American and Caucasian recipients with stable renal function and no history of diabetes pre-transplantation in order to characterize the occurrence of post-transplant diabetes in our clinical population. The survey was conducted from January 1985 to January 1992 in recipients with graft survival of at least 3 months. Post-transplant diabetes was defined as two fasting glucose serum concentrations greater than 140 mg/dl or one random serum glucose concentration greater than 200 mg/dl which was confirmed by a fasting serum glucose value greater than 140 mg/dl and a 2 hour post-prandial greater than 200 mg/dl. A 24-hour pharmacokinetic evaluation was conducted in a sub-group of African-American and Caucasian patients after intravenous administration of methylprednisolone. Over the survey period, 75 renal transplants (30 females; 45 males) were performed and 50 of these transplant recipients (24 females; 26 males) were not diabetic prior to the allograft placement. Of these 50 patients, 22 males and 17 females fulfilled the inclusion criteria established for the retrospective survey.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:7579735
Tornatore, K M; Biocevich, D M; Reed, K A; Tousley, K; Gray, V; Singh, J P; Murray, B M; Venuto, R C
In current clinical praxis, monitoring of immunosuppressive agents in organ transplantation is restricted to measurement of drug blood levels and does not consider the drug's variable effect on the individual patient's immune system. Establishment of biological markers that measure the biological effect of immunosuppressive drugs is desirable and would enable the identification of patients who are at risk of developing rejection, or patients who are suitable for minimization or weaning of immunosuppressive therapy. Several studies demonstrated that the technically simple posttransplant measurement in serum of the T cell activation marker soluble CD30 (sCD30) allows prediction of subsequent graft loss in kidney transplant recipients. sCD30 is a relatively large molecule and therefore an attractive biological marker which is resistant to repeated thawing cycles and temperature differences and easily determined using commercial ELISA. Whether sCD30-based prospective adjustment of immunosuppressive therapy can prevent irreversible graft damage and improve long-term graft outcome awaits evaluation in randomized controlled trials. PMID:22037199
Süsal, Caner; Opelz, Gerhard
Cancer has been a serious complication of kidney transplantation ever since the outcome of this procedure improved. The incidence of cancer among kidney transplant (KT) recipients is increasing, and these patients have a higher risk of developing cancer than the general population. The present retrospective cohort study compared the cancer rate of kidney recipients in a single transplantation center in Korea with that in healthy Korean individuals using the standardized incidence ratio (SIR). The medical records of all 2365 patients who underwent renal transplantation between 1989 and 2009 were reviewed retrospectively. During the study period, 136 renal allograft recipients developed 140 malignancies. The cumulative cancer incidence one, five, 10, and 15 yr post-transplantation was 0.60%, 3.24%, 5.69%, and 8.90%, respectively. Non-Hodgkin lymphoma (NHL) and thyroid cancer were the most common cancers after renal transplantation, occurring significantly more frequently than in the general Korean population. The SIR of all cancers was 1.9 (women: 2.4; men: 1.6). Comparison with similar studies in Korea and other countries suggests transplant center-related differences dictate post-transplant malignancy incidence more strongly than ethnic or geographic factors. Early surveillance programs for de novo malignancies after kidney transplantation focusing on kidney-transplantation-related tumors and postoperative time period should be established. PMID:24750289
Kim, Ji Hyun; Kim, Seon-Ok; Han, Duck Jong; Park, Su-Kil
We describe a patient with acquired von Willebrand's disease and Waldenström's macroglobulinemia. He suffered from an acquired tendency to bleed. The laboratory findings were identical to those of congenital von Willebrand's disease. The acquired form of this bleeding disorder is seen in association with immunologically active B cell lymphomas, certain other malignant tumours, and autoimmune diseases. The incidence and prevalence are unknown, but this disorder is probably uncommon. We discuss possible pathogenetic mechanisms. Acquired von Willebrand's disease should be considered in patients with an acquired tendency to bleed, especially if the patient also has a lymphoproliferative, neoplastic, or autoimmune disease. PMID:8332973
Berentsen, S; Hammerstrøm, J
The splenic marginal zone lymphoma (SMZL) is a relatively rare chronic B lymphoproliferative disease, which primarily manifest increase of peripheral blood lymphocyte count and/or scale, and splenomegaly, while the peripheral superficial lymph nodes are often not swollen. Therefore, the splenectomy are usually needed to confirm the diagnosis, but the majority of patients could not accept such management, resulting in early difficult diagnosis. This study was purposed to explore the more prior way for diagnosis based flow cytometry (FCM). Six patients with suspected diagnosis of SMZL were used as research objects, 10 healthy bone marrow donors and 10 cases of chronic lymphocytic leukemia (CLL), 3 cases of hairy cell leukemia (HCL), 3 cases of lymphatic plasma cell lymphoma/Waldenströ's macroglobulinemia (LPL/WM) were selected as control. The immunophenotype of bone marrow cells were analyzed and compared by FCM using a panel of antibodies including CD45, CD5, CD10, CD19, CD20, CD22, CD23, CD25, CD103, CD11c, CD123, ?,?, Cyclin D1, and combined with bone marrow cell morphology. The results indicated that 6 cases of suspected SMZL showed a large increase of lymphocytes and splenomegaly. Because absence of peripheral lymphadenopathy, 6 patients did not suffer from lymph node biopsy, only 1 patient underwent diagnostic splenectomy. The immunophenotypes of bone marrow in patients and controls were analyzed by FCM, as a result, except for the healthy donors, varying degrees of abnormal mature B cell clones were found in bone marrow of all patients, and the further differentiation from other B-cell tumors was performed through CD5, CD10 expression and combination with other B-cell phenotype. All 6 cases of SMZL patients expressed CD19(+) and CD20(+), but CD10 expression was negative, 4 patients expre-ssed CD5(-), 2 patients expressed CD5(+). The expressions of CD23, CD38, ZAP-70, CD11c, CD103, CD123, Cyclin D1 were negative. The morphological examination of bone marrow cells showed velutinous abnormal lymphocytes. Combined with clinical characteristics, 6 patients were diagnosed as SMZL, 1 patient suffered from splenectomy because of concurrent hypersplenism, and this postoperative pathologic examination confirmed the patient with SMZL. Ten cases of CLL mainly expressed CD5, CD23; 3 cases of HCL had more typical morphology of "hairlike" in addition to CD11c, CD103 and CD123 positive; 3 cases of LPL/WM had significantly increased light chain restriction expression, IgM, plasmacytoid lymphocytes. It is concluded that the FCM immunophenotype analysis can be used as a powerful tools for clinical diagnosis of SMZL. PMID:24763004
Hu, Yang; Chen, Yan; Wang, Li-Hua; Chen, Xue; Fang, Fang; Liu, Shi-Qin; Wu, Xue-Qiang; Zhu, Ping
Approximately 5% of patients with end-stage cirrhosis undergoing orthotopic liver transplantation have occult hepatocellular carcinoma. Careful follow up is required to detect recurrent tumour, and knowledge of the patterns of recurrence may avoid diagnostic confusion with other malignancies, such as post-transplantation lymphoproliferative disorder. This case report illustrates an unusual presentation of recurrent hepatocellular carcinoma in a 56-year-old man presenting with a para-aortic soft tissue mass, thought clinically and radiologically to represent lymphoma or post-transplantation lymphoproliferative disorder. This case demonstrates that recurrent hepatocellular carcinoma can present late after transplantation as retroperitoneal lymphadenopathy, and should alert physicians and radiologists to be aware of the radiological appearances of recurrence and of the need for early biopsy to avoid diagnostic confusion with other malignancies. PMID:16026439
Ho, S G F; Phillips, A J; Browne, R F J; Munk, P L; Legiehn, G M; Yoshida, E M; Davis, J E; Chung, S W; Scudamore, C H
Objective Identify the etiology of elevated B12 in autoimmune lymphoproliferative syndrome (ALPS). Design Peripheral blood of ALPS patients with elevated B12 and controls were evaluated. Results Total and holo-haptocorrin (HC) levels were 26- and 23-fold higher in ALPS patients, respectively. No abnormal B12-binding proteins were found. Western blot revealed HC in lymphocyte lysates only from ALPS patients. Conclusion Elevated concentrations of B12 found in ALPS patients were due to increased lymphocyte expression of HC.
Bowen, Raffick A.R.; Dowdell, Kennichi C.; Dale, Janet K.; Drake, Steven K.; Fleisher, Thomas A.; Hortin, Glen L.; Remaley, Alan T.; Nexo, Ebba; Rao, V. Koneti
Autoimmune lymphoproliferative syndrome (ALPS) is characterized by lymphadenopathy, elevated numbers of T cells with ??-T cell receptors but neither CD4 nor CD8 co-receptors, and impaired lymphocyte apoptosis in vitro. Defects in the Fas receptor are the most common cause of ALPS (ALPS Ia), but in rare cases other apoptosis proteins have been implicated, including caspase-10 (ALPS II). We investigated the
Shigui Zhu; Amy P. Hsu; Marla M. Vacek; Lixin Zheng; Alejandro A. Schäffer; Janet K. Dale; Joie Davis; Roxanne E. Fischer; Stephen E. Straus; Donna Boruchov; Frank T. Saulsbury; Michael J. Lenardo; Jennifer M. Puck
The correlates of long-term protection from measles infection are poorly understood. We followed the development of measles-specific antibody and lymphoproliferative (LP) responses in 60 children for 6 months after MMR vaccination. Prevaccine plaque reduction neutralization antibody (PRN Ab) values were low (mean±SEM 9.9±1.1). Ninety-three percent (56\\/60) had excellent PRN values at 6 months (PRN 1816±207). Prevaccine LP activity was also
Norma Bautista-López; Brian J Ward; Elaine Mills; Deirdre McCormick; Nathalie Martel; Sam Ratnam
We investigated age-related EBV(+) B-cell lymphoproliferations in the Western population. The clinical features, histology, immunophenotype, EBV-encoded RNA in situ hybridization, and clonality by PCR of T-cell receptor gamma and immunoglobulin genes were categorized in 122 EBV(+) lesions as follows: (1) reactive lymphoid hyperplasia; (2) polymorphic extranodal or (3) polymorphic nodal lymphoproliferative disease (LPD); and (4) diffuse large B-cell lymphoma (DLBCL). Interphase FISH for IG and PAX5 gene rearrangements was performed on 17 cases of DLBCL. The overall median age was 75 years (range, 45-101 years; 67 men, 55 women), and 67, 79, 73, and 77 years, respectively, for groups 1 through 4. Sixteen of 21 cases of polymorphic extranodal LPD were classified as EBV(+) mucocutaneous ulcer. PCR for immunoglobulin genes was polyclonal in reactive lymphoid hyperplasia (84%) and monoclonal in 33%, 63%, and 56% of polymorphic extranodal and nodal LPD cases and DLBCL, respectively. All groups showed restricted/clonal T-cell receptor responses (27%-70%). By FISH, 19% of DLBCLs showed IGH@ rearrangements, but PAX5 was unaffected. Disease-specific 5-year survival was 100%, 93%, 57%, and 25% for groups 1-4, respectively, and 100% for patients with EBV(+) mucocutaneous ulcer. Disease volume was predictive of therapy response (P = .0002), and pathologic subtype was predictive of overall outcome (P = .001). Age-related EBV(+) B-cell LPD encompasses a wider disease spectrum than previously recognized and includes both reactive and neoplastic conditions. Reduction in the T-cell repertoire may contribute to decreased immune surveillance. PMID:21385849
Dojcinov, Stefan D; Venkataraman, Girish; Pittaluga, Stefania; Wlodarska, Iwona; Schrager, Jeffrey A; Raffeld, Mark; Hills, Robert K; Jaffe, Elaine S
The skin immune system is characterized by the presence of two types of CD1a expressing cells: langerhans cells and dermal dendritic cells, which are professional antigen processing and presenting cells. It is well established that several dermatoses are associated with T-cell mediated immune responses. In these pathological skin conditions, T-cells are activated by professional antigen presenting cells and dendritic cells are the most potent antigen presenting cells for both T-helper cells and T-cytotoxic cells. Therefore, it is plausible that dendritic cells are crucially involved in the pathogenesis of lymphoproliferative skin conditions characterized by the presence of a T-cell infiltrate. In this study, we examined the frequency and distribution of CD1a expressing cells and CD3+ cells in both the dermal and epidermal compartment in a wide range of lymphoproliferative dermatoses with a T-lymphoid infiltrate. In the skin conditions investigated, the CD1a molecule was highly expressed in mycosis fungoides, T-cutaneous lymphoid hyperplasia, lymphomatoid papulosis and parapsoriasis, whereas few CD1a-positive cells were observed in cutaneous B-cell lymphomas. Our study demonstrates a distinct pattern of CD1a staining in the infiltrates of cutaneous lympho-proliferative disorders which may reflect different immunoregulatory events involving T-lymphocytes and CD1a-positive dermal and epidermal dendritic cells. PMID:16391853
Pigozzi, Barbara; Bordignon, Matteo; Belloni Fortina, Anna; Michelotto, Giorgio; Alaibac, Mauro
X-linked lymphoproliferative disease (XLP) is an inherited immunodeficiency characterized by the clinical triad of increased susceptibility to primary Epstein-Barr virus (EBV) infection, dysgammaglobulinaemia and lymphoma. Most cases are caused by germline mutations in the SH2D1A gene, which encodes the adaptor molecule Signalling Lymphocytic Activation Molecule (SLAM)-associated protein (SAP). Recently, a subset of patients with an XLP-like phenotype was found to carry mutations in XIAP, the gene encoding the X-linked inhibitor of apoptosis protein (XIAP). Studies of XLP patients and Sap-/- mice reveal that loss of SAP expression impairs immune cell activities, such as natural killer and CD8+ T cell cytotoxicity, T cell cytokine production, activation-induced cell death, germinal centre formation and natural killer T cell development. Efforts to dissect the diverse roles of SAP and XIAP are enhancing our understanding of immune cell biology and defining how genetic defects in these molecules predispose to EBV-specific as well as more general cellular and humoral immune dysfunction. These studies are also highlighting critical signalling pathways that might be amenable to pharmacological targeting to improve the treatment of XLP and other disorders associated with impaired antiviral and antitumour immunity. PMID:21083659
Rezaei, Nima; Mahmoudi, Elham; Aghamohammadi, Asghar; Das, Rupali; Nichols, Kim E
Accurate diagnosis of lymphoma includes the assessment of lineage-specific markers. Hematopoietic and lymphoid tissues express PAX5 exclusively in pro-B-cell to mature B-cell stages. However, some mature PAX5+ T-cell lymphomas have been reported. We report three cases of primary cutaneous CD30+ T-cell lymphoproliferative disorders (LPDs) with PAX5 expression: one cutaneous anaplastic large cell lymphoma (ALCL) and two cases of lymphomatoid papulosis (LyP). The three patients were 26 years old and female, 75 years old and female, and 65 years old and male. In all cases, Hodgkin's and Reed-Sternberg-like large lymphoid cells were present, positive for CD30, fascin, and PAX5, and negative for CD3, CD4, CD8, CD20, CD45RO, CD56, cytotoxic markers, and Epstein-Barr virus. The ALCL was accompanied by lymphadenopathy; the patient died of progressive disease 5 months after diagnosis. The LyP cases were localized in the skin with spontaneous regression. One case was diagnosed during pregnancy, transformed to ALCL, and ended in death 32 months after diagnosis despite multi-agent chemotherapy. This study is the first to address the clinical significance of PAX5+ primary cutaneous CD30+ T-cell LPDs. These cases were distinct regarding PAX5 expression and a relatively aggressive clinical course versus conventional primary cutaneous CD30+ T-cell LPDs. PMID:22449230
