Clinical, Immunological and Genetic Analyses of ALPS

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Abstract

Advances in ALPS:[unreadable] [unreadable] 1.) Some cases of SHML (Sinus histiocytosis with massive lymphadenopathy, aka Rosai-Dorfman syndrome) may represent ALPS. Similar to ALPS, SHML is a rare disorder that usually presents in childhood. SHML is a proliferative histiocytic disorder of unknown cause. As part of the tissue evaluation of ALPS patients, the histologic observation of SHML was made, suggestive of the possibility of an association between ALPS and SHML. All available reactive lymph node materials from 44 ALPS Type Ia patients were evaluated for features of SHML: 41% (18 of 44 patients) had one or more lymph nodes that fulfilled the criteria for SHML as assessed on hematoxylin and eosin sections and confirmed by S-100 immunostaining. Representative cases of SHML were also evaluated. The results suggest that some cases of SHML may represent ALPS[unreadable] [unreadable] 2.) Somatic Fas mutations: In 2004, ALPS investigators from Europe reported 6 patients with somatic Fas mutations limited to their CD3+CD4-CD8-TCR+ T cells (?DNT?s") population, a cell population with a known survival advantage, thus providing new insights into causation in a subset of patients with ALPS. Based upon their findings, we evaluated 20 patients from our cohort with unidentified mutations for the presence of somatic Fas mutations (12 ALPS Type III?s and 8 with ALPS phenotype): 1 of 12 (8 %) and 3 of 8 (38 %) patients were positive for somatic mutations, respectively. These results provide evidence that patients classified as either ALPS phenotype or ALPS Type III with atypical late onset of ALPS presenting features would benefit from screening for the presence of a Fas mutations in their peripheral blood DNT population. Further research to characterize this patient subset at the molecular and clinical level, along with associated risks and outcomes are continuing aims of investigation.[unreadable] [unreadable] 3.) Provided is the classification scheme that we have devised for ALPS patients based on the site of their mutation:[unreadable] Type Ia: mutations in the TNFRSF6 gene, encodes Fas.[unreadable] Type Ia, somatic mutant: TNFRSF6 defect in the DNT population [unreadable] Type Ib: mutations in the TNFSF6 gene, encodes for Fas ligand.[unreadable] Type IIa: mutations in CASP10 gene, encodes Caspase-10.[unreadable] Type IIb: mutations in the CASP8 gene, encodes Caspase 8.[unreadable] Type III: associated mutation unidentified to date. [unreadable] 4.) Evidence that a caspase-10 alteration (mutation), V410I, demonstrates a protective effect against severe disease when present together with dominant Fas mutations in members of ALPS Type Ia kindreds. [unreadable] 5.) The human lymphocyte antigen, HLA B44, appears to confer a protective role against disease severity. We evaluated HLA as a potential candidate modifier locus. Analysis included HLA A, B (including subtypes) and DQB alleles in 356 individuals from 63 unrelated families with defined TNFRSF6 mutations associated with ALPS. The transmission of HLA B44 was significantly overrepresented (P value: <0.0074) in healthier mutation-bearing individuals as compared to transmission in patients with severe clinical features of ALPS, suggesting a protective role in ALPS. The numbers were too small to determine whether the association is caused by the B44 allele or an allele at some other nearby locus.[unreadable] 6.) Availability of a disease severity score for investigators. We have developed and validated a quantitative severity score rating system including both clinical and laboratory metrics to assist in analysis and disease severity scoring. Feedback is welcome.[unreadable] 7.) Mycophenolate mofetil (MMF) confers therapeutic benefit to ALPS patients with difficult to control cytopenias (anemia, neutropenia, thrombocytopenia). [unreadable] [unreadable] Background of ALPS: In 1990, we identified and began to characterize a new chronic disorder we have termed autoimmune lymphoproliferative syndrome, or ALPS. It manifests as chronic nonmalignant adenopathy and splenomegaly; the expansion of an unusual population of CD4-CD8-T cells (DNT?s); and the development of autoimmune disease including but not limited to hemolytic anemia, thrombocytopenia and neutropenia. Through our family-based association studies, we learned to identify and diagnose the syndrome and to identify and treat most of its major complications effectively. We have documented a variety of humoral and cellular immunologic abnormalities in ALPS patients, including circulation of multiple autoantibodies leading to immune cytopenias, alterations in lymphocyte subsets and disordered regulation of cytokines. In vitro studies with human cells and cell lines showed that ALPS is associated with inherited defects in genes involving lymphocyte apoptosis pathways. [unreadable] [unreadable] Inherited mutations in genes that regulate cell death, a process referred to as apoptosis, is causal in the development of ALPS and related disease. Mutations in more than four genes associated with ALPS have been identified to date. Most cases of ALPS (over 70 percent) are classified as Type Ia, these involve functional heterozygous mutations in the APT1 gene, which encodes Fas (CD95, APO-1, TNFRSF6-Tumor necrosis Factor Receptor SuperFamily-6), a lymphocyte surface protein; Type Ib is associated with mutations in Fas ligand, Type IIa with caspase-10 and Type IIb with caspase-8. Patients for whom the involved apoptotic gene has yet to be identified are classified as Type III.[unreadable] [unreadable] We have determined that inherited mutations in Fas represent a novel risk factor for the subsequent development of B and T cell lymphomas. The risk of non-Hodgkin and Hodgkin lymphomas compared to that of the general population, matched by age, are 14 and 51 fold elevated, respectively. This represents a challenge that we are addressing by defining an algorithm for patient follow up and lymphoma detection under a protocol in which PET scanning is being evaluated for its ability to discriminate ALPS nodes from lymphomatous nodes. Our hope over time will be to determine whether PET scanning helps us identify ALPS patients who are in transition of lymphoma or at risk for doing so. We are testing agents that stimulate lymphocyte apoptosis in MRL/lpr mice bearing homozygous deletions of the Fas gene. We plan to undertake sequential pilot studies of treatments derived from the LPR mouse model and implemented in Phase I-II studies among ALPS patients. We will test their capacity to reduce adenopathy and splenomegaly, and to lessen immunoglobulin, autoantibody and IL-10 levels. In addition, we continue to evaluate the role of immunomodulating agents in the prevention of splenectomy for the treatment of hypersplenism.