Research accomplishments of this project include: 1) This project allows us to study the largest cohort of patients with ALPS, one of the first genetic disorders of immunedysregulation. ALPS natural history study based on follow up of these patients over 18 yeas has been completed and a manuscript is being generated summarizing the critical features of the clinical and molecular pathogenesis in 150 patients with ALPS-FAS with a median followup of 13 years. This included the validation of new biomarkers as well as establishing new modes of treatment for the disorder. It elucidates the role of fas mediated apoptosis in lymphocyte homeostasis and lymphoma genesis. 2)This project has also led to identifying new genetic causes of ALPS like disorders by identification of mutations affecting RAS pathway in 14 patients, otherwise known as Ras Associated Leukoproliferative Disorder (RALD) : RALD: Patients with this ALPS like syndrome caused by somatic mutations in NRAS and KRAS are currently classified separately as ALPS related apoptosis disorders. These patients with somatic NRAS and KRAS mutations present with autoimmune phenomena, massive splenomegaly, modest lymphadenopathy and normal or only marginally elevated TCR alpha/beta+ DNT cells. Their lymph node histopathology is also not typical of ALPS-FAS. Additionally, these patients show abnormalities of the myeloid compartment, with chronic persistent monocytosis, mimicking juvenile myelomonocytic leukemia (JMML) in otherwise asymptomatic young patients. 3) 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 TNFSF6 gene, encodes the protein CD95 ligand (Fas ligand). ALPS-CASP10: mutations in CASP10 gene, encodes caspase-10. ALPS-U: associated mutation unidentified to date. 4) Recently we clarified that the cause of disordered FAS protein function leading to ALPS is based on haploinsuffiiciency caused by mutations affecting the extracellular portion of the protein in some patients. This is a newly emerging unique mechanism of genetic dysfunction. With support from NCBI we have implemented a web based publication of the existing databases of pathogenic FAS mutations, by far the commonest cause of ALPS, which is publicly available and can be used for diagnostic help by referring to NCBI NIH ALPS website <www.ncbi.nlm.nih.gov/lovd/home.php?select_db=FAS>. 5) 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. 6) 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-FAS in approximately 10% of our patients. Ongoing critical surveillance for lymphoma and its early diagnosis and treatment has been pursued over the last 20 years of longitudinal follow up of these patients. 7) Continued search for new genetic mutations in the subgroup of patients with ALPS and undetermined genetic defects using emerging genomic and cell biology tools. Currently a large group of patients with unknown molecular etiologies are being subjected to whole exome DNA sequencing and analysis. 8) More recently the ALPS Clinical group is being repositioned to tackle new classes of immunological disorders which has involved the recruitment of new members of the team as well as special inservices on genetics and molecular biology for the nursing and ancillary support staff. 9) Continued efforts to streamline the techniques of apoptosis assay by evaluating Fas mediated cell death in lymphocyte subsets so that this test procedure can be readily adapted in more clinical laboratories for patient evaluation. 10) Confounding factors in the clinical presentation of ALPS and another hematological condition called HLH (Hemophagocytic lymphohistiocytosis) have been identified and clinicians are being advised to be aware of the distinguishing biomarkers in both conditions.

Project Start
Project End
Budget Start
Budget End
Support Year
19
Fiscal Year
2013
Total Cost
$477,005
Indirect Cost
City
State
Country
Zip Code
Similuk, Morgan; Rao, V Koneti; Churpek, Jane et al. (2016) Predispositions to Lymphoma: A Practical Review for Genetic Counselors. J Genet Couns :
Rao, V Koneti (2016) Serendipity in splendid isolation: rapamycin. Blood 127:5-6
Ucar, Didar; Kim, Jane S; Bishop, Rachel J et al. (2016) Ocular Inflammatory Disorders in Autoimmune Lymphoproliferative Syndrome (ALPS). Ocul Immunol Inflamm :1-7
Lau, Chuen-Yen; Mihalek, Andrew D; Wang, Jing et al. (2016) Pulmonary Manifestations of the Autoimmune Lymphoproliferative Syndrome. A Retrospective Study of a Unique Patient Cohort. Ann Am Thorac Soc 13:1279-88
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Moraitis, Andreas G; Freeman, Lita A; Shamburek, Robert D et al. (2015) Elevated interleukin-10: a new cause of dyslipidemia leading to severe HDL deficiency. J Clin Lipidol 9:81-90
Lo, Bernice; Zhang, Kejian; Lu, Wei et al. (2015) AUTOIMMUNE DISEASE. Patients with LRBA deficiency show CTLA4 loss and immune dysregulation responsive to abatacept therapy. Science 349:436-40
Butt, Danyal; Chan, Tyani D; Bourne, Katherine et al. (2015) FAS Inactivation Releases Unconventional Germinal Center B Cells that Escape Antigen Control and Drive IgE and Autoantibody Production. Immunity 42:890-902
Milner, Joshua D; Vogel, Tiphanie P; Forbes, Lisa et al. (2015) Early-onset lymphoproliferation and autoimmunity caused by germline STAT3 gain-of-function mutations. Blood 125:591-9
Rao, V Koneti (2015) Approaches to Managing Autoimmune Cytopenias in Novel Immunological Disorders with Genetic Underpinnings Like Autoimmune Lymphoproliferative Syndrome. Front Pediatr 3:65

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