CHARACTERISTIC T-HELPER-2 T-CELL CYTOKINE ABNORMALITIES IN AUTOIMMUNELYMPHOPROLIFERATIVE SYNDROME, A SYNDROME MARKED BY DEFECTIVE APOPTOSIS AND HUMORAL AUTOIMMUNITY

Autoimmune lymphoproliferative syndrome (ALPS) is marked by massive ly mphadenopathy, hepatosplenomegaly, autoimmunity and the presence of in creased numbers of circulating and tissue TCR-alpha beta, CD4(-)CD8(-) T cells. The underlying defect is that of decreased T cell and B cell apoptosis, due in most, but not all, cases to heterozygous mutations of the Fas gene and corresponding defective Fas signaling function. He re we measure in vivo and in vitro cytokine secretion in ALPS to shed light on the relation of apoptosis defects to the development of autoi mmunity. In in vivo studies, ALPS patients manifested greatly increase d circulating levels of IL-10 (>100-fold), compared with both healthy individuals and various disease controls; in contrast, their levels of IL-1 beta, IL-4, and IFN-gamma were normal and their levels of IL-2 a nd TNF-alpha were marginally increased. in parallel in vitro studies, ALPS patients CD4(+)DR(+) T cells stimulated either with anti-CD3/CD28 or anti-CD2/CD28 produced increased amounts of IL-4 and IL-5 (10 to 2 0-fold) and decreased amounts of IFN-gamma, (4-fold) as compared with those of control CD4(+)DR(+) T cells. In contrast, ALPS patients' CD4( -)/CD8(-) T cells produced very low amounts of cytokines. Finally, ALP S patients' peripheral monocytes/macrophages produced decreased amount s of IL-12 (30-fold) and increased amounts of IL-10 (5-fold). In concl usion, ALPS is marked by the presence of DR(+) T cells that exhibit a skewed Th2 cytokine response upon various forms of stimulation. This c ytokine response, in the presence of increased circulating IL-10 level s, is likely to define the cytokine milieu that accounts for the humor al autoimmune features of ALPS and, perhaps, of other humoral autoimmu ne states.