STUDIES OF PRIMARY IMMUNODEFICIENCY DISEASES

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The aim of this project is to define the immunopathogenetic mechanisms responsible for human immunodeficiency syndromes. During the past year we have focused on the functional capacities of T and B cells from patients with common variable immunodeficiency (CVI). In studies of CVI patient T cells, we showed that while purified CD4 T cells proliferate normally in response to proliferation by PHA, staphylococcal enterotoxin B (SEB) and anti-CD2 antibodies, these stimuli induce significantly less IL-2 than normal CD4+ T cells. On the other hand, immobilized anti-CD3 antibody and this stimulus in combination with anti-CD28 antibody induced CVI T cells to produce normal amounts of IL-2. These studies thus demonstrate that the IL-2 production defect in CD4+ T cells is due to a specific signalling pathway abnormality. In a second series of studies, in this case focused on B cell function in CVI patients, we showed first that circulating B cells express normal amounts of sIgM+, but greatly reduced amounts of sIgG+ and sIgA+; this result implies that patients have an in vivo defect of isotype switch differentiation. In other studies, we showed that upon stimulation of purified patient B cells with anti-CD40 antibody plus IL-10, patient B cells expressed Cmu, Cgamma and Calpha mRNA; furthermore, stimulation of cells with anti-CD40 plus IL-10, followed by stimulation with activated T cells (which express the CD40 ligand), led to partial restoration of IgG and IgA synthesis. These studies thus indicate that CVI B cells can be partially restored to normal function in vitro, suggesting that the cells are not irreversibly blocked from isotype and terminal differentiation.