Immune Evaluation in Patients with Autoimmune Lymphoproliferative Syndrome

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Abstract

The NIH ALPS group currently follows a cohort of over 400 families, and we are investigating several aspects of the disease. To discover biomarkers for ALPS we completed in 2010 an extensive evaluation of the clinical and laboratory findings in 562 ALPS patients and their family members. It revealed that a level of double negative T cells above 4% together with an elevation of soluble FasL, Vitamin B12 or IL-10 has up to 98% of predictive value for ALPS with both germline and somatic FAS mutations. The results were incorporated into the new diagnostic criteria for ALPS. Our group recently described that most mutations affecting the extracellular region of FAS disrupt protein function by inducing haploinsufficiency, with consequent low FAS expression, low DISC formation and suppressed apoptosis. These defects were milder as compared to mutations affecting the intracellular domains of FAS, potentially explaining the variable expressivity and lower penetrance seen in patients with mutations in the extracellular domains. Linking the biomarker data in patients with increased double negative T cells but normal genomic DNA sequencing of the gne encoding FAS has provided the basis for evaluating to isolated DNT cells for somatic mutations affecting primarily DNT cells as a genetic cause for ALPS. We have now determinted that somatic FAS mutations represent the second most common genetic basis for ALPS. Our group has tested novel drug compounds for the treatment of ALPS. One of such drugs, named ABT-737, was tested in vitro in the lpr mouse model of ALPS, with control of autoimmunity and improvement lymphadenopathy and splenomegaly, specially if used in conjunction with steroids. An oral analog of this drug is currently being tested for therapy of hematological malignancies, and it may prove very useful in ALPS. We plan on starting a phase 1 study for testing in humans.