B lymphocytes are activated by signals through their antigen-specific surface immunoglobulin (slg) receptors, through cytokine receptors, and by interactions with other cells mediated by defined adhesion receptors. The long-term goal of this research proposal is to elucidate how signals via cell-cell interactions are coordinated and regulated during the activation and maturation of human B cells.
Aim 1 will focus on defining the mechanisms leading to T cell-dependent activation of human B cells. After T cells are specifically activated by antigen-presenting cell (APC) B lymphocytes, they rapidly deliver to B cells a signal inducing the B cells to release intracellular free calcium [Ca2+]i. This early signal from the T cell requires an active CD11a/18 complex on the T cell and CD54 on the B cell. We plan to elucidate the mechanism and receptors required for the early T cell signal to the B cell and the consequences of this signal. Subsequent molecular interactions and crosstalk between B cells and T cells leading to T cell-dependent B cell activation will be investigated. We will also determine what signals are required for converting resting human B cells into effective APC (Aim 2). Once B cells are activated by T cells, germinal centers are formed where B cells undergo selection and class switching.
Aim 3 will investigate the molecular interactions and signals between activated B cells and follicular dendritic cells (FDC). We have found that human tonsillar cells with the characteristics of FDC can be cultured in vitro and can induce B cells to proliferate. We plan to define the adhesions and cytokines involved in optimal FDC-induced B cell stimulation. Cultured FDC are responsive to lipopolysaccharides; therefore, we will elucidate which products of periodontopathic bacteria including Porphyromonas gingivalis and Actinobacillus actinomycetemcomitans, affect B cell and/or FDC interactions leading to the production of IgG antibody-producing cells (Aim 4). Elucidation of how B cell activation and maturation is regulated by other cells including T cells and FDC, may provide new insights into the pathogenesis of diseases associated with activated or dysfunctional B cells, including periodontal disease and certain autoimmune diseases.
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