Research accomplishments of this project during the past year include: 1.) Clarified the designation of a seventh subtype of ALPS, ALPS Type IV, based on the identification of the new molecular defect described above. Identified more patients belonging to all subgroups, but most significantly underscored value of somatic gene mutations limited to circulating DNT cells causing a nonmalignant disease in 11 patients, by far the largest second subgroup. Provided is the classification scheme that we have devised for ALPS patients based on the particular molecular defect present: Type Ia: mutations in the TNFRSF6 (tumor necrosis factor receptor superfamily 6) gene, encodes the protein CD95 (Fas, Apo-1). Type Ia: somatic mutant: TNFRSF6 gene defect in the double negative T (DNT) cell population. Type Ib: mutations in TNFRSF6 gene, encodes the protein CD95 ligand (Fas ligand). Type IIa: mutations in CASP10 gene, encodes caspase-10. Type IIb: mutations in the CASP8 gene, encodes caspase 8. Type III: associated mutation unidentified to date. Type IV: mutations in NRAS. 2.) The extended 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.) Extended in vitro and in vivo studies of potential therapeutic drugs in the MRL/lpr (ALPS) mice, testing their capacity to reduce lymphadenopathy and splenomegaly, and key biological markers in ALPS. Valproic acid, a histone deacetylase inhibitor, reduced splenomegaly, lymphadenopathy and CD3+CD4-CD8-alpha beta TCR+T cells (DNTs) in the spleen and blood of MRL/lpr mice. In vitro, using both normal and ALPS Type Ia peripheral blood mononuclear cells (PBMCs), valproic acid was able to induce cell death in a dose-dependent manner. Cell death appeared to be both caspase-dependent and -independent based on partial inhibition with the pan-caspase inhibitor, Z-VAD-FMK. 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 and noted lymphoma in one patient with ALPS Type IV. 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.

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Comrie, William A; Faruqi, Aiman J; Price, Susan et al. (2018) RELA haploinsufficiency in CD4 lymphoproliferative disease with autoimmune cytopenias. J Allergy Clin Immunol 141:1507-1510.e8
Buchbinder, David; Seppanen, Mikko; Rao, V Koneti et al. (2018) Clinical Challenges: Identification of Patients With Novel Primary Immunodeficiency Syndromes. J Pediatr Hematol Oncol 40:e319-e322
Ucar, Didar; Kim, Jane S; Bishop, Rachel J et al. (2017) Ocular Inflammatory Disorders in Autoimmune Lymphoproliferative Syndrome (ALPS). Ocul Immunol Inflamm 25:703-709
Ozen, Ahmet; Comrie, William A; Ardy, Rico C et al. (2017) CD55 Deficiency, Early-Onset Protein-Losing Enteropathy, and Thrombosis. N Engl J Med 377:52-61
Rao, V Koneti; Webster, Sharon; Dalm, Virgil A S H et al. (2017) Effective ""activated PI3K? syndrome""-targeted therapy with the PI3K? inhibitor leniolisib. Blood 130:2307-2316
Dulau Florea, Alina E; Braylan, Raul C; Schafernak, Kristian T et al. (2017) Abnormal B-cell maturation in the bone marrow of patients with germline mutations in PIK3CD. J Allergy Clin Immunol 139:1032-1035.e6
Xie, Yi; Pittaluga, Stefania; Price, Susan et al. (2017) Bone marrow findings in autoimmune lymphoproliferative syndrome with germline FAS mutation. Haematologica 102:364-372
Weinreich, Michael Alexander; Vogel, Tiphanie P; Rao, V Koneti et al. (2017) Up, Down, and All Around: Diagnosis and Treatment of Novel STAT3 Variant. Front Pediatr 5:49
Rao, V Koneti (2016) Serendipity in splendid isolation: rapamycin. Blood 127:5-6
Cruz, Anthony C; Ramaswamy, Madhu; Ouyang, Claudia et al. (2016) Fas/CD95 prevents autoimmunity independently of lipid raft localization and efficient apoptosis induction. Nat Commun 7:13895

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