Hagiwara, Masahiro; Tomita, Akihiro; Takata, Katsuyoshi; Shimoyama, Yoshie; Yoshino, Tadashi; Tomita, Yasushi; Nakamura, Shigeo
Human islet isolation is associated with adverse conditions inducing apoptosis and necrosis. The aim of the present study was to assess whether antiapoptotic preconditioning can improve in vitro and posttransplant function of isolated human islets. A dose-finding study demonstrated that 200 ?mol/L of the caspase-3 inhibitor Ac-DEVD-CMK was most efficient to reduce the expression of activated caspase-3 in isolated human islets exposed to severe heat shock. Ac-DEVD-CMK-pretreated or sham-treated islets were transplanted into immunocompetent or immunodeficient diabetic mice and subjected to static glucose incubation to measure insulin and proinsulin secretion. Antiapoptotic pretreatment significantly deteriorated graft function resulting in elevated nonfasting serum glucose when compared to sham-treated islets transplanted into diabetic nude mice (p < 0.01) and into immunocompetent mice (p < 0.05). Ac-DEVD-CMK pretreatment did not significantly change basal and glucose-stimulated insulin release compared to sham-treated human islets but increased the proinsulin release at high glucose concentrations (20 mM) thus reducing the insulin-to-proinsulin ratio in preconditioned islets (p < 0.05). This study demonstrates that the caspase-3 inhibitor Ac-DEVD-CMK interferes with proinsulin conversion in preconditioned islets reducing their potency to cure diabetic mice. The mechanism behind this phenomenon is unclear so far but may be related to the ketone CMK linked to the Ac-DEVD molecule. Further studies are required to identify biocompatible caspase inhibitors suitable for islet preconditioning. PMID:23536200
Brandhorst, Daniel; Brandhorst, Heide; Maataoui, Vidya; Maataoui, Adel; Johnson, Paul R V
Methotrexate (MTX)-associated B-cell lymphoproliferative disorders (B-LPD) may first present in the skin, but their clinicopathologic features are still ill defined. Differentiation from primary cutaneous follicle center lymphoma and primary cutaneous diffuse large B-cell lymphoma, leg type (PCLBCL-LT) is important, as MTX-associated B-LPD may show spontaneous regression after withdrawal of MTX therapy. In the present study, the clinicopathologic and phenotypical features of 10 patients with MTX-associated B-LPD first presenting in the skin, including 5 EBV and 5 EBV cases, were investigated. Six patients had skin-limited disease. Clinically, abrogation of MTX therapy resulted in a complete response in 4 cases and a partial response in another 2. The 5-year disease-specific survival was 90%. MTX-associated B-LPD differed from primary cutaneous follicle center lymphoma by the presence of ulcerating and/or generalized skin lesions, an infiltrate composed of centroblasts/immunoblasts rather than large centrocytes, reduced staining for CD79a, and expression of BCL2, IRF4, and FOXP1 in most cases. EBV MTX-associated B-LPD differed from PCLBCL-LT by the presence ulcerative skin lesions, marked tumor cell polymorphism, reduced staining for CD79a, and expression of CD30 and EBV. EBV cases showed morphologic and immunophenotypical similarities to PCLBCL-LT but differed by presentation with generalized skin lesions in 4 of 5 cases. The results of this study, showing a relatively good clinical outcome and spontaneous disease regression after only withdrawal of MTX in a considerable proportion of patients, underscores the importance of a careful wait-and-see policy before considering more aggressive therapies in patients with MTX-associated B-LPD of the skin. PMID:24805861
Koens, Lianne; Senff, Nancy J; Vermeer, Maarten H; Willemze, Rein; Jansen, Patty M
Epstein-Barr Virus (EBV) is a herpesvirus usually infecting B-cells but may occasionally infect T- or natural killer (NK)-cells. EBV-associated T- or NK-cell lymphoproliferations represent a continuous spectrum of diseases ranging from asymptomatic infection, infectious mononucleosis (IM), to clonal and malignant lymphoproliferations including systemic EBV-positive T/NK-cell lymphoproliferative disease (EBV-T/NK-LPD) of childhood and hydroa-vacciniforme-like lymphoma of the skin. The clonal diseases are more prevalent in East Asia and exhibit overlapping clinical and pathological features with chronic active EBV infection. Here we report our experience on 10 cases of EBV-associated T-cell lymphoproliferation from Taiwan including five males and five females with a median age of 18 years old (range, 15-28). The most common clinical symptoms were fever, neck mass and hepatosplenomegaly. Eight of these patients showed elevated lactate dehydrogenase level and half of the patients had cytopenia. All patients had either elevated EBV antibody titers or increased serum EBV DNA levels. Five cases were clinically IM-like with polyclonal (3 cases) or clonal (2 cases) T-cell lymphoproliferation. Two patients each had chronic active EBV infection (CAEBV) and hemophagocytic lymphohistiocytosis (HLH). One patient had both CAEBV and HLH. One of the HLH patients with marrow infiltration by intra-sinusoidal large atypical lymphocytes experienced a fulminant course. In a median follow-up time of 21.5 months, seven patients were free of disease, one was alive with disease, and two died of disease in 31 and 3 months, respectively, despite chemotherapy. We confirmed a wide clinicopathological range of EVB-associated T-cell lymphoproliferation in Taiwan. Furthermore, monomorphic LPD and the single case with fulminant course as defined by Ohshima et al (Pathol Int 2018) as categories A3 and B, respectively, died of disease despite chemotherapy. Our report, the largest series in the recent decade from Taiwan, adds to the understanding of these rare diseases with variable clinical and histopathological presentations.
Wang, Ren-Ching; Chang, Sheng-Tsung; Hsieh, Yen-Chuan; Huang, Wan-Ting; Hsu, Jeng-Dong; Tseng, Chih-En; Wang, Ming-Chung; Hwang, Wei-Shou; Wang, John; Chuang, Shih-Sung
Background Serum levels of soluble CD30 (sCD30) have been considered as a predictor of acute kidney allograft rejection. We have evaluated\\u000a the pre-transplant and post-transplant levels of sCD30 with the aim of determining its value in predicting and diagnosing\\u000a kidney rejection.\\u000a \\u000a \\u000a \\u000a Methods We measured sCD30 serum levels before kidney transplantation, 5 days post-operatively, and at creatinine elevation episodes.\\u000a The predictive value of
Mohsen Nafar; Farhat Farrokhi; Mohammad Vaezi; Amir-Ebrahim Entezari; Fatemeh Pour-Reza-Gholi; Ahmad Firoozan; Behzad Eniollahi
Occult HCV infection is a form of chronic HCV infection characterized by absence of detectable anti-HCV antibodies or plasma HCV-RNA but presence of HCV-RNA in liver biopsy and/or peripheral blood mononuclear cells (PBMCs). The aim of this study was to determine the presence of HCV-RNA in PBMCs of patients with lymphoproliferative disorders. One hundred and four consecutive patients with lymphoproliferative disorders admitted to Firouzgar Hospital from January 2010 to March 2011 were recruited in this cross-sectional study. A 6-ml sample of whole blood was taken from the patients, the total RNA was extracted from the samples after the separation of plasma and PBMCs. The HCV-RNA of the samples was amplified by reverse transcriptase-nested polymerase chain reaction (RT-nested PCR). The HCV genotypes of the positive samples were tested using the INNO-LiPA™ HCV II kit, and the HCV genotypes were then confirmed by sequencing of the 5'-UTR fragments after the PCR products were cloned into a pJET1.2/blunt cloning vector. The mean age of the patients was 48.3?±?1.76 years (range: 16-83). HCV-RNA was found in PBMCs from 2 (1.9%) of the 104 patients. Genotyping showed that the patients were infected with HCV subtype 1a. One patient suffered non-Hodgkin's lymphoma and the other suffered chronic lymphocytic leukemia. Patients with lymphoproliferative disorders with negative anti-HCV antibodies and negative plasma HCV-RNA may have occult HCV infection. Therefore, in the absence of a liver biopsy, the testing of PBMCs for the detection of genomic HCV-RNA may be beneficial. PMID:23168913
Farahani, Maryam; Bokharaei-Salim, Farah; Ghane, Masood; Basi, Ali; Meysami, Parisa; Keyvani, Hossein
Delayed graft function (DGF) increases the risk of acute allograft rejection and may affect long-term graft survival. We compared pre-transplant, early post-transplant, and late post-transplant serum creatinine (Cr) and plasma levels of neopterin, cytokines, and cytokine receptors/antagonists in patients with DGF (n = 39), slow graft function (SGF) (n = 43), or immediate graft function (IGF) (n = 30). Three and eight days post-transplant, plasma neopterin (p < 0.001; p < 0.001), Soluble Interleukin-6 (IL-6) receptor (R) (p = 0.002; p = 0.001), and IL-10 (p = 0.003; p = 0.001) were higher in DGF than IGF patients. One month post-transplant, plasma neopterin (p < 0.001) and IL-10 (p < 0.001) were higher in DGF than IGF patients. Three days post-transplant, the results indicated reduced sIL-1 receptor antognist (RA) production in DGF patients (p = 0.001). Simultaneously, plasma sIL-6R and IL-10 increased in DGF (p < 0.001; p = 0.003) and SGF (p = 0.007; p = 0.030) patients, indicating increased production of sIL-6R and IL-10. Lower sIL-1 production in DGF than IGF patients early post-transplant might promote the increased production of monocyte-derived neopterin, sIL-6R, and IL-10. This monocyte/macrophage activation might induce inflammation in the graft and subsequently cause an impairment of graft function. Blocking of monocyte activity after renal transplantation may be considered a potential approach for improving graft outcome. PMID:19925477
Sadeghi, Mahmoud; Daniel, Volker; Naujokat, Cord; Schmidt, Jan; Mehrabi, Arianeb; Zeier, Martin; Opelz, Gerhard
The US kidney allocation system adopted in 2013 will allocate the best 20% of deceased donor kidneys (based on the kidney donor risk index [KDRI]) to the 20% of waitlisted patients with the highest estimated posttransplant survival (EPTS). The EPTS has not been externally validated, raising concerns as to its suitability to discriminate between kidney transplant candidates. We examined EPTS using data from the Australia and New Zealand Dialysis and Transplant (ANZDATA) Registry. We included 4983 adult kidney-only deceased donor transplants over 2000-2011. We constructed three Cox models for patient survival: (i) EPTS alone; (ii) EPTS plus donor age, hypertension and HLA-DR mismatch; and (iii) EPTS plus log(KDRI). All models demonstrated moderately good discrimination, with Harrell's C statistics of 0.67, 0.68 and 0.69, respectively. These results are virtually identical to the internal validation that demonstrated a c-statistic of 0.69. These results provide external validation of the EPTS as a moderately good tool for discriminating posttransplant survival of adult kidney-only transplant recipients. PMID:24903739
Clayton, P A; McDonald, S P; Snyder, J J; Salkowski, N; Chadban, S J
This study investigated the incidence and types of post-transplant malignancy in Chinese renal transplant recipients and the risk factors associated with malignancy. Data from 3,462 patients who underwent renal transplantation at Beijing Friendship Hospital were combined with data from 26 previous reports describing malignancy rates in 27,170 Chinese renal transplant recipients. Between 1974 and 2014, 179/3,462 (5.17 %) patients who underwent renal transplantation at our center developed malignancy. The most common site of malignancy was the urinary system, and the most common type was urothelial transitional cell carcinoma. Combined data from our center and previous reports showed malignancy in 671 (2.19 %) Chinese renal transplant recipients. The ten most common malignancies were urothelial transitional cell carcinoma (n = 283), hepatocellular carcinoma (n = 68), gastrointestinal cancer (n = 63), renal cell carcinoma (n = 42), lymphoma (n = 42), lung cancer (n = 28), breast cancer (n = 19), skin cancer (n = 18), Kaposi's sarcoma (n = 12), and cervical cancer (n = 10). The incidence of post-transplant malignancy in renal transplant recipients was lower in China than the reported rates in other countries, and the most common sites of malignancy were the urinary and digestive system. The relative frequency of malignancy sites differed between northern and southern China. Renal transplant recipients on long-term immunosuppressive therapy should receive careful follow-up, including annual or biannual screening for malignancy in high-risk individuals. PMID:24908063
Zhang, Jian; Ma, Linlin; Xie, Zelin; Guo, Yuwen; Sun, Wen; Zhang, Lei; Lin, Jun; Xiao, Jing; Zhu, Yichen; Tian, Ye
Autoimmune lymphoproliferative syndrome (ALPS) is a genetic disorder of the immune system caused by inadequate induction of apoptosis via the Fas pathway, mainly characterized by generalized lymphadenopathy, splenomegaly, and autoimmune cytopenias, as well as increased risk of lymphoma. Although the clinical course of ALPS is highly variable, without treatment long-term prognosis is unsatisfactory for most patients. ALPS has been treated with most of the existing immunosuppressive agents, with variable success. We hereby present a case of a child with ALPS whose greatly enlarged lymph nodes rapidly regressed upon initiation of rapamycin, a novel potential therapeutic agent in the treatment of ALPS. PMID:19588524
Jani?, Mihailo Dragana; Brasanac, Cedomir Dimitrije; Jankovi?, Jovan Srda; Dokmanovi?, Bogdan Lidija; Krstovski, Radmio Nada; Kraguljac Kurtovi?, Janko Nada
Several recent studies have reported detection of HTLV-I genetic sequences in patients with cutaneous T-cell lymphoma (CTCL) including mycosis fungoides and Sezary syndrome. The purpose of this study was to determine whether HTLV-I was detectable in lesional tissues of patients suffering from diseases known to be associated with CTCL. Thirty-five cases were obtained from diverse geographical locations including Ohio, California, Switzerland, and Japan. Six of them had concurrent CTCL. Cases were analyzed using a combination of genomic polymerase chain reaction (PCR)/ Southern blot, dot blot, and Southern blot analyses. All assays were specific for HTLV-I provirus. Sensitivity ranged from approximately 10(-6) for PCR-based studies to 10(-2) for unamplified genomic blotting. Lesional DNA from patients with lymphomatoid papulosis (fourteen cases), Hodgkin's disease (twelve cases), and CD30+ large-cell lymphoma (nine cases) was tested for the HTLV-I proviral pX region using a genomic PCR assay followed by confirmatory Southern blot analysis with a nested oligonucleotide pX probe. All cases were uniformly negative. All of the Hodgkin's disease cases, eight of the large-cell lymphoma cases, and six of the lymphomatoid papulosis cases were then subjected to dot blot analysis of genomic DNA using a full-length HTLV-I proviral DNA probe that spans all regions of the HTLV-I genome. Again, all cases were negative. Finally, eleven of the Hodgkin's disease cases were also subjected to Southern blot analysis of EcoRI-digested genomic DNA using the same full-length HTLV-I probe. Once again, all cases were negative. These findings indicated that, despite utilization of a variety of sensitive and specific molecular biological methods, HTLV-I genetic sequences were not detectable in patients with CTCL-associated lymphoproliferative disorders. These results strongly suggest that the HTLV-I retrovirus is not involved in the pathogenesis of these diseases. Images Figure 1 Figure 2 Figure 3 Figure 4 Figure 5
Wood, G. S.; Schaffer, J. M.; Boni, R.; Dummer, R.; Burg, G.; Takeshita, M.; Kikuchi, M.
