STUDIES OF PRIMARY IMMUNODEFICIENCY DISEASES

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Studies on our laboratory have focused on defining the nature of the B cell and T cell defects in Common Variable Immunodeficiency (CVI), a primary acquired human immunodeficiency state characterized by hypogammaglobulinemia and impaired functional antibody responses. Previous studies of purified B cells of patients with CVI show that although the cells have a normal capacity to proliferate, they manifest differentiation defects at multiple levels. Thus, as compared with normal B cells, circulating CVI B cells contain reduced numbers of sIgG+ and sIgA+ cells with a commensurate increase in sIgM+ B cells, suggesting an in vivo defect in isotype switch. In addition, they fail to undergo differentiation into immunoglobulin-producing cells. In the present study, we show that CVI B manifest an abnormality of surface B7 expression associated with the capacity to induce normal T cells to manifest suppression cell capacity. In particular, positively-selected CVI B cells (i.e., cells exposed to anti-CD19 antibody) when subsequently activated with anti-IgM manifest premature expression of B7-1 followed by decreased expression of B7-2. Since B7-1 through its interaction with CTLA-4 on T cells acts as a suppressor of T cell activity, we performed extensive co-culture studies in which CVI T cells were pre-incubated with normal T cells and the latter were tested for their capacity to produce lymphokines and to help B cell Ig production. It was found that normal T cells pre-cultured with CVI B cells but not normal B cells exerted greatly decreased helper T cell activity. These studies thus define a functional consequence of premature B7-1 expression. In addition, they explain the fact that T cells in CVI patients have been shown to manifest excessive suppressor function. The above studies of B7 expression in CVI strongly suggest the presence of a B cell signaling defect. We have therefore begun a systematic search for a signaling abnormality in CVI and have shown that CVI B cells manifest normal levels of MAP Kinase and Stat 1.