Aging is associated with an increased prevalence of serum autoantibodies and autoimmune diseases with concomitant reduction in immunologic competence. The long-term goal of this research proposal is to identify the immunologic dysfunctions which contribute to the development of autoantibodies and autoimmunity in the elderly human. Recent experimental data from our laboratory have provided information regarding autoantibody production by human bone marrow cells and the age-related alteration in that population. The bone marrow is a major site for antibody and autoantibody production in humans. Very little is known about B lymphocyte differentiation and factors that regulte B lymphocyte function in human marrow. We plan to investigate whether changes in the age associated prevalence of autoantibody production may result from defects occurring in both the bone marrow and peripheral blood regulatory cells controlling the expression and expansion of autoreactive B cells. Specifically we plan to investigate what is the change with age in the prevalence of autoantibody production by human bone marrow cells relative to the peripheral blood by limiting dilution analysis of Epstein-Barr virus (polyclonal activation)-inducible autoantibody producing B cells. The nature of the autoantibody producing B cells will be examined by cell separation, phenotypic analysis, idiotypic analysis and functional characterization. Studies will be conducted examining the bone marow and peripheral blood regualtory cells involved in the control of auto-antibody production and possible deficiencies in the regulatory system in the aged. Our preliminary studies support an age-associated defect in a bone marrow suppressor factor which is associated with the regulation of immunoglobulin production as well as control of autoantibody synthesis. We hypothesize that a deficiency in the factor(s) may contribute to the appearance of age-associated autoantibody production as well as to generalized autoimmunity in the elderly.