The most common lymphoproliferative disease in chickens is Marek's disease (MD), which is caused by the oncogenic herpesvirus Marek's disease virus (MDV). The emergence of hypervirulent pathotypes of MDV has led to vaccine failures, which have become common and which have resulted in serious economic losses in some countries, and a revaccination strategy has been introduced in practice. The mechanism
Changxin Wu; Junji Gan; Qiao Jin; Chuangfu Chen; Ping Liang; Yantao Wu; Xuefen Liu; Li Ma; Fred Davison
Allogeneic hematopoietic cell transplantation (HCT) is a complex and costly procedure. Unrelated umbilical cord blood (UCB) is an alternative graft source for patients without matched related donors (MRD); however, costs of UCB HCT have not been described. We compared the costs of HCT within the first 100 days among recipients of MRD (myeloablative = 67, nonmyeloablative = 54) or UCB (myeloablative = 63, nonmyeloablative = 110) HCT. Cost and hospitalization data were obtained from the institutional accounting department. The 100-day probabilities of overall survival (OS) and cumulative incidence of treatment-related mortality (TRM) were comparable among 4 transplant types; however, neutrophil recovery was delayed and graft failure was more likely in UCB recipients. The median cost per day survived (excluding costs of graft acquisition) was $1016 for myeloablative MRD, $2082 for myeloablative UCB, $612 for nonmyeloablative MRD, and $1156 for nonmyeloablative UCB recipients, respectively (P < .001). In multivariate analysis, adjusting for important patient, disease, and HCT-related characteristics, as well as major post-HCT complications, factors associated with higher costs within the first 100 days were myeloablative UCB HCT (relative risk 1.3 [95% confidence intervals, 1.1-1.5] versus myeloablative MRD HCT), graft failure (1.8 [1.7-1.9]), need for dialysis (1.3 [1.1-1.5]) or mechanical ventilation (1.3 [1.2-1.4]) and total hospital stay in the highest tertile (>48 days; 2.1 [1.9-2.3]). The median cost per day survived for patients with graft failure was $6976 (versus $1105 for no graft failure), dialysis was $4764 (versus $1102 for no dialysis), and $5099 for mechanical ventilation (versus $977 for no mechanical ventilation). Within the first 100 days, the absolute costs of myeloablative and nonmyeloablative UCB are higher than myeloablative and nonmyeloablative MRD transplantation. These costs are primarily driven by severe posttransplant complications, graft failure, and prolonged inpatient stay. Strategies to enhance engraftment will decrease the costs of UCB transplantation. PMID:19361748
Majhail, Navneet S; Mothukuri, Jaya M; Brunstein, Claudio G; Weisdorf, Daniel J
We investigated the bone phenotype of mice with generalized lymphoproliferative disorder (gld) due to a defect in the Fas ligand-mediated apoptotic pathway. C57BL/6-gld mice had greater whole body bone mineral density and greater trabecular bone volume than their wild-type controls. gld mice lost 5-fold less trabecular bone and had less osteoclasts on bone surfaces after ovariectomy-induced bone resorption. They also formed more bone in a model of osteogenic regeneration after bone marrow ablation, had less osteoclasts on bone surfaces and less apoptotic osteoblasts. gld and wild-type mice had similar numbers of osteoclasts in bone marrow cultures, but marrow stromal fibroblasts from gld mice formed more alkaline phosphatase-positive colonies. Bone diaphyseal shafts and bone marrow stromal fibroblasts produced more osteoprotegerin mRNA and protein than wild-type mice. These findings provide evidence that the disturbance of the bone system is a part of generalized lymphoproliferative syndrome and indicates the possible role of osteoprotegerin as a regulatory link between the bone and immune system. PMID:12538719
Katavi?, Vedran; Luki?, Ivan Kresimir; Kovaci?, Natasa; Grcevi?, Danka; Lorenzo, Joseph A; Marusi?, Ana
Background. Occult hepatitis C virus infection (OCI) was identified as a new form of Hepatitis C virus (HCV), characterized by undetectable HCV antibodies and HCV RNA in serum, while HCV RNA is detectable in liver and peripheral blood cells only. Aim. The aim of this study was to investigate the occurrence of OCI in Egyptian patients with lymphoproliferative disorders (LPDs) and to compare its prevalence with that of HCV in those patients. Subjects and Methods. The current study included 100 subjects, 50 of them were newly diagnosed cases having different lymphoproliferative disorders (patients group), and 50 were apparently healthy volunteers (controls group). HCV antibodies were detected by ELISA, HCV RNA was detected in serum and peripheral blood mononuclear cells (PBMCs) by reverse transcription polymerase chain reaction(RT-PCR), and HCV genotype was detected by INNO-LiPA. Results. OCI was detected in 20% of patients group, compared to only 4% OCI in controls group. HCV was detected in 26% of patients group with a slightly higher prevalence. There was a male predominance in both HCV and OCI. All HCV positive patients were genotype 4. Conclusion. Our data revealed occurrence of occult HCV infection in Egyptian LPD patients at a prevalence of 20% compared to 26% of HCV.
Youssef, Samar Samir; Nasr, Aml S.; El Zanaty, Taher; El Rawi, Rasha Sayed; Mattar, Mervat M.
INTRODUCTION: The differential diagnosis of B-cell lymphoproliferative processes remains a challenge for pathologists, dermatologists and oncologists, despite advances in histology, immunohistochemistry and molecular biology. OBJECTIVE: Evaluate aid and limitations of clonality analysis in the diagnosis of primary cutaneous B-cell lymphomas and B-cell pseudolymphomas. METHODS: This study included 29 cases of B-cell lymphoproliferative processes classified as primary cutaneous B-cell lymphomas (13), B-cell pseudolymphomas (6) and inconclusive cases (10) using histology and immunohistochemistry. The clonality analysis was performed by polymerase chain reaction analysis of immunoglobulin light chain and heavy chain rearrangements. RESULTS: DNA quality was shown to be generally poor; eight samples were inadequate for polymerase chain reaction analysis. The results showed monoclonality in eight of the primary cutaneous B-cell lymphomas and polyclonality in four of the B-cell pseudolymphomas. In addition, monoclonality was shown in two of the inconclusive cases by histology and immunohistochemistry, demonstrating the utility of polymerase chain reaction as an ancillary diagnostic tool for primary cutaneous B-cell lymphomas. DISCUSSION: The low quality DNA extracted from these cases demanded the use of an IgH protocol that yielded small fragments and IgK. Both methods used together improved detection. CONCLUSION: Use of the two protocols, immunoglobulin heavy chain FR3-trad and immunoglobulin light chain-Kappa Biomed protocols for clonality analysis improved diagnostic accuracy.
Melotti, Claudia Z; Amary, Maria Fernanda Carriel; Sotto, Miriam Nacagami; Diss, Timothy; Sanches, Jose Antonio
Because survival of recipients of allogeneic hematopoietic stem cell transplantation (HSCT) has improved, long-term complications become more important. We studied the incidence and risk factors of chronic kidney disease in these patients and evaluated associated posttransplant complications and mortality. We performed a retrospective cohort study of 266 adults who received myeloablative allogeneic HSCT and who survived for >6 months in
Sabina Kersting; Ronald J. Hené; Hein A. Koomans; Leo F. Verdonck
Chorionic Villous Biopsy (CVS) for diagnosis of XLP was undertaken at 10 weeks gestation in an obligate carrier. The fetus was found to be male by cytogenetic analysis. XLP (Xq25-q26) is closely linked to the RFLP markers DXS10, DXS37 and DXS42, but only DXS10 (distal to XLP) was informative for prenatal diagnosis in this family. RFLP analysis using this marker gave a 7% risk that the fetus was affected, based on the known recombination frequency between DXS10 and XLP. Further investigation was then undertaken to obtain a rapid and more accurate diagnosis using the three highly polymorphic PCR based markers. These were the AC repeat markers DXS424 (XL5A) and DXS425 (XL90A3) and the tetramer repeat marker within HPRT. DX425 is approximately 10 cM proximal to DXS10 and HPRT but is not known with certainty to map proximal or distal to XLP. DXS424 is proximal to DXS10 and HPRT and was inferred to be proximal to XLP on the basis of map distance from HPRT estimated by linkage analysis of data from CEPH pedigrees. This was confirmed by a recombinant in the XLP family between DXS424 and DXS425, placing DXS424 proximal to XLP. Diagnosis by linkage using DXS424 and DXS425, at least one of which is proximal to XLP, and distal markers DXS10 and HPRT, increased the accuracy of diagnosis using flanking marker analysis to greater than 99% that the fetus was unaffected. HLA DR typing of the CVS showed that the fetus was DR identical to a male sibling with XLP. HLA compatibility was confirmed at delivery by full HLA typing and MLC.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:1358486
Mulley, J C; Turner, A M; Gedeon, A K; Berdoukas, V A; Huang, T H; Ledbetter, D H; Grierson, H; Purtilo, D T
A laboratory and clinical evaluation of 24 patients with hairy cell leukemia was carried out over a 23-month period. Most patients had splenomegaly without adenopathy or pancyotpenia. Nine of the patients had undergone splenectomy prior to referral; their median WBC count was 6600\\/mmÂ³. The median WBC count for the 14 patients who had no prior therapy was 3550\\/mmÂ³, and their
Harvey M. Golomb
Bleeding and thrombosis are important complications in patients with malignant lymphomas. They may be due to direct actions of the lymphoma, such as venous compression or bone marrow infiltration, but they may also be caused by paraneoplastic phenomena, which are immune-mediated in most of the cases. The most important paraneoplastic immune-mediated disorders in lymphomas causing bleeding are autoimmune thrombocytopenia, acquired hemophilia A and acquired von Willebrand syndrome. In addition, there are a variety of other less common immune-mediated bleeding conditions, such as acquired thrombasthenia, acquired factor X-, V-, XI-, XII-, or prothrombin deficiency. The presence of antiphospholipid antibodies is a rare condition predisposing to venous and arterial thrombosis and there are other very uncommon conditions, which predispose exclusively to arterial thrombosis such as hyperlipidemic xanthomatosis. Interestingly, there is hardly any correlation between the histological type and the aggressiveness of lymphoma and the type and prevalence of the immune-mediated conditions. Successful treatment of the underlying lymphoma is often associated with definite and sustained resolution of the immune-mediated disorder. PMID:24615692
Lechner, Klaus; Pabinger, Ingrid; Obermeier, Hanna Lena; Knoebl, Paul
BackgroundLevels of sCD30 represent a biomarker for early outcome in kidney transplantation. The purpose of this study was to determine the role of sCD30 levels for prediction of graft loss in the late post-transplant period.
Julio C. Delgado; Igor Y. Pavlov; Fuad S. Shihab
Summary Hematopoietic stem cell transplantation (HSCT) is a curative treatment of many hemato- logical disorders. Recent studies have shown the associations between polymorphic fea- tures of cytokine-encoding genes and the incidence of post-transplant complications in the recipients of allogeneic HSCT. This review focuses on the relationship between the polymorphic patterns of patient genes encoding tumor necrosis factor (TNF)-? and TNF-?
Epstein–Barr virus (EBV) is closely associated with the progressive and often fatal lymphoproliferative disorders (LPD) in post bone marrow transplantation (BMT) and immunocompromised hosts. The incidence increases significantly when alternative donors or manipulation of marrow graft are used. A total of 318 consecutive BMT from partially mismatched related family donors (PMRD) were performed between February 1993 and June 1998. Known
K-Y Chiang; LJ Hazlett; KT Godder; SH Abhyankar; NP Christiansen; F van Rhee; CG Lee; K Bridges; RS Parrish; PJ Henslee-Downey
Posttransplantation lymphoproliferative disorders (PTLD) is not uncommon and can occur in 2% to 5% of solid organ recipients on immunosuppression. Epstein-Barr virus (EBV) infection or reactivation and intensive anti-T lymphocyte treatment are important pathogenetic factors for a large proportion of these disorders. Nonclonal lesions with polymorphous histology have a potential for regressing when the immunosuppressants are reduced or stopped. Clonal
PK Li; K Tsang; CC Szeto; TY Wong; CB Leung; SF Lui; S Yu; FM Lai
Background: Malignancy is a common complication after renal transplantation. Death with functioning graft and chronic graft loss are two competing outcomes in patients with post-transplant malignancies. Objectives: The purpose of our study was to evaluate the risk factors associated with cumulative incidence of these two outcomes. Patients and Methods: Fine-Gray model was used for 266 cases with post-transplant malignancy in Iran. These patients were followed-up from the diagnosis until the date of last visit, chronic graft loss, or death, subsequently. Results: At the end of the study, as competing events, chronic graft loss and death with functioning graft were seen in 27 (10.2%) and 53 cases (19.9%), respectively, while 186 cases (69.9%) were accounted as censored. The incidence rate of death was approximately two-time of the incidence rate of chronic graft loss (8.6 vs. 4.4 per 100 person-years). In multivariate analysis, significant risk factors associated with cumulative incidence of death included age (P < 0.007, subhazard ratio (SHR) = 1.03), type of cancer (P < 0.0001), and response to treatment (P < 0.0001, SHR = 0.027). The significant risk factors associated with cumulative incidence of chronic graft loss were gender (P = 0.05, SHR = 0.37), treatment modality (P < 0.0001), and response to treatment (P = 0.048, SHR = 0.47). Conclusions: Using these factors, nephrologists may predict the occurrence of graft loss or death. If the probability of graft loss was higher, physicians can decrease the immunosuppressive medications dosage to decrease the incidence of graft loss.
