Aging is associated with an increased prevalence of serum autoantibodies and autoimmune diseases with concomitant reduction in immunologic competence. The long-term goal is to identify the immunologic dysfunctions which contribute to the development of antibodies and autoimmunity in the elderly human. Age-associated prevalence of autoantibodies may be explained by the increased in the frequency of autospecific precursor B cells. Such precursors have been detected in the human peripheral blood and bone marrow in higher numbers with advancing age. The level of autoantibodies in marrow cultures has been found to exceed that of peripheral blood cultures for the same individuals, thus suggesting that the bone marrow may be giving rise to precursor autoreactive B cells. Little data are available regarding the nature of autoantibody producing cells in the marrow and peripheral blood. Little is known about what regulatory mechanisms may control the expression and expansion of these cells. This grant proposes to investigate the change with age the frequency of autoantibody producing cells in man. The nature of these cells in the marrow as compared to the peripheral blood will be examined by cell separation, phenotypic analysis with monoclonal antibodies, idiotypic analysis, and functional characterization. The role of anti-idiotypic antibodies in the regulation of autoantibodies will be investigated by detection of auto-antiidiotypic antibodies in in vitro culture supernatants and by examining their capacity to regulate in vitro synthesis of autoantibodies. Through these experiments useful and novel information will be derived which may aid in delineating the controlling factors in age-associated autoimmunity. Knowledge of the immunologic controlling factors will permit design of specific therapeutic regiments for the prevention or modulation of age-associated autoimmune diseases.
