Clinical, Immunological and Genetic Analyses of ALPS

National Institute Of Allergy And Infectious Diseases

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Abstract

Research accomplishments of this project during the past year include: 1.) Clarified the diagnosis and classification designation of subtypes of ALPS, following a NIH sponsored International ALPS workshop in September 2009 leading to a consensus among all clinical and basic science researchers studying ALPS and related conditions. A) Revised Diagnostic Criteria for ALPS as outlined below: Required Criteria: 1. Chronic (>6 months), non-malignant, non-infectious lymphadenopathy and/or splenomegaly. 2. Elevated CD3+ TCRalpha beta+CD4-CD8- DNT cells (equal to or greater than 1.5% of total lymphocytes or 2.5% of CD3+ lymphocytes) in the setting of normal or elevated lymphocyte counts. Accessory Criteria: Primary 1. Defective lymphocyte apoptosis (in 2 separate assays); 2. Somatic or germline pathogenic mutation in FAS, FASLG, or CASP10; Secondary 1. Elevated plasma sFASL levels (>200 pg/ml) OR elevated plasma IL-10 levels (>20 pg/ml) OR elevated serum or plasma Vitamin B12 levels (>1500 ng/L) OR elevated plasma IL-18 levels above 500 pg/ml; 2. Typical immuno-histological findings as reviewed by an experienced hematopathologist; 3. Autoimmune cytopenias (hemolytic anemia, thrombocytopenia, or neutropenia) AND elevated IgG levels (polyclonal hypergammaglobulinemia); 4. Family history of a non-malignant/non-infectious lymphoproliferation with or without autoimmunity. Definitive diagnosis: Both required criteria plus one primary accessory criterion. Probable diagnosis: Both required criteria plus one secondary accessory criterion. B) Provided below is the current classification scheme that we have devised for ALPS patients based on the particular molecular defect present: ALPS-FAS : mutations in the TNFRSF6 (tumor necrosis factor receptor superfamily 6) gene, encodes the protein CD95 (Fas). ALPS-sFas: somatic mutant: TNFRSF6 gene defect in the double negative T (DNT) cell population. ALPS-FASLG: mutations in TNFRSF6 gene, encodes the protein CD95 ligand (Fas ligand). ALPS-CASP10: mutations in CASP10 gene, encodes caspase-10. ALPS-U: associated mutation unidentified to date. C) Separated related disorders of apoptosis with variant clinical phenotypes into ALPS Related Disorders as defined during the 2009 NIH ALPS workshop. CEDS:Caspase Eight Deficiency State due to mutations in the CASP8 gene, encodes caspase 8. RALPS: RAS associated leukoproliferative syndromes due to mutations in NRAS and related genes. 2.) The expanded the diagnostic algorithm for ALPS by way of validated biomarkers like Serum Vitamin B12, IL-10, IL-18 and sFasL. Continued to explore and refine guidelines for evaluation, management and duration of follow-up using Mycophenolate mofetil (MMF) for the treatment and prevention of ALPS-related autoimmune complications which include refractory cytopenias and other end organ damage. Our experience with MMF as an effective, well-tolerated steroid-sparing long-term maintenance immunomodulatory therapy in the subset of children with refractory ALPS-associated cytopenias associated with splenomegaly and/or autoimmunity is positive. Reviewed and published our experience with MMF, Rituximab in the context of ALPS patients with refractory cytopenias over the last 10 years. 3.) Further characterized the pathophysiology and clinical phenotype of the second largest subgroup of ALPS patients in our cohort with somatic mutations in the FAS gene mostly limited to their ALPS signature cells, also known as double negative T lymphocytes. 4.) Extended the use of PET scans as an imaging modality in patients with ALPS associated lymphadenopathy as a tool to monitor patients with suspected ALPS associated cancer of the lymphoid system (lymphoma). We have identified lymphomas associated with ALPS Type Ia in approximately 10% of our patients. Ongoing critical surveillance for lymphoma and its early diagnosis and treatment has been pursued over the last 15 years of longitudinal follow up of these patients. 5.) Continued enrolling patients in a clinical protocol to study the safety and efficacy of valproic acid in ALPS associated lymphoproliferation and hypersplenism.