Salesi, Mahmoud; Rostami, Zohreh; Rahimi Foroushani, Abbas; Mehrazmay, Ali Reza; Mohammadi, Jamile; Einollahi, Behzad; Asgharian, Saeed; Eshraghian, Mohammad Reza
Epstein-Barr virus (EBV), an ubiquitous human B lymphotropic virus, is the cause of infectious mononucleosis. Moreover, EBV infection can be followed by lymphoproliferative diseases in patients with inherited and acquired immunodeficiencies. Primary EBV infection may be a threat to all children after marrow or organ transplantation or those receiving chronic immunosuppressive treatment for various other reasons. The virus has been
V. Schuster; H. W. Kreth
Observation of a patient with acquired hypogammaglobulinemia associated with a mononucleosis syndrome led to the identification of one of the largest families affected by the X-linked lymphoproliferative (XLP) syndrome in the world. It is the first such family identified in Switzerland and the largest in Europe. At least nine male subjects over two generations presented phenotypic expressions consistent with the XLP syndrome. Study of the pedigree extending over seven generations suggests that the mutation occurred in the proband's great-grandmother. In the next generation, a second mutation of the X chromosome in one branch of the family resulted in expression of hemophilia A in the children. This remarkably large family, comprising six living obligate female carriers, displays a wide spectrum of the XLP syndrome and offers valuable information for future genetic linkage studies and for genetic counseling. PMID:3348254
Hayoz, D; Lenoir, G M; Nicole, A; Pugin, P; Regamey, C
The World Health Organization (WHO) recently defined systemic Epstein-Barr virus (EBV)-positive T-cell lymphoproliferative disorders (LPD) of childhood as a life-threatening illness. However, this rare disease has not been extensively studied. Here we report a case of systemic EBV-positive T-cell LPD in a previously healthy middle-aged man with a chief complaint of chronic diarrhea. The initial colon biopsy showed focal infiltration of EBV-positive small lymphocytes without any atypia. However, the disease rapidly progressed and the patient required a total colectomy due to severe gastrointestinal bleeding. Three and half months after admission, the patient died from a complication of disseminated intravascular coagulation. The resected colon showed diffuse infiltration of EBV-positive atypical lymphocytes with ischemic change. Most atypical lymphocytes were CD3+ or CD5+. The monoclonality of EBV was demonstrated by sequence variation analysis of the latent membrane protein 1 (LMP1) gene in the colectomy specimen as well as in the initial biopsy.
Abdul-Ghafar, Jamshid; Kim, Jae Woo; Park, Kwang Hwa
Cold agglutinin disease (CAD) is a rare autoimmune hemolytic anemia. Although it can occur secondary to lymphoproliferative disorders and autoimmune or infectious diseases, CAD is rarely reported as secondary to solid tumors. We report a case of a woman aged 18 years diagnosed with a well-differentiated hepatocellular carcinoma of the fibrolamellar subtype, who was shown to have CAD also. Her general condition, including CAD, improved after targeted therapy with sorafenib for the hepatocellular carcinoma and only conservative measures for the CAD that consisted of avoidance of cold. In summary, although it is an extremely rare association and less common than lymphoproliferative disorders, CAD can be associated with solid tumors. PMID:21293066
Al-Matham, Khalid; Alabed, Iehab; Zaidi, Syed Z A; Qushmaq, Khalid A
This study was designed to determine the complete response (CR) rate, event-free survival (EFS) and overall survival (OS) in patients with metastatic breast cancer treated with an adriamycin-based induction regimen, high-dose chemotherapy consisting of cyclophosphamide and thiotepa with autologous bone marrow or stem cell reinfusion, followed by post-transplant 5-fluorouracil and cisplatin. Forty-eight consecutive patients were enrolled and 35 received two
Tallman; AW Rademaker; L Jahnke; SG Brown; A Bauman; C Mangan; C Kelly; H Rubin; J Shaw; K Kiel; LI Gordon; WJ Gradishar; JN Winter
The use of monoclonal antibody, rituximab, had been reported to be associated with some severe viral infections. The inference\\u000a of rituximab therapy and post-transplant cytomegalovirus (CMV) infectious complications in non-Hodgkin’s lymphoma (NHL) patients\\u000a is still unclear now. From 2002 to 2005, 46 patients with relapsed indolent or high-risk aggressive B cell NHL who received\\u000a rituximab (17 patients) or not (29
Ming-Yang Lee; Tzeon-Jye Chiou; Liang-Tsai Hsiao; Muh-Hwa Yang; Pang-Chan Lin; Say-Bee Poh; Chueh-Chuan Yen; Jin-Hwang Liu; Hao-Wei Teng; Ta-Chung Chao; Wei-Shu Wang; Po-Min Chen
The lymphoproliferative response and T lymphocyte subsets were evaluated at different stages of carcinogenesis in male Wistar rats sequentially initiated with N-diethylnitrosamine (DEN), N-butyl-N-4(hydroxybutyl)nitrosamine (BBN), N-methyl-N-nitrosourea (MNU), dihydroxy-di-N-propylnitrosamine (DHPN) and N,N?-dimethylhydrazine (DMH) (DMBDD initiation). One group was evaluated at the 4th week and other initiated group at the 30th week. Two initiated groups were also exposed through diet to 2-acetylaminofluorene
Ana Lúcia Tozzi Spinardi-Barbisan; Ramon Kaneno; Maria Aparecida Marchesan Rodrigues; Daisy Maria Fávero Salvadori; Eduardo Luiz Trindade Moreira; Lu??s Fernando Barbisan; João Lauro Viana de Camargo
Leukemic B-chronic lymphoproliferative disorders (B-CLPDs) are generally be- lieved to derive from a monoclonal B cell; biclonality has only occasionally been reported. In this study, we have explored the incidence of B-CLPD cases with 2 or more B-cell clones and established both the phenotypic differences between the coexisting clones and the clinicobiologic features of these patients. In total, 53 B-CLPD
Maria-Luz Sanchez; Julia Almeida; David Gonzalez; Marcos Gonzalez; Maria-Antonia Garcia-Marcos; Ana Balanzategui; Maria-Consuelo Lopez-Berges; Josep Nomdedeu; Teresa Vallespi; Marcos Barbon; Alejandro Martin; Pilar de la Fuente; Guillermo Martin-Nunez; Javier Fernandez-Calvo; Jesus-Maria Hernandez; Jesus F. San Miguel; Alberto Orfao
Lymphomas were studied in kindreds with autoimmune lymphoproliferative syn- drome (ALPS; Canale-Smith syndrome), a disorder of lymphocyte homeostasis usually associated with germline Fas mu- tations. Fas (CD95\\/APO-1) is a cell sur- face receptor that initiates programmed cell death, or apoptosis, of activated lym- phocytes. Lymphoma phenotype was de- termined by immunohistochemistry, fre- quency of CD31CD42CD82 T-cell-receptor a\\/b cells by flow
Stephen E. Straus; Elaine S. Jaffe; Jennifer M. Puck; Janet K. Dale; Keith B. Elkon; Angela Rosen-Wolff; Anke M. J. Peters; Michael C. Sneller; Claire W. Hallahan; Jin Wang; Roxanne E. Fischer; Christine M. Jackson; Albert Y. Lin; Caroline Baumler; Elke Siegert; Alexander Marx; Akshay K. Vaishnaw; Tamara Grodzicky; Thomas A. Fleisher; Michael J. Lenardo
Patients with X-linked lymphoproliferative syndrome (XLP) experience excessive T cell proliferation after primary Epstein–Barr virus (EBV) infection, due to mutations in the signalling lymphocyte activation molecule (SLAM) associated protein (SAP) molecule. We examined the impact of dysfunctional proliferative control on the extent of CD8+ T cell differentiation in XLP patients who recovered from primary EBV infection. Although these young patients
Fiona J. Plunkett; Ornella Franzese; Lavina L. Belaramani; Jean M. Fletcher; Kimberly C. Gilmour; Reza Sharifi; Naeem Khan; Andrew D. Hislop; Andrea Cara; Mike Salmon; H. Bobby Gaspar; Malcom H. A. Rustin; David Webster; Arne N. Akbar
A 20-month-old male with fulminant infectious mononucleosis and the X-linked lymphoproliferative syndrome (XLP) was studied. Epstein-Barr virus (EBV)-determined nuclear antigen (EBNA) and EBV DNA were detected in various tissues. Despite a combined treatment with acyclovir, immunoglobulin, and methylprednisolone, the patient deteriorated rapidly. Following treatment with recombinant interferon-gamma (IFN-?), defervescence occurred and circulating EBNA-positive cells markedly decreased. IFN-? prior to treatment
Motohiko Okano; Geoffrey M. Thiele; Roger H. Kobayashi; Jack R. Davis; Mark S. Synovec; Helen L. Grierson; Howard S. Jaffe; David T. Purtilo
X-linked lympho-proliferative (XLP) is an immunodeficiency condition caused by mutation or deletion of the gene encoding the adaptor protein SAP\\/SH2D1A. Besides defects in T cell and NK cell function and an absence of NKT cells, XLP can also manifest as lymphomas resulting primarily from uncontrolled B cell proliferation upon acute infection by Epstein–Barr virus. While it has been demonstrated that
Chengjun Li; Brian Chung; Jianping Tao; Cristiana Iosef; Ala Aoukaty; Yefu Wang; Rusung Tan; Shawn Shun-Cheng Li
Primary cutaneous (PC) CD30-positive large cell lymphoma and lymphomatoid papulosis (LyP) represent the spectrum of PC CD30-positive lymphoproliferative disorders (LPDs) associated with a favorable prognosis. Noncutaneous CD30-positive anaplastic large cell lymphoma (ALCL), although morphologically similar to PC CD30-positive LPDs, seems to be a biologically distinct entity. Cell lines derived from noncutaneous ALCL express CD95 and undergo CD95-induced apoptosis. Little is
Jessica E. Sigel; Eric D. Hsi
One hundred fifty three kidney transplant recipients whose grafts functioned for longer than one year were evaluated for evidence of post-transplant diabetes mellitus (PTDM). Twenty-six patients (17%) developed PTDM. Patients with PTDM were older than controls (mean age 49.4 vs 37.9 years). There was no demonstrable association between sex of patients and PTDM. The body mass index (BMI) was persistently higher in patients with PTDM compared to controls, although the difference did not amount to statistical significance. The association of PTDM with HLA-A28, A30 and B8 observed in other studies was not seen in our patients. Similarly, neither the positive association of HLA-DR3 and DR4, nor the negative association of HLA-B7 and DR2 seen in population-based studies of insulin dependent diabetes mellitus, were seen in our patients with PTDM. To our knowledge, this is the first report that has looked into the association of HLA antigens and PTDM in Saudi Arabia. PMID:18209345
Addous, A; Mohamed, A S; Ismail, G; Al-Hashemy, A
Fulminant Epstein-Barr virus (EBV)-driven clonal T-cell lymphoproliferative disorder (T-LPD) is rare and most patients are of Asian origin. The disease usually develops shortly after primary acute EBV infection and the mechanism remains poorly understood. Here we report such a rare case in a 28-year-old Caucasian female with systemic lupus erythematosus (SLE). Immunophenotypic and molecular studies revealed that the proliferating lymphoid cells displayed a CD8+ T-cell phenotype with clonal rearrangement of the T-cell receptor gamma gene. Epstein-Barr virus-encoded RNA was also observed in the clonal lymphoid cells by in situ hybridization. The patient subsequently developed fatal virus-associated hemophagocytic syndrome one month after the primary acute EBV infection. The case represents the first report of fulminant EBV-driven CD8+ T-LPD occurring in an immunocompromised Caucasian SLE patient. This study, along with studies of similar Asian cases reported in the literature, suggests that dysregulated immunity due to either acquired or genetically determined susceptibility may result in an abnormal response to primary EBV infection and contribute to the pathogenesis of EBV-mediated fatal T-LPD.
