The aim of this project is to further define the immunopathogeneic mechanisms responsible for the clinical syndrome known as common variable immunodeficiency (CVI). During the past year we expanded our studies on the functional properties of the expanded population of CD8 T cells seen in a subgroup of patients with CVI. We demonstrated that these cells exhibit a defect in proliferation and IL-2 production. However, these CD8 T cells showed increased production of IL-5 and gamma-interferon. In addition, we found that these T cells were fully functional as cytotoxic T lymphocytes in anti-CD3 mediated cytotoxicity assays and exhibited increased suppressor activity for B cell immunoglobulin production. Taken together, this phenotypic and functional profile suggests that the expanded CD8 T cell subpopulation in this group of CVI patients contain highly differentiated (effector) T cells which are "anergic" from a proliferation and IL-2 production standpoint, but which nevertheless are immunoreactive from the point of view of gamma-interferon/IL-5 production and cytotoxic/suppressor activity. These findings raise the possibility that the CD8T cells in this group of CVI patients are "foot prints" of a chronic viral infection which is the basic cause of the disease. In a separate line of investigation, we have been able, for the first time, to propagate nontransformed B cell lines from CVI patients, and show that these cells retain an abnormal phenotype in that they produce reduced amounts of immunoglobulin in vitro when compared to lines established from normal donors. The addition of a variety of lymphokines failed to normalize immunoglobulin production by CVI B cell lines. Electron microscopy and reverse transcriptase assays performed on the patient B cell lines failed to provide evidence of viral infection. Preliminary molecular studies performed on these cell lines suggest that the B cell defect in CVI may relate in part to a failure in immunoglobulin isotype switch. The ability to obtain large numbers of nontransformed CVI B cells should greatly facilitate studies into the biochemical and molecular mechanisms of the CVI B cell defect.
NIH ExPorter
NIH ExPorter