The spectrum of apoptotic defects and clinical manifestations, including systemic lupus erythematosus, in humans with CD95 (Fas/APO-1) mutations

Objective. To determine the clinical spectrum of disease in humans with mut ations in the CD95 (Fas/ APO-1) receptor and to obtain mechanistic insight into the different clinical phenotypes observed. Methods. Clinical information for each of the index cases, first-degree rel atives, and any family members reported to have Canale-Smith syndrome (or a nother autoimmune disease) was gathered by direct interview, chart review, and verification of data by the physician or pathologist concerned. Apoptos is of activated T or B lymphocytes was induced by agonistic anti-CD95 antib odies and quantified by a cell death assay (propidium iodide staining in th e subdiploid peak) or cell viability assay (alamar blue or H-3-thymidine in corporation). Results. Evaluation of an additional 8 probands with novel heterozygous CD9 5 mutations revealed hypergammaglobulinemia and immune-mediated cytopenias in all patients, as well as urticarial rash, oral ulceration, lymphopenia, and peripheral neuropathy in some individuals. One patient (P4) had systemi c lupus erythematosus (SLE) characterized by a World Health Organization cl ass V lupus nephropathy, a recurrent, reversible multifocal central nervous system disorder, high-titer antiphospholipid autoantibodies, and autoimmun e cytopenias. In the P4 pedigree, the father had reduced T and B cell apopt osis associated with a CD95 mutation, whereas an independent B cell apoptot ic defect was demonstrated in maternal family members who did not have a CD 95 mutation. Three cases of B cell lymphoma occurred in carriers of the CD9 5 mutation. Conclusions. CD95 mutations are associated,vith loss of regulation of B lym phocytes, which predisposes to systemic autoimmunity including SLE. The P4 family provides a model of the complex genetic and functional interactions that are required for the development of a lupus-like syndrome.