Young, Ken H; Zhang, Dahua; Malik, Jeffery T; Williams, Eliot C
SH2D1A gene defects are the cause of X-linked lymphoproliferative disorder (XLP-1), a rare condition characterized by severe immune dysregulation. We present a patient lacking the typical symptoms of XLP-1, but experiencing a severe unusual skin condition encompassing features of dermatosclerosis and vesiculobullous skin disease. A maternal cousin of the patient was diagnosed with XLP-1 and found to carry a deletion of the SH2D1A gene. SH2D1A deletion was also identified in our patient, which offered a possible explanation for his skin symptoms. Subsequent analysis showed that the deletion in both cousins was identical and involved the whole SH2D1A gene and a part of the adjacent ODZ1 gene. High phenotypic variability of XLP-1 observed in this family prompted us to analyze the genotype-phenotype correlation of 2 different-sized deletions involving SH2D1A and ODZ1 in 5 patients from 2 families, and we report the clinical and laboratory data on these individuals. Our findings illustrate the wide clinical variability of XLP-1, both inter- and intrafamilial, which may complicate the diagnosis of this condition. The comparison of phenotypes of our patients argues against a strong involvement of the ODZ1 gene in the skin disorder and other symptoms observed in our index patient. His hitherto not described severe skin condition extends the phenotypic range of XLP-1. PMID:22271700
Mejstríková, Ester; Janda, Ales; Hrusák, Ondrej; Bucková, Hana; Vlcková, Markéta; Hancárová, Miroslava; Freiberger, Tomás; Ravcuková, Barbora; Vesely, Karel; Fajkusová, Lenka; Kopecková, Lenka; Sumerauer, David; Kabícková, Edita; Sedivá, Anna; Stary, Jan; Sedlácek, Zdenek
The asymptomatic hemizygous female carriers of the X-linked lymphoproliferative syndrome (XLP) have abnormal antibody responses to EBV. This suggests partial expression of the defect that leads to EBV-provoked life-threatening diseases in their affected sons. EBV specific antibodies were measured in 65 serum samples of 12 obligate carrier females and seven of their daughters (females at risk) during periods ranging from 1 to 5 yr. Abnormal qualitative antiviral capsid antigen (VCA) IgG titers were nearly fourfold higher than normal controls, two carriers had persistent IgM anti-VCA antibody, two-thirds had persistent IgA anti-VCA antibody, and half of the women had titers to early antigen (EA). Five of seven females exhibited a similar persistent pattern. In contrast, none of the unaffected family members nor 23 normal controls expressed IgA or IgM titers to VCA even with high exposure to the virus, and anti-EA was detected in only one control. Therefore, these findings may prove useful for detecting carriers of the syndrome. Abnormal anti-EBV titers similar to the carrier pattern have been reported in patients and other immunosuppressed individuals, and are indicative of active viral infection. PMID:6274962
Sakamoto, K; Seeley, J K; Lindsten, T; Sexton, J; Yetz, J; Ballow, M; Purtilo, D T
The X-linked lymphoproliferative syndrome (XLP) is a rare, inherited immunodeficiency characterized by recurrent episodes of hemophagocytic lymphohistiocytosis, hypogammaglobulinemia, and/or lymphomas. Recently, X-linked inhibitor of apoptosis (XIAP/BIRC4) gene defects, in families with XLP but without SH2D1A gene defects, has been defined. The distinction from primary immunodeficiencies with a defined genetic cause is mandatory. A six-year-old male patient was admitted with the complaints of persistent general lymphadenopathy, for two years had fever, bilateral cervical multiple microlymphadenopathy, hepatic/splenic enlargement with laboratory findings as decreased serum immunoglobulins, negative EBV VCA IgM (viral capsid antigen) and anti-EBV EA (antibody to early D antigen), positive EBV VCA IgG (viral capsid antigen) and EBV EBNA (antibody to nuclear antigen). SH2D1A gene analysis was negative. XIAP/BIRC4 sequencing revealed two novel single nucleotide variants (exon 7, 1978G > A, and 1996T > A) in the 3'UTR of the gene in both patient and mother which were not disease causing. XIAP protein expression was found to be normal. The clinical and laboratory resemblance, no gene mutations, and normal XIAP protein expression led us to think that there may be another responsible gene for XLP. The patient will to be followed up as CVID until he presents new diagnostic signs or until the identification of a new gene. PMID:21541208
Gulez, Nesrin; Aksu, Guzide; Berdeli, Afig; Karaca, Neslihan; Tanr?verdi, Sema; Kutukculer, Necil; Azarsiz, Elif
We have studied a 19-year-old male with X-linked lymphoproliferative syndrome (XLP) and infectious mononucleosis (IM) who was treated with high-dose immunoglobulin (500 mg/kg/day) and recombinant interferon (IFN)-alpha (2 x 10(6) IU/m2/day). Fulminant hepatitis was delayed; however, virus-associated hemophagocytic syndrome, cholestatic jaundice, and renal failure occurred terminally. Initially, nonspecific natural killer (NK) cell activity against K562 cells was normal but it gradually decreased. Although reactive T cells were markedly increased in his blood during the acute phase, spontaneous EBV-positive cell lines were easily established. Additionally, his mononuclear cells produced IFN-gamma but not IFN-alpha prior to treatment. Based on results of in vitro studies, we conclude that both IFN-alpha and IFN-gamma production are likely necessary for inhibiting EBV immortalization in vitro. Both IFN-alpha and -gamma were produced in cultures of B95-8 EBV-infected mononuclear cells from EBV-seropositive healthy individuals. These results suggest that defective EBV-specific cytotoxic T cell activity accompanied with defective or discordant IFN-alpha and -gamma production permitted the development of fatal IM in this patient. Combined treatment with immunoglobulin and IFN-alpha appeared to be partially effective during the early stage of this disease. PMID:2302842
Okano, M; Pirruccello, S J; Grierson, H L; Johnson, D R; Thiele, G M; Purtilo, D T
The CD30-positive cutaneous lymphoproliferative disorders (CLPD) include lymphomatoid papulosis (LyP) and primary cutaneous anaplastic large T-cell lymphoma (cALCL). Despite the malign-appearing histology, an excellent prognosis and spontaneous regression of single lesions characterize LyP. Even after years of clinical remission newly erupting lesions often harbor a T-cell clone identical to the initial one. This fact raises the question whether the clonal T-cell population persists in the peripheral blood. Therefore we investigated genomic DNA of 126 samples of lesional skin and peripheral blood from 31 patients with CLPD, obtained during both active disease and clinical remission. We performed molecular genetic analysis by combining T-cell receptor (TCR)-gamma PCR with the GeneScan technique and assessed the TCR repertoire in selected blood samples by beta-variable complementarity-determining region 3 (CDR3) spectratyping qualitatively and quantitatively. We were able to detect a clonal T-cell population in 36/43 (84%) skin samples and in 35/83 (42%) blood samples. Comparison of the compartments in each patient demonstrated different T-cell clones in skin and blood, suggesting a reactive nature of the clonal T cells in the blood. Moreover, CDR3 spectratyping revealed a restricted T-cell repertoire in the blood, suggesting T-cell stimulation by an unknown antigen. PMID:18633437
Humme, Daniel; Lukowsky, Ansgar; Steinhoff, Matthias; Beyer, Marc; Walden, Peter; Sterry, Wolfram; Assaf, Chalid
"Cryoglobulinemia" refers to the presence of cryoglobulins (immunoglobulins that precipitate at variable temperatures < 37 degrees C [98.6 degrees F]) in serum. Monoclonal cryoglobulinemia (type I) involves a single type of monoclonal immunoglobulin, while mixed cryoglobulinemia involves a mixture either of polyclonal immunoglobulin (Ig) G and monoclonal IgM (type II), or of polyclonal IgG and polyclonal IgM (type Ill); both monoclonal and polyclonal IgM have rheumatoid factor activity. Cryoglobulinemia is a unique model of human disease for several reasons: (1) cryoglobulins are detected using a simple technical approach that is based on in vitro laboratory observation of cold precipitation in serum; (2) cryoglobulinemic organ damage may be produced by two different etiopathogenic mechanisms (accumulation of cryoglobulins and autoimmune-mediated vasculitic damage); and (3) cryoglobulinemia is associated with a wide range of etiologies, symptoms, and outcomes, and is considered a disease that combines elements of autoimmune and lymphoproliferative diseases. There are three main broad treatment strategies in cryoglobulinemia-conventional immunosuppression, antiviral treatment, and biologic therapy. Some agents, such as corticosteroids and rituximab, have been successfully used in all types of cryoglobulinemia; however, treatment should be modulated according to the underlying associated disease (chronic viral infections, autoimmune diseases, or cancer), the predominant etiopathogenic damage (vasculitis vs. hyperviscosity), and the severity of internal organ involvement. PMID:24575538
Retamozo, Soledad; Brito-Zerón, Pilar; Bosch, Xavier; Stone, John H; Ramos-Casals, Manuel
The pregnancy determines a deep variation in the human physiology mediated through sexual hormones. These changes can entail the appearance of diseases that affect the liver such as hyperemesis gravidarum, HELLP syndrome, intrahepatic cholestasis of pregnancy and acute fatty liver of pregnancy. The knowledge of the specific features of these diseases is crucial for their prompt recognition, since they are uncommon diseases in the clinical daily setting of the hepatologist. In addition, several preexisting chronic hepatopathies, including the liver post-transplant status, can affect the course of pregnancy and the maternal-fetal health. Understanding the distinct hepatic diseases which develop during pregnancy must be based on the knowledge of the perceptible physiological changes both on physical examination and laboratory tests which occur during the uneventful gestation. PMID:11766287
Nicolás Pérez, D; Ortiz Bellver, V; Pastor Plasencia, M A; Berenguer Haym, M; Ponce García, J
\\u000a In 1969, Rosai and Dorfman described the triad of massive cervical lymphadenopathy, expanded lymph node sinuses and characteristic\\u000a histiocytes showing “emperipolesis” as a new, rare, idiopathic, nonneoplastic, lymphoproliferative disorder known as Rosai\\u000a Dorfman Disease (RDD) or ‘sinus histiocytosis with massive lymphadenopathy (SHML) (Rosai and Dorfman 1969). Since then, over\\u000a 750 cases have been reported in the literature (Hargett and Bassett
Osama Raslan; Leena M. Ketonen; Gregory N. Fuller; Dawid Schellingerhout
Post-transplantation lymphoproliferative disorder (PTLD) is an infrequent, but serious complication of solid organ and bone marrow transplantations. The vast majority of the cases are of B-cell origin and usually associated with Epstein-Barr virus (EBV) infection. The non-B (T and NK cell) PTLDs account for up to 14% of the PTLD cases in Western countries. We report a case of a 66-year-old man who received an orthotopic heart transplant for cardiomyopathy 7 years prior to presentation. He was referred to our institution with a hypermetabolic solitary right lower lobe lung nodule with an SUV of 9.2 on PET scan. The combined histomorphological and immunohistochemical pattern was most consistent with monomorphic PTLD, peripheral T-cell lymphoma with angioimmunoblastic features. Molecular studies showed clonal T-cell gamma receptor gene rearrangement. Primary pulmonary involvement of T-cell PTLD is extremely rare. This is the third reported case of T-cell PTLD after cardiac transplantation, primarily involving the lung. Further, studies will be required to determine the appropriate treatment and prognosis of this rare entity.
Aqil, Barina; Krishnan, Bhuvaneswari; Curry, Choladda V; Elghetany, M Tarek; Szigeti, Reka
X-linked lymphoproliferative (XLP) syndrome is a rare primary immune-deficiency disorder caused by mutations of the SH2D1A or XIAP genes. Males with the disorder are usually in good health until contracting Epstein-Barr virus (EBV) whereupon the majority of patients die from fulminant infectious mononucleosis, lymphoma or hypogammaglobulinaemia. This report describes a female carrier with an XLP phenotype who was retrospectively identified after her grandson died from the disorder. Subsequent genetic testing identified the patient's mother and affected maternal grandmother as XLP carriers. The family's medical records were significant. The proband had lymphoma at ages 2 and 8 and made a full recovery following treatment. Both the maternal grandmother and uncle died of non-Hodgkin's lymphoma. We were concerned that the XLP carrier mother may be predisposed to lymphoma if the normal X chromosome is skewed towards inactivation. The human androgen receptor assay detected random X chromosome inactivation in the carrier mother. EBV was not detected in the lymphoma tissues of the proband and his grandmother, confirming previous findings that EBV is not always associated with lymphoma in XLP. More significantly, our study highlights the importance of identifying XLP in families with a high incidence of lymphoma. PMID:18702745
Woon, S-T; Ameratunga, R; Croxson, M; Taylor, G; Neas, K; Edkins, E; Browett, P; Gane, E; Munn, S
Autoimmune lymphoproliferative syndrome (ALPS) is a disorder of dysregulated lymphocyte homeostasis. Biomarkers including elevated CD3+TCR??+CD4-CD8- double negative T cells (TCR??+ DNT), IL-10, sCD95L and vitamin B12 can be used to differentiate between ALPS and common variable immunodeficiency (CVID) patients with an overlapping clinical phenotype. We investigated the utility of ALPS biomarkers in 13 CVID patients with lymphoproliferation and/or autoimmune cytopaenia with comparison to 33 healthy controls. Vitamin B12 (P < 0.01) and IL-10 (P < 0.0001), but not sCD95L or TCR??+ DNT, were increased in CVID compared to controls. The 95th percentile for TCR??+ DNT in healthy controls was used to define a normal range up to 2.3% of total lymphocytes or 3.4% of T cells. These frequencies lie markedly beyond the cut offs used in current ALPS diagnostic criteria (? 1.5% of total lymphocytes or 2.5% of CD3+ lymphocytes), suggesting these limits may have poor specificity for ALPS. PMID:23993982
Roberts, C A; Ayers, L; Bateman, E A L; Sadler, R; Magerus-Chatinet, A; Rieux-Laucat, F; Misbah, S A; Ferry, B L
HUS is characterized by hemolytic anemia, thrombocytopenia, and acute renal failure. While "typical" HUS is usually associated with Shiga toxin-producing Escherichia coli infections and recovers in the majority of cases, aHUS is caused by mutations of complement components or antibodies against CFH leading to uncontrolled activation of alternative complement pathway and often to ESRD. Recently, THBD gene mutations have been reported in aHUS. Theoretically, the risk of disease recurrence after renal transplantation should be low because THBD is primarily a membrane-bound protein expressed by endothelial cells; however, a small proportion of THBD is present as a soluble form in plasma. We report the case of a 19-yr-old man with aHUS secondary to a THBD mutation that relapsed twice after two renal transplantations performed 12 yr apart. Despite successful control of HUS with plasma exchange and eculizumab after the second transplantation, the graft was ultimately lost due to severe steroid-resistant cellular rejection. The present report suggests that THBD mutations may favor-relapse of aHUS after renal transplantation. PMID:24118826
Sinibaldi, Serena; Guzzo, Isabella; Piras, Rossella; Bresin, Elena; Emma, Francesco; Dello Strologo, Luca
A 12-year-old girl with a history of steroid and cyclosporine (CsA) resistant nephrotic syndrome owing to focal and segmental glomerulosclerosis (FSGS) has progressed to end-stage renal disease (ESRD) for which she underwent hemodialysis for 18 months before she successfully received a fully matched kidney transplant from her sister at the age of nine years. The post transplantation (Tx) period was marked by an early and massive proteinuria indicating recurrent FSGS for which she received 12 sessions of plasmapheresis (PP); unfortunately, she did not appear to have any response to the PP therapy; thereafter, a conservative management comprising essentially enalapril and losartan has been initiated and was also not successful during the first four months, however, a very gradual response has been noticed to occur after five months of conservative therapy and ultimately, the patient attained complete remission after 21 months of treatment. Amazingly, 15 months after discontinuation of enalapril and losartan, she remained in a complete and sustained remission with a good renal allograft function. To the best of our knowledge, this is the first case ever reported in the literature of a "spontaneous" remission of post transplant recurrent FSGS. PMID:22089787
