Poster Board III-451
Patients with autoimmune lymphoproliferative syndrome (ALPS) are the only described patients in which a known genetic defect leads directly to autoimmunity. In these patients, mutations in FAS or FASL result in an inability of activated lymphocytes to die resulting in defective lymphocyte homeostasis. The disorder manifests itself in autoimmunity directed towards platelets, red cells and neutrophils in addition to lymphadenopathy, splenomegaly and an increased risk of lymphoma. Inheritance of the defect is dominant, however there is variable penetration and patients even within the same family and with the same mutation can have a different phenotype. A definitive diagnosis requires clinical symptoms, elevated (>1%) TCRab+CD3+CD4-CD8- (DNT) cells in the peripheral blood and the demonstration of defective lymphocyte apoptosis in vitro. Given the tendency for patients with ALPS to develop ITP, we hypothesised that patients with ITP may also have mutations or polymorphisms within this pathway and hence abnormal lymphocyte homeostasis as an etiology of their ITP. DNA from 88 children and adults with chronic ITP (48 post splenectomy, all more than 1 year from diagnosis) were screened for mutations in the FAS gene. None had the mutations typically associated with ALPS. However, in 6 patients single nucleotide polymorphisms (SNPs) were detected: 3 at 528(+6)C>T and 3 at 836C>T; one patient had both polymorphisms. Three of these patients also had haemolysis. In three patients, FAS induced apoptosis studies were normal (the remaining await analysis). DNT cells (the signature cells of ALPS) ranged from 0.5% to 2.9% in these 6 patients with all but one above the normal adult range (0.1-0.9%). DNT cells were also raised in 3 of 4 patients with no SNPs in FAS, (median 1.8 - range 1.1 to 6.1%). One individual with the 836C>T SNP had 2.9% DNT cells with an absolute number of 91 cells (DNT cells NR 2-17 cells) with virtually absent gamma-delta DNTs. In addition, this patient had evidence activation of T cells with raised CD4/HLA-DR. and CD8/HLA-DR and CD27+ B cells were <16% of B cells. This patient had severe ITP with a complete response to rituximab for the last 8 years. This data, although not quite conclusive, suggests that SNPs in the FAS pathway may contribute to the autoimmunity seen in patients with ITP. In addition, the presence of increased DNT cells, even in patients without SNPs in the FAS gene, suggests defect in the immune system not previously investigated and that the DNT cells may have a role in immune homeostasis.
Cooper:GSK: Consultancy, Honoraria; Amgen: Consultancy. Bussel:Genzyme: Research Funding; GlaxoSmithKline: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cangene: Research Funding; Amgen: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Research Funding; Immunomedics: Research Funding; Ligand: Membership on an entity's Board of Directors or advisory committees, Research Funding; Eisai, Inc: Research Funding; Sysmex: Research Funding; Scienta: Speakers Bureau; Shionogi: Membership on an entity's Board of Directors or advisory committees.
Asterisk with author names denotes non-ASH members.