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Regulation of B cell receptor signaling : B cell activation through complement and the role of protein tyrosine phosphatase Shp2

  • Author(s): Kolla, Ravi V.
  • et al.
Abstract

My thesis is focused upon mechanisms regulating B cell receptor (BCR) activation and regulation. There are two branches of the immune system, the innate and adaptive. Proper cross-talk between the innate and adaptive immune system is crucial in initiating proper and effective immune responses and preventing inappropriate immune reactions such as autoimmunity and lymphoma. Arguably the most crucial link between B cell function and the innate immune system is through the complement receptor CD21 (Cr2). CD21 is the receptor for the complement breakdown product C3d. Cross-linking of antigen with C3d has been shown to augment antigen specific antibody titers far above normal immune responses. In chapter 1, I have shown that conjugation of protective antigen (PA) of anthrax with C3d produces 3-fold greater antibody titers as compared to PA in alum - the vaccine currently being developed for human administration. These antigen-specific antibodies are produced very rapidly during the primary response, are of all IgG isotypes, and are sustained long after primary immunization. Finally, I see that C3d may augment this response by enhancing the efficiency of germinal center formation and plasma cell differentiation. In chapter 2, I focus upon the mechanism of CD21 function on B cells and follicular dendritic cells (FDCs). By immunizing WT and CD21-/- mice, I found that CD21 is important in initiating proper B cell function during the primary immune response but had little role in eliciting secondary or memory immune responses. I further examine CD21 function by examining the mechanisms by which CD21 functions on the surface of B cells. By using deconvolution microscopy and immunoprecipitation, I lend support to the sequestration model of CD21 function. This model implicates CD21 is an inhibitory receptor on B cells which actively sequesters CD19, the cardinal member of the BCR co-receptor complex. Finally, in chapter 3, I look downstream of surface receptor regulation of BCR function and look at the role of the protein tyrosine phosphatase, Shp2, in B cell development, signaling and function. By using Cre/lox-p technology, I create a B cell specific deletion of Shp2 and show that Shp2 may be an important regulator of marginal zone versus follicular B cell development and is a crucial regulator in the GC reaction

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