Saeed, Bassam; Mazloum, Houda; Askar, Munaf
This study aimed to investigate the predictive power of anti-HLA antibodies, sCD30 levels and IgA-anti-Fab autoantibody before and early after transplantation in relation to long-term kidney allograft survival. Pre- and post-transplant sera samples of 59 living-unrelated donor kidney recipients were tested for above risk factors by enzyme-linked immunoabsorbent assay. 15 out of 59 cases experienced rejection episodes (failure group). Pre- and post-transplant high sCD30 levels were significantly associated with graft failure (P=0.02 and P=0.004) and decreased 4 year graft survival (P = 0.009 and P = 0.001). Higher frequency of post-transplant HLA class-II antibody in the absence of class-I antibody was observed in failure group (P=0.007). Patients with post-transplant HLA class-I and class-II antibodies either alone or in combination showed significant lower 4 year graft survival. Recipients with high sCD30 levels in the presence of HLA class-I or class-II antibodies within 2 weeks post-transplant had poor graft survival (P = 0.004 and P = 0.002, respectively). High levels of post-transplant IgA-anti-Fab antibody was more frequent in functioning-graft patients (P = 0.00001), correlated with decreased serum creatinine levels (P = 0.01) and associated with improved graft survival (P = 0.008). Our findings indicate the deleterious effect of early post-transplant HLA antibodies and increased sCD30 levels dependently and protective effect of IgA-anti-Fab antibodies on long-term renal graft outcomes. PMID:24055694
Amirzargar, Mohammad Ali; Amirzargar, Aliakbar; Basiri, Abbas; Hajilooi, Mehrdad; Roshanaei, Ghodratollah; Rajabi, Gholamreza; Mohammadiazar, Sina; Solgi, Ghasem
Marek’s disease (MD) is a highly contagious lymphoproliferative disease of poultry caused by the oncogenic herpesvirus designated Marek’s disease virus (MDV). MD has a worldwide distribution and is thought to cause an annual loss over US$1 bn to the poultry industry. Originally described as a paralytic disease, today MD is mostly manifested as an acute disease with tumours in multiple
: Castleman disease is a rare lymphoproliferative disorder that has many presentations ranging from unifocal or multifocal mass lesions to a monoclonal gammopathy. It has features that may overlap with osteosclerotic myeloma or POEMS (polyneuropathy, organomegaly, endocrinopathy, M protein, skin changes) syndrome. We report a patient with papilledema, enlarged lymph nodes, and monoclonal IgG, who subsequently developed a polyneuropathy. Biopsy of enlarged mediastinal lymph nodes confirmed the diagnosis of Castleman disease. PMID:24423600
Tian, Guohong; Jing, Yun; Jiang, Hanqiu; Wang, Jingwen; Zhang, Xiaojun
X-linked lymphoproliferative syndrome (XLP; Duncan's disease) is a primary immunodeficiency disease that manifests as an inability to regulate the immune response to Epstein-Barr virus (EBV) infection. Here we examine the ability of the product of the gene defective in XLP, SAP (DSHP/SH2D1A), to associate with the cytoplasmic domains of several members of the CD2 subfamily of cell surface receptors, including SLAM, 2B4, and CD84. While recruitment of SAP to SLAM occurred in a phosphorylation-independent manner, SAP was found to bind preferentially to tyrosine-phosphorylated cytoplasmic domains within 2B4 and CD84. Missense or nonsense mutations in the SAP open reading frame were identified in five of seven clinically diagnosed XLP patients from different kindreds. Four of these variants retained the ability to bind to the cytoplasmic tails of SLAM and CD84. While ectopic expression of wild-type SAP was observed to block the binding of SHP-2 to SLAM, mutant SAP derivatives that retained the ability to bind SLAM did not inhibit recruitment of SHP-2 to SLAM. In contrast, SAP binding to CD84 had no effect on the ability of CD84 to recruit SHP-2, but instead displaced SHP-1 from the cytoplasmic tail of CD84. These results suggest that mutations in the gene encoding the XLP protein SAP lead to functional defects in the protein that include receptor binding and SHP-1 and SHP-2 displacement and that SAP utilizes different mechanisms to regulate signaling through the CD2 family of receptors. PMID:11414741
Lewis, J; Eiben, L J; Nelson, D L; Cohen, J I; Nichols, K E; Ochs, H D; Notarangelo, L D; Duckett, C S
It was recently demonstrated that classification of posttransplantation lymphoproliferative disorders (PT-LPDs) into morphological and molecular categories is clinically relevant. It was also reported that PT-LPD not associated with Epstein-Barr virus (EBV) had a more aggressive course than most lesions associated with EBV. Because the cyclin-dependent kinase inhibitor p16/INK4a has been reported to be frequently inactivated in high-grade lymphomas, we evaluated 17 PT-LPD to determine whether p16/INK4a expression could be correlated to morphology, EBV detection, and a Ki-67 labeling index. We demonstrated that tumors with no p16/INK4a expression (n = 8) had a predominantly monomorphic appearance, and most were EBV negative (respectively, 7/8 and 5/8), whereas lesions with p16/INK4a expression (n = 9) were mostly polymorphic PT-LPD (6/9) (P = 0.049) and associated with EBV (9/9) (P = 0.015). In particular, strong p16/INK4a expression was observed in atypical immunoblasts and Reed-Sternberg-like cells. Furthermore, the proliferation index was significantly higher in tumors lacking p16/INK4a expression than in other lesions (P = 0.0008). In conclusion, down-regulation of p16/INK4a was mostly observed in PT-LPD lesions known to follow more aggressive courses: monomorphic tumors and EBV-negative PT-neoplasms. Conversely, overexpression of p16/INK4a was associated with EBV-positive PT-LPD. While p16/INK4a might play a role in the proliferative rate of LP-LPD, further investigations are needed to assess the clinical relevance of p16/INK4a expression in predicting the evolution of tumors and to explain how EBV could favor p16/INK4a protein accumulation in lesions.
Martin, Antoine; Baran-Marzak, Fanny; El Mansouri, Said; Legendre, Christophe; Leblond, Veronique; Charlotte, Frederic; Davi, Frederic; Canioni, Danielle; Raphael, Martine
The conjunction of clinical features, cell morphology and immunological characteristics allows an accurate diagnosis in most cases of B cell chronic lymphoproliferative disorders (CLD). However, the diagnosis remains uncertain in a small percentage of cases, often referred as to unclassified B cell proliferation or atypical chronic lymphocytic leukemia (CLL). We have studied retrospectively the 192 cases of leukemic CLD seen in our institution over a 3-year period, for which both clinical and routine biological data at presentation were available. Forty cases (20%) did not fit into any of the well-identified categories according to the FAB criteria and remained unclassified. We assessed cyclin D1 expression in all of these cases and found that 10 of them expressed a high level of cyclin D1 protein. We compared the characteristics of these 10 cases with those of the 30 cyclin D1 negative CLD. Despite non-distinctive cytological and phenotypic features, the 10 cyclin D1 positive patients exhibited a strikingly uniform clinical presentation with elevated leukocytosis, massive spleen enlargement and no superficial lymphadenopathy. Their outcome was very poor with a median survival of 10 months, contrasting with the prolonged survival of the cyclin D1 negative patients. The cytological features of tumor cells from these 10 patients with cyclin D1 positive unclassified leukemic CLD were similar to those of the circulating lymphoid cells from 15 patients with histologically proven mantle cell lymphoma (MCL) and primary or secondary blood involvement. Therefore, cyclin D1 expression allowed identification among the unclassified CLD, a subset of aggressive disorders which represent a leukemic counterpart of MCL (mantle cell leukemia). We suggest that determination of cyclin D1 expression by any technique available should be systematically included when investigating atypical CLL. PMID:10482984
Levy, V; Ugo, V; Delmer, A; Tang, R; Ramond, S; Perrot, J Y; Vrhovac, R; Marie, J P; Zittoun, R; Ajchenbaum-Cymbalista, F
The homeostasis of the immune response requires tight regulation of the proliferation and apoptosis of activated lymphocytes. In humans, defects in immune homeostasis result in lymphoproliferation disorders including autoimmunity, haemophagocytic lymphohystiocytosis and lymphomas. The X-linked lymphoproliferative syndrome (XLP) is a rare, inherited immunodeficiency that is characterized by lymphohystiocytosis, hypogammaglobulinaemia and lymphomas, and that usually develops in response to infection with Epstein-Barr virus (EBV). Mutations in the signalling lymphocyte activation molecule (SLAM)-associated protein SAP, a signalling adaptor molecule, underlie 60% of cases of familial XLP. Here, we identify mutations in the gene that encodes the X-linked inhibitor-of-apoptosis XIAP (also termed BIRC4) in patients with XLP from three families without mutations in SAP. These mutations lead to defective expression of XIAP. We show that apoptosis of lymphocytes from XIAP-deficient patients is enhanced in response to various stimuli including the T-cell antigen receptor (TCR)-CD3 complex, the death receptor CD95 (also termed Fas or Apo-1) and the TNF-associated apoptosis-inducing ligand receptor (TRAIL-R). We also found that XIAP-deficient patients, like SAP-deficient patients, have low numbers of natural killer T-lymphocytes (NKT cells), indicating that XIAP is required for the survival and/or differentiation of NKT cells. The observation that XIAP-deficiency and SAP-deficiency are both associated with a defect in NKT cells strengthens the hypothesis that NKT cells have a key role in the immune response to EBV. Furthermore, by identifying an XLP immunodeficiency that is caused by mutations in XIAP, we show that XIAP is a potent regulator of lymphocyte homeostasis in vivo. PMID:17080092
Rigaud, Stéphanie; Fondanèche, Marie-Claude; Lambert, Nathalie; Pasquier, Benoit; Mateo, Véronique; Soulas, Pauline; Galicier, Lionel; Le Deist, Françoise; Rieux-Laucat, Frédéric; Revy, Patrick; Fischer, Alain; de Saint Basile, Geneviève; Latour, Sylvain
In up to 5-15% of studies of lymphoproliferative disorders (LPD), flow cytometry (FCM) or immunomorphologic methods cannot discriminate malignant from reactive processes. The aim of this work was to determine the usefulness of PCR for solving these diagnostic uncertainties. We analyzed IGH and TCR? genes by PCR in 106 samples with inconclusive FCM results. A clonal result was registered in 36/106 studies, with a LPD being confirmed in 27 (75%) of these cases. Specifically, 9/9 IGH clonal and 16/25 TCR? clonal results were finally diagnosed with LPD. Additionally, two clonal TCR? samples with suspicion of undefined LPD were finally diagnosed with T LPD. Although polyclonal results were obtained in 47 of the cases studied (38 IGH and nine TCR?), hematologic neoplasms were diagnosed in 4/38 IGH polyclonal and in 1/9 TCR? polyclonal studies. There were also 14 PCR polyclonal results (four IGH, 10 TCR?), albeit nonconclusive. Of these, 2/4 were eventually diagnosed with B-cell lymphoma and 3/10 with T-cell LPD. In eight IGH samples, the results of PCR techniques were noninformative but in 3/8 cases a B lymphoma was finally confirmed. We concluded that PCR is a useful technique to identify LPD when FCM is inconclusive. A PCR clonal B result is indicative of malignancy but IGH polyclonal and nonconclusive results do not exclude lymphoid neoplasms. Interpretation of T-cell clonality should be based on all the available clinical and analytical data. PMID:23943305
Ribera, Jordi; Zamora, Lurdes; Juncà, Jordi; Rodríguez, Inés; Marcé, Silvia; Cabezón, Marta; Millá, Fuensanta
A considerable proportion of cases of myeloproliferative and lymphoproliferative disorders exhibit renal involvement. However, it is unclear whether the cytologic features, immunophenotype or grade of malignancy of the cells infiltrating the kidney differ from those of the primary tumor. This study was performed on 120 autopsy cases with the following diagnoses: acute myelogenous leukemia (AML, n = 22; subtypes M1 + M2, n = 12, subtype M4, n = 10), chronic myelogenous leukemia (CML, n = 7), agnogenic myeloid metaplasia/myelofibrosis (AMM/MF, n = 6), acute lymphocytic leukemia (ALL, n = 6), chronic lymphocytic leukemia (CLL, n = 9), other low-grade non-Hodgkin's lymphomas (low-grade NHL, n = 24), high-grade NHL (n = 21) and multiple myeloma (MM, n = 25). Renal involvement was investigated by light microscopy and immunohistochemistry. It was found in 34% of the cases, and was most common in ALL (83%) and low-grade NHL (50%) and least common in high-grade NHL (10%) and MM (12%). Dense infiltration of almost the entire kidney was most commonly seen in AML, low-grade NHL and ALL. Infiltration was bilateral and involved both the cortex and medulla in the majority of cases. When involvement of other organs was compared with that of the kidney, the lung was found to be involved in approximately the same number of cases, but liver involvement was more common and heart involvement less common. Reactive lymphocytic infiltration of the kidney was found in 18 of the 120 cases (15%), and was distinguished from scanty tumorous infiltration by immunohistochemical staining. No major phenotypical differences were found between the tumor cells infiltrating the kidney and those of the primary tumors in the bone marrow or lymph nodes. However, in one case of CML, the cells infiltrating the kidney were negative for KP1 and chloroacetate esterase, but could be identified by reactivity for CD34. The grade of malignancy in NHL was similar in both the nodal and renal manifestations. PMID:9065578
Xiao, J C; Walz-Mattmüller, R; Ruck, P; Horny, H P; Kaiserling, E
Intravenous immunoglobulin replacement therapy represents the standard treatment for hypogammaglobulinemia secondary to B-cell lymphoproliferative disorders. Subcutaneous immunoglobulin infusion is an effective, safe and well-tolerated treatment approach in primary immunodeficiencies but no extensive data are available on their use in secondary hypogammaglobulinemia, a frequent phenomenon occurring after treatment with anti-CD20 monoclonal antibodies in lymphoproliferative disorders. In this retrospective study we evaluated efficacy (serum IgG trough levels, incidence of infections per year, need for antibiotics) and safety (number of adverse events) of intravenous (300 mg/kg/4 weeks) versus subcutaneous (75 mg/kg/week) immunoglobulin replacement therapy in 61 patients. In addition, the impact of the infusion methods on quality of life was compared. All patients were treated with subcutaneous immunoglobulin, and 33 out of them had been previously treated with intravenous immunoglobulin. Both treatments appeared to be effective in replacing Ig production deficiency and in reducing the incidence of infectious events and the need for antibiotics. Subcutaneous immunoglobulin obtained a superior benefit when compared to intravenous immunoglobulin achieving higher IgG trough levels, lower incidence of overall infection and need for antibiotics. The incidence of serious bacterial infections was similar with both infusion ways. As expected, a lower number of adverse events was registered with subcutaneous immunoglobulin, compared to intravenous immunoglobulin, with no serious adverse events. Finally, we observed an improvement in health-related quality of life parameters after the switch to subcutaneous immunoglobulin. Our results suggest that subcutaneous immunoglobulin is safe and effective in patients with hypogammaglobulinemia associated to lymphoproliferative disorders.
