Age brings complex and often debilitating changes in the immune response, rendering the elderly increasingly susceptible to common infectious diseases. Aged individuals often produce lower titers of serum antibody after immunization but also generate antibodies with lower affinity for the antigen ligand. Thus, even when quantitatively robust, the quality of antibody produced may be insufficient for protection. The goal of this program is to understand the fundamental cellular and molecular events that lead to age-associated dysfunction in humoral immunity. In Project (Kelsoe), studies will continue on delineating the failure of germinal centers (GCs) in aged mice to support V(D) J hypermutation and the consequent absence of affinity maturation. This project will make use of soluble CD40-ligand to reactivate mutation in the GCs of aged mice, study the expression of DNA repair enzymes in GCs, and study B cell activation requirements in transgenic mice. DNA repair may be a crucial factor in cellular aging. Identification of processes involved in hypermutation would help solve a fundamental question of immunology and could provide insight into measures that recover high affinity antibody responses in the elderly. Elucidation of the molecular basis for disregulated MHC expression may lead to the identification of molecular control points. Project (Cemy) will study the role of T helper cells in the antibody repertoire shifts seen in aged animals and the cellular defects that may lead to the absence of hypermutation in GCs. Recent molecular studies have demonstrated that the CD21(CD19/TAPA-1 complex acts to lower the threshold of B cell activation dramatically. Project Carroll will use mice deficient for the ligand of CD21, C3d/C4d, to study the importance of complement in B cell activation and differentiation. These studies will also focus on the role of complement in the GC reaction and effective humoral immunity to shed light on new strategies for enhancing the quantity and quality of serum antibody responses.
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