74 autoimmune lymphoproliferative syndrome (alps): a disorder of defective lymphocyte apoptosis marked by predominant th2 cytokine responses and elevated circulating il-10 levels.

ALPS is a lymphoproliferative syndrome characterized by massive nonmalignant lymphadenopathy, hepatosplenomegaly and autoimmune phenomena including hemolytic anemia, thrombocytopenia, and hypergammaglobulinemia. On phenotypic studies these patients display a B and T cell lymphocytosis exemplified by expanded populations of CD3+CD4-CD8- T cells, CD3+DR+ T cells and CD19+ B cells. This lymphocytosis is associated with and presumably due to defective B and T cell apoptosis which, in most but not all cases, results from a variety of identified Fas gene locus mutations. When ALPS patients mutant Fas genes is co-transfected with a normal Fas gene into BW514 murine thymoma cells it results in the dominant inhibition of the normal Fas function and thereby leads to defective Fas-mediated cell death. To define the role apoptosis plays in immunologic responsiveness circulating levels and in vitro production of cytokines (IL-1,IL-2,IL-4,IL-5,IL-6,IL-10,IL-12 and IFN-γ) were analyzed from plasma or culture supernatants of purified lymphocytes and monocytes respectively, utilizing specific ELISA. In ALPS patients circulating levels of IL-10 were elevated 300-fold, while the levels of IL-1, IL-2, IL-4, and IL-6 were normal. Stimulated CD4+DR+T cells of ALPS patients produced increased amounts of IL-4 and IL-5 (10-fold) with decreased amounts of IL-2 and IFN-γ (2-4-fold). Finally, patient peripheral monocytes produced decreased amounts of IL-12 (40-fold) while secreting increased amounts of IL-10 (15-fold). In summary, ALPS patients exhibit defective Fas-mediated cell death with increased levels of IL-10 and activated T cells (DR+) that upon stimulation respond with a Th2 cytokine response. This skewed Th2 cytokine response favors the differentiation of B cells into autoimmune nontumorigenic B cells producing autoantibodies. The findings in ALPS contrasts with those in post-hepatic transplant lymphoproliferative disease (PTLD), another syndrome characterized by lymphoproliferation and autoimmunity. PTLD, in contrast to ALPS, is associated with B cell lymphomas and elevated IL-6 levels which has been shown to promote growth and malignant transformation of EBV-infected B cells. B cells may fail to undergo malignant changes in ALPS despite preexisting EBV infection because the markedly increased IL-10 levels downregulate IL-6 production.