Compagno, Nicolo; Cinetto, Francesco; Semenzato, Gianpietro; Agostini, Carlo
Intravenous immunoglobulin replacement therapy represents the standard treatment for hypogammaglobulinemia secondary to B-cell lymphoproliferative disorders. Subcutaneous immunoglobulin infusion is an effective, safe and well-tolerated treatment approach in primary immunodeficiencies but no extensive data are available on their use in secondary hypogammaglobulinemia, a frequent phenomenon occurring after treatment with anti-CD20 monoclonal antibodies in lymphoproliferative disorders. In this retrospective study we evaluated efficacy (serum IgG trough levels, incidence of infections per year, need for antibiotics) and safety (number of adverse events) of intravenous (300 mg/kg/4 weeks) versus subcutaneous (75 mg/kg/week) immunoglobulin replacement therapy in 61 patients. In addition, the impact of the infusion methods on quality of life was compared. All patients were treated with subcutaneous immunoglobulin, and 33 out of them had been previously treated with intravenous immunoglobulin. Both treatments appeared to be effective in replacing Ig production deficiency and in reducing the incidence of infectious events and the need for antibiotics. Subcutaneous immunoglobulin obtained a superior benefit when compared to intravenous immunoglobulin achieving higher IgG trough levels, lower incidence of overall infection and need for antibiotics. The incidence of serious bacterial infections was similar with both infusion ways. As expected, a lower number of adverse events was registered with subcutaneous immunoglobulin, compared to intravenous immunoglobulin, with no serious adverse events. Finally, we observed an improvement in health-related quality of life parameters after the switch to subcutaneous immunoglobulin. Our results suggest that subcutaneous immunoglobulin is safe and effective in patients with hypogammaglobulinemia associated to lymphoproliferative disorders. PMID:24682509
Compagno, Nicolò; Cinetto, Francesco; Semenzato, Gianpietro; Agostini, Carlo
Composite mature B-cell lymphoproliferative neoplasms are rare entities characterized by the simultaneous presence of two or more distinctive B-cell derived monoclonal malignancies. This retrospective study used multiparametric flow cytometric analysis aimed at immunophenotypic profiling of composite mature B-cell lymphoproliferative neoplasms in a cohort of 413 subsequent patients with de novo leukemic B-cell chronic lymphoproliferative disorders diagnosed in our institution during a 30-month period. Biclonality was found in 16 (3.9 %) patients. The vast majority (88 %) of the cases had one of the clones phenotypically corresponding to chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). Only when composite cases were categorized by phenotype of the non-CLL/SLL malignant population did we find a statistically significant (P = 0.001) higher frequency of biclonality among cases with hairy cell leukemia (22 %). Biclonal cases had the overall B-cell membrane ? to ? ratio within the normal range (median, 1.9; reference interval 0.5-4.0), making recognition of malignancy somewhat challenging. Our analysis strategy was therefore based on the detection of aberrant B-cell phenotypes, with subsequent confirmation of the monoclonal nature of neoplastic clones with regards to light chain restriction analysis. Discrimination of the coexisting clones in biclonal cases was possible on the basis of the expression of other antigen(s) (63 %), light scatter properties (44 %), different surface light chain restriction (69 %) and/or pattern of expression (44 %). The most informative cell surface antigens proved to be CD22, CD20, surface IgM, and CD23. In conclusion, historic ?/? ratio is not a reliable approach and is a poor measurement for the detection of composite lymphomas. More creative analysis techniques should be utilized for this purpose. PMID:24061774
Perkovi?, Sanja; Baši?-Kinda, Sandra; Aurer, Igor; Ugrina, Ivo; Duleti?-Na?inovi?, Antica; Lozi?, Dominik; Batini?, Drago
Background Post-transplant anemia (PTA) has long been a less-recognized complication in kidney transplant recipients, and its prevalence also tends to be underestimated. This study sought to evaluate the prevalence, management, and risk factors of PTA from a group of long-term follow-up Chinese kidney transplant recipients. Methods One hundred and fifty-four adult kidney transplant recipients were followed up at Fuzhou General Hospital, China, and retrospectively studied. Results PTA prevalence at transplant and at 5-yearly time points after transplantation were 45.5%, 10.7%, 9.6%, 14.8%, 13.5%, and 19.6%, respectively. Overall, 38.3% of patients had been anemic at least once during the follow-up period, and 42% of these patients had recurrent anemia. Correlation analysis indicated that hemoglobin levels were associated with graft function. No correlations between anemia and age, gender, immunosuppressive regimens, or antihypertensive agents were observed. Binary logistic regression analysis suggested that serum creatinine and blood urea nitrogen were associated with the diagnosis of anemia at 1 year post-transplant. At 5 years post-transplant, only serum creatinine concentrations correlated with anemia. Although iron drugs are frequently used, erythropoietin was rarely administered in those anemic patients suffering poor graft function that necessitated such therapies. Conclusions The prevalence of PTA is noticeably high, and impaired kidney graft function seemed to be the major risk factor for anemia. There is an urgent need to improve current PTA management and to establish modified guidelines for this common complication in kidney transplant recipients.
Non-alcoholic fatty liver disease (NAFLD) is one of the most prevalent causes of chronic liver disease worldwide. In the last decade it has become the third most common indication for liver transplantation in the United States. Increasing prevalence of NAFLD in the general population also poses a risk to organ donation, as allograft steatosis can be associated with non-function of the graft. Post-transplant survival is comparable between NAFLD and non-NAFLD causes of liver disease, although long term outcomes beyond 10 year are lacking. NAFLD can recur in the allograft frequently although thus far post transplant survival has not been impacted. De novo NAFLD can also occur in the allograft of patients transplanted for non-NAFLD liver disease. Predictors for NAFLD post-transplant recurrence include obesity, hyperlipidemia and diabetes as well as steroid dose after liver transplantation. A polymorphism in PNPLA3 that mediates triglyceride hydrolysis and is linked to pre-transplant risk of obesity and NAFLD has also been linked to post transplant NAFLD risk. Although immunosuppression side effects potentiate obesity and the metabolic syndrome, studies of immunosuppression modulation and trials of specific immunosuppression regimens post-transplant are lacking in this patient population. Based on pre-transplant data, sustained weight loss through diet and exercise is the most effective therapy for NAFLD. Other agents occasionally utilized in NAFLD prior to transplantation include vitamin E and insulin-sensitizing agents. Studies of these therapies are lacking in the post-transplant population. A multimodality and multidisciplinary approach to treatment should be utilized in management of post-transplant NAFLD.
Abstract Castleman disease is a non-neoplastic cause of lymphadenopathy, first described in 1956 by Dr. Benjamin Castleman. Orbital involvement in Castleman disease is extremely rare. We report a case of bilateral orbital Castleman disease in a 48-year-old Asian male who presented with bilateral inferior dystopia. MRI revealed bilateral extraconal superior orbital mass. Histopathology and immunohistochemistry of the mass revealed features of Castleman disease of hyaline vascular type. Castleman disease should be a differential in suspected idiopathic orbital inflammatory disease and lymphoproliferative disorders. PMID:24831817
Mukherjee, Bipasha; Alam, Mohammad Shahid; Krishnakumar, S
Primary cutaneous CD30 (Ki-1)+ large cell lymphoma (KiL) and lymphomatoid papulosis (LyP) type A are collectively termed as primary cutaneous CD30-positive lymphoproliferative disorders. We examined the cytokine profile of skin-infiltrating cells and the therapeutic efficacy of recombinant interferon-? (rIFN-?) in primary cutaneous KiL and LyP type A. By reverse transcriptase-polymerase chain reaction, mRNAs for interleukin-4 (IL-4) and IL-b were detected
Hiroaki Yagi; Yoshiki Tokura; Fukumi Furukawa; Masahiro Takigawa
Since 1995 to date, more than 250 patients with EBV-related diseases received virus-specific CTL. Cell therapy proved to be\\u000a safe and effective, and achieved some complete remissions also in patients who failed all previous standard treatments. The\\u000a first clinical results with EBV-specific CTL were obtained for both prophylaxis and treatment of post-transplant lymphoproliferative\\u000a disease arising in stem cell transplant or
Anna Merlo; Riccardo Turrini; Riccardo Dolcetti; Paola Zanovello; Antonio Rosato
Primary cutaneous CD30+ T-cell lymphoproliferative disorders (PC-CD30+ LPD) as a group are one of the more common types of T-cell lymphoma. More specifically primary cutaneous anaplastic lymphoma (PC-ALCL), one of these lymphoproliferative disorders, is the second most common cutaneous T-cell lymphoma. We report an unusual presentation of PC-ALCL. A 90-year-old, uncircumcised male presented with a 3-week history of painful penile swelling and discharge. The patient was treated with cephalexin and underwent emergent circumcision for paraphimosis. The diagnosis of ALCL was made on microscopic evaluation of the foreskin along with follow-up staging studies. A literature review revealed 31 previously reported cases of penile lymphoma, one of which reported a primary penile CD30+ T-cell lymphoma similar to ours. Only one case report described a lymphoma presenting as paraphimosis. Our case is the second reported case of PC-ALCL of the penis and the first of its kind to present as paraphimosis. Lymphomas must be included in the differential diagnosis of penile lesions and paraphimosis. When present, clinicians should be able to differentiate primary cutaneous lymphoma from lymphomas with secondary skin involvement. All foreskins should be submitted to pathology for proper evaluation of penile lesions. PMID:21810388
McNab, Patricia Moody; Jukic, Drazen M; Mills, Omie; Browarsky, Irwin
The purpose of this human study was to investigate the effect of oxygen pretreatment in living kidney donors on early renal function of transplanted kidney. Sixty living kidney donor individuals were assigned to receive either 8-10?L/min oxygen (Group I) by a non-rebreather mask with reservoir bag intermittently for one hour at four times (20, 16, 12, and 1 hours before transplantation) or air (Group II). After kidney transplantation, urine output, blood urea nitrogen (BUN), serum creatinine, need to additional diuretics (NTADs) in the first 24?hours after transplantation, delayed graft function (DGF), the creatinine clearance (CrCL) on 10th day, and duration of hospital stay from the first posttransplant day till normalization of renal function was recorded and compared in two groups. Mean CrCL in posttransplant day 10, NTAD after 24 hours of transplantation, and urine output during 6 hours after operation were significantly better in Group I compared with Group II (P < .05). Also, DGF during the first week after operation and duration of hospital stay was less in Group I compared with Group II. Intermittent exposure of human living kidney donor to hyperoxic environment may improve renal function following kidney transplantation. PMID:21559250
Montazeri, Kamran; Vakily, Mohammadali; Honarmand, Azim; Kashefi, Parviz; Safavi, Mohammadreza; Taheri, Shahram; Rasoulian, Bahram
The purpose of this human study was to investigate the effect of oxygen pretreatment in living kidney donors on early renal function of transplanted kidney. Sixty living kidney donor individuals were assigned to receive either 8–10?L/min oxygen (Group I) by a non-rebreather mask with reservoir bag intermittently for one hour at four times (20, 16, 12, and 1 hours before transplantation) or air (Group II). After kidney transplantation, urine output, blood urea nitrogen (BUN), serum creatinine, need to additional diuretics (NTADs) in the first 24?hours after transplantation, delayed graft function (DGF), the creatinine clearance (CrCL) on 10th day, and duration of hospital stay from the first posttransplant day till normalization of renal function was recorded and compared in two groups. Mean CrCL in posttransplant day 10, NTAD after 24 hours of transplantation, and urine output during 6 hours after operation were significantly better in Group I compared with Group II (P < .05). Also, DGF during the first week after operation and duration of hospital stay was less in Group I compared with Group II. Intermittent exposure of human living kidney donor to hyperoxic environment may improve renal function following kidney transplantation.
Montazeri, Kamran; Vakily, Mohammadali; Honarmand, Azim; Kashefi, Parviz; Safavi, Mohammadreza; Taheri, Shahram; Rasoulian, Bahram
In this multicentre retrospective study we have studied the impact of T cell chimerism on the outcome of 133 patients undergoing an alemtuzumab based reduced intensity conditioning allograft (RIC). The median age of the patients was 50 years (range 42-55 years). 77 patients were transplanted using an HLA identical sibling donor while 56 patients received a fully matched volunteer unrelated donor graft. 64 patients had a lymphoid malignancy and 69 were transplanted for a myeloid malignancy. 38 patients (29%) relapsed with no significant difference in risk of relapse between patients developing full donor and mixed donor chimerism in the T-cell compartment on D+90 and D+180 post transplant. Day 90 full donor T cell chimerism correlated with an increased incidence of acute GVHD according to NIH criteria (p=0.0004) and the subsequent development of chronic GVHD. Consistent with previous observations, our results confirmed a correlation between the establishment of T cell full donor chimerism and acute GVHD in T deplete RIC allografts. However our study failed to identify any correlation between T cell chimerism and relapse risk and challenge the use of pre-emptive donor lymphocyte infusions (DLI) in patients with mixed T cell chimerism transplanted using an alemtuzumab based RIC regimen. PMID:23395505
Nikolousis, E; Robinson, S; Nagra, S; Brookes, C; Kinsella, F; Tauro, S; Jeffries, S; Griffiths, M; Mahendra, P; Cook, M; Paneesha, S; Lovell, R; Kishore, B; Chaganti, S; Malladi, R; Raghavan, M; Moss, P; Milligan, D; Craddock, C
We reported a case of X-linked lymphoproliferative syndrome (XLP) with multiple nodular lesions in the brain and lungs. A 21-year-old man was admitted because of one month history of low grade fever, headache, nausea, and amnesia. He developed agammaglobulinemia following Epstein-Barr virus infection at 3-year-old, and thereafter was administered 7.5g of immunoglobulin every 3 weeks with a diagnosis of XLP. Physical examination was unremarkable on admission. Neurological examination revealed disorientation of time, and bilateral gaze-evoked nystagmus. Neuropsychological tests demonstrated impairment of recent memory and calculation. Pleocytosis (83/microl) and increase of protein (1269 mg/dl) and IgG (141 mg/dl) in the CSF were observed. Brain MRI showed multiple nodular lesions with high intense signal on T2-weighted images and Gd-DTPA enhancement on T1-weighted images. Chest CT showed multiple nodular lesions in the bilateral lungs. The needle lung biopsy was performed, which showed infiltration of lymphocytes around the vessels. An immunohistochemical study showed that the infiltrating cells were mainly CD8 positive T lymphocytes. B lymphocyte and plasma cells were not seen. The histological findings excluded intravascular malignant lymphoma and lymphomatoid granulomatosis. Therefore we diagnosed lymphoid vasculitis. The patient developed pancytopenia caused by hemophagocytic syndrome 48 days after admission and was treated with 1 g of methylprednisolone per day for 3 days and a tapered dose of steroid (500 mg to 125 mg of methylprednisolone and 60 mg to 10mg of predonisolone) for 21 days, which resulted in the improvement of clinical features (hemophagocytic syndrome and central nervous system symptoms) and the abnormal CSF findings. The multple nodular lesions in the brain and the lungs shrank 1 month after treatment and disappeared 11 months later. There are few reports concerning lymphoid vasculitis with XLP, and no effective treatment has been described. Our case suggests that steroid therapy may be useful for the treatment of lymphoid vasculitis in XLP. PMID:16768091
Tateishi, Takahisa; Tanaka, Kimihiro; Ito, Yoshikiyo; Mitsuo, Kunihiko
Background: Heavy-chain diseases (HCDs) are human lymphoproliferative neoplasias that are characterized by the secretion of truncated immunoglobulin heavy chains devoid of light chains. We have previously proposed — by analogy to the process by which mutated growth factor receptors can be oncogenic — that because the genetic defects in HCDs result in the production of abnormal membrane-associated heavy chains lacking
Daniel Corcos; Olga Dunda; Cécile Butor; Jean-Yves Cesbron; Patrick Lorès; Danielle Bucchini; Jacques Jami
A 36-year-old man underwent matched unrelated donor bone marrow transplantation for chronic myeloid leukaemia. He developed\\u000a severe hepatic veno-occlusive disease as an early post-transplant complication. Tissue plasminogen activator was initially\\u000a felt to be contraindicated since the patient had concomitant pericarditis. Defibrotide was therefore commenced as treatment\\u000a for veno-occlusive disease. The pericarditis improved but the veno-occlusive disease continued to worsen (peak
MJ Jenner; INM Micallef; AZ Rohatiner; SM Kelsey; AC Newland; JD Cavenagh
We observed the occurrence of celiac disease following allogeneic bone marrow transplantation in a patient transplanted for acute leukemia. The marrow donor was his HLA-identical sister, who had suffered from celiac disease since birth. The post-transplant period was characterized by recurrent episodes of diarrhea. Detailed workup showed atrophic intestinal mucosa on histology and anti-gliadin and anti-endomysium antibodies in the serum,
MJ Bargetzi; A Schönenberger; A Tichelli; R Fried; G Cathomas; E Signer; B Speck; A Gratwohl
Rationale: Bilateral lung transplantation (BLT) improves survival compared with single lung transplantation (SLT) for some individuals with chronic obstructive pulmonary disease (COPD). However, it is unclear which strategy optimally uses this scarce societal resource. Objectives: To compare the effect of SLT versus BLT strategies for COPD on waitlist outcomes among the broader population of patients listed for lung transplantation. Methods: We developed a Markov model to simulate the transplant waitlist using transplant registry data to define waitlist size, donor frequency, the risk of death awaiting transplant, and disease- and procedure-specific post-transplant survival. We then applied this model to 1,000 simulated patients and compared the number of patients under each strategy who received a transplant, the number who died before transplantation, and total post-transplant survival. Measurements and Main Results: Under baseline assumptions, the SLT strategy resulted in more patients transplanted (809 vs. 758) and fewer waitlist deaths (157 vs. 199). The strategies produced similar total post-transplant survival (SLT = 4,586 yr vs. BLT = 4,577 yr). In sensitivity analyses, SLT always maximized the number of patients transplanted. The strategy that maximized post-transplant survival depended on the relative survival benefit of BLT versus SLT among patients with COPD, donor interval, and waitlist size. Conclusions: In most circumstances, a policy of SLT for COPD improves access to organs for other potential recipients without significant reductions in total post-transplant survival. However, there may be substantial geographic variations in the effect of such a policy on the balance between these outcomes.
Christie, Jason D.; Halpern, Scott D.
Castleman's disease (CD) is a rare lymphoproliferative disorder of uncertain cause. The most common site of involvement is the mediastinum. Endotracheal CD is extremely rare. We report a case of unicentric, hyaline-vascular type CD presenting as an obstructive tracheal mass. The tumor was successfully managed by rigid bronchoscopy with argon plasma coagulation. There was no recurrence at the 2-month follow-up visit. PMID:24792274
Yu, Jin Yeong; Oh, In Jae; Kim, Kyu Sik; Kim, Yu Il; Lim, Sung Chul; Kim, Young Chul; Choi, Yoo Duk; Kwon, Yong Soo
Nonalcoholic fatty liver disease (NAFLD) is becoming rapidly one of the most common indications for orthotopic liver transplantation in the world. Development of graft steatosis is a significant problem during the post-transplant course, which may happen as a recurrence of pre-existing disease or de novo NAFLD. There are different risk factors that might play a role in development of graft steatosis including post-transplant metabolic syndrome, immune-suppressive medications, genetics and others. There are few studies that assessed the effects of NAFLD on graft and patient survival; most of them were limited by the duration of follow up or by the number of patients. With this review article we will try to shed light on post-liver transplantation NAFLD, significance of the disease, how it develops, risk factors, clinical course and treatment options.
Shaker, Mina; Tabbaa, Adam; Albeldawi, Mazen; Alkhouri, Naim
CD30+ cutaneous lymphoproliferative disorders (CLPDs) are usually characterized by a benign clinical course. The prognostic value of cytotoxic markers in these lymphomas has not been evaluated in large series. We describe a case of borderline CD30+ CLPD with cytotoxic phenotype, presenting in a 22-year-old male patient as an ulcer on the forearm. He reported having had similar ulcers on the buttock and thigh that spontaneously regressed over the course of 1 year. The lesion resolved with a single course of clarithromycin; a subsequent lesion, too, responded to clarithromycin, and no recurrences or systemic involvement have been documented in the 9-month follow-up. A conservative approach in the management of CD30+ CLPD is recommended. We believe that the anti-inflammatory and apoptotic effects of clarithromycin on T cells may have hastened the remission process. PMID:19922478
Ponte, Pedro; Serrão, Vasco; Viana, Isabel; Vale, Esmeralda; João, Alexandre; Cerroni, Lorenzo
The X-linked lymphoproliferative syndrome (XLP) is characterized by a combined variable immunodeficiency with vulnerability to Epstein-Barr virus (EBV)-induced fatal or chronic infectious mononucleosis, acquired agammaglobulinemia, aplastic anemia, or malignant B cell lymphomas. Diagnosis of XLP requires documentation of two or more maternally related males with these phenotypes. Epstein-Barr virus must be demonstrated in circulating blood, lymphoid tissues, or saliva of infected males. Characteristically, the patients have low-titer antibodies to EBV and often lack anti-EB nuclear-associated antibody due to T cell defects. Thymus gland is often depleted and epithelium may be destroyed. Thymic-dependent regions in lymph nodes and spleen are depleted and immunoblastic transformation with plasma cell differentiation is seen. The carrier females exhibit partial immune deficiency and have paradoxically elevated antibodies to EBV. Our registry of XLP provides consultation and comprehensive study of persons and families with the syndrome. PMID:6894075
Purtilo, D T
Four cases of CD30-positive T-cell lymphoproliferative disorder (CD30+ LPD) of the oral mucosa are described. This article aims to draw attention to this entity and to emphasize its usual benign clinical behavior despite its resemblance to T-cell lymphoma. All the patients were adults. Three of the lesions were on the dorsal surface of the tongue and 1 affected the buccal mucosa. All biopsies showed a dense lymphoid infiltrate composed of CD30+ atypical T cells with a polymorphous infiltrate in the background, which included eosinophils. In 1 case, monoclonal T-cell expansion was detected by molecular techniques. Three cases tested for Epstein-Barr virus were all negative. It is concluded that primary CD30+ T-cell LPD of the oral mucosa can be regarded as the oral counterpart of cutaneous CD30+ LPD such as lymphomatoid papulosis or anaplastic large cell lymphoma. Recognition of the condition is important to avoid overtreatment. PMID:18387994
Agarwal, Monica; Shenjere, Patrick; Blewitt, Robert W; Hall, Gillian; Sloan, Philip; Pigadas, N; Banerjee, S Sankar
Background: Flow cytometry has come to occupy the vanguard of the high through put diagnostic techniques that have been used to differentiate between various chronic lymphoproliferative disorders (CLPD). However, economic considerations have created the need for minimal consensus panels that can yield maximum information at reasonable costs. Aims: To collect, analyse and correlate the morphologic, immunophenotypic, and the cytogenetic data from the cases of chronic lymphoproliferative disorders, which were diagnosed at an Indian speciality cancer centre. Methods and Material: The morphology was recorded after staining the samples with the Leishman or the MGG stains. The lineage assignment was done by using three colour flow cytometry with a primary panel of antibodies. For the cytogenetic studies, the short term culture of the sample cells were arrested by using colcemid and they were G-banded by using trypsin and Giemsa stain. FISH studies were conducted by using a CLL-specific diagnostic kit. Results and Conclusions: A total of 66 cases were evaluated, which had a median age of 64.5 years and a sex ratio of 2.3:1. Of these 66 cases, 40 cases were of CLL and 9 cases were of atypical CLL. 17 cases were classified as CLPD and these included 13 cases of Non-Hodgkin's Lymphoma, two cases of Hairy Cell Leukaemia, one case of Follicular Lymphoma and one case of Prolymphocytic Leukaemia. In immunophenotyping, the lack of expression of CD22 had the highest correlation with a definitive diagnosis of CLL. Cytogenetics demonstrated a classical follicular lymphoma abnormality, t (14; 18) (q32; q21), in one case. A basic minimal panel is sufficient for the routine diagnosis of CLL. However, the stratification of CLPD requires the use of more extensive panels. PMID:23998067
Okaly, Geeta V Patil; Nargund, Ashwini R; E, Venkataswamy; Jayanna, Prashanth K; Juvva, Chandra Rao; Prabhudesai, Shilpa
Resistance to Leishmania parasite infection requires the development of a cellular immune response that activates macrophage leishmanicidal activity. In this study we have investigated the lymphoproliferative responses and in vitro cytokine production of peripheral blood mononuclear cells (PBMC) from individuals living in an endemic area for L. major infection in Tunisia. The results were compared with the DTH reaction of the leishmanin skin test (LST). Sixty-seven individuals were included in the study: 22 persons (age range 9–60 years) who developed, 2 years before the present study, a parasitologically confirmed localized cutaneous leishmaniasis (LCL) that healed spontaneously, and 45 individuals (age range 18–20 years) born and living in the same area, with no previous history of LCL. LST was positive (skin induration ? 5 mm) in 20/22 cured cases of LCL and in 75% of healthy individuals without history of LCL. LST+ individuals expressed vigorous Leishmania-specific lymphoproliferative responses associated with in vitro production of interferon-gamma (IFN-?) but not IL-4. Interestingly, IL-10 was detected in parallel with the highest levels of IFN-? in PBMC supernatants from 3/20 cured LCL and 8/25 individuals without history of LCL. Our results showed a 98% concordance between the DTH reaction assessed by LST and the in vitro proliferative assay induced by soluble leishmanial antigens. Moreover, proliferative assays as well as cytokine analysis did not show any significant difference of the immune memory to parasite antigens developed by patients who had overt cutaneous leishmaniasis and those who had apparently asymptomatic infection.
SASSI, A; LOUZIR, H; BEN SALAH, A; MOKNI, M; BEN OSMAN, A; DELLAGI, K
We present a rare case of a 16-year-old male patient with Castleman's disease (CD) manifest by a suspicious mass within the left suprarenal region abutting the left adrenal gland, mimicking an adrenal neoplasm. CD is an uncommon and poorly understood lymphoproliferative disorder that, when observed, typically occurs as a mediastinal mass. Two percent of cases reportedly occur in the pararenal region. Although rare, Castleman's disease should be considered in the differential diagnosis of a retroperitoneal mass. PMID:21316092
Santomauro, Michael; Choe, Chong; Heimbigner, Jared; Roberts, John; Auge, Brian
Castleman's disease (CD) is a rare, localized or generalized, lymphoproliferative disorder with a frequent mediastinal location, but possible in any lymph node or extra nodal site. It usually appears in young adults whilst it rarely occurs in childhood. There are only about 100 pediatric cases published, five of them in Italy. We report 3 cases of localized Castleman's disease, investigated in our Department in a 3 years period and reviewed the literature.
Mycoplasma gallisepticum causes a lymphoproliferative response in the tracheal mucosa of infected birds. The studies reported here aimed to determine, using immunohistochemical and immunofluorescent staining, which lymphocyte subsets were infiltrating the mucosa during the acute and chronic phases of disease and to determine whether these subsets differed in birds that had been vaccinated with strain ts-11. In vaccinates there was
J. E. Gaunson; C. J. Philip; K. G. Whithear; G. F. Browning
In addition to triggering the activation of B- or T-cell antigen receptors, the binding of a ligand to its receptor at the cell surface can sometimes determine the physiological outcome of interactions between antigen-presenting cells, T and B lymphocytes. The protein SLAM (also known as CDw150), which is present on the surface of B and T cells, forms such a
J. Sayos; C. Wu; M. Morra; N. Wang; X. Zhang; D. Allen; S. van Schaik; L. Notarangelo; R. Geha; M. G. Roncarolo; H. Oettgen; J. E. de Vries; G. Aversa; C. Terhorst