MECHANISMS THAT REGULATE B CELL TOLERANCE

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DESCRIPTION: The mechanisms, which are thought to be important for the maintenance of B cell tolerance, include deletion of self-reactive cells both in the bone marrow and the periphery, immunoglobulin receptor editing, and the induction of clonal anergy. This laboratory has recently shown that anergic B cells express significant surface levels of CD5, a molecule normally found on T cells and a subset of B-1 cells. Breeding of the en egg lysozyme (HEL) transgenic model for B cell anergy onto the CD5 null background resulted in a spontaneous loss of B cell tolerance in vivo. Evidence for this included elevated levels of anti-HEL IgM antibodies in the serum of CD5-/- mice transgenic for both a HEL-specific B cell receptor (BCR) and soluble lysozyme. "Anergic" B cells lacking CD5 also showed enhanced proliferative responses in vitro and elevate intracellular Ca++ levels at rest and following IgM crosslinking. These data sup ort the hypothesis that CD5 negatively regulates immunoglobulin receptor signaling in anergic B cells and functions to inhibit autoimmune B cell responses. Additional preliminary experiments suggest a role for CD5 in regulating B cell receptor signaling in antigen naive B cells. Also, we have begun to characterize CD5-/- HEL-Ig/sHEL mice that develop a profound loss of tolerance. In these mice we hypothesize that autoantibody secretion effectively titrates self-antigen leading to a reversal of the anergic B cell phenotype. The experiments described here will focus n these in vivo models, and are designed to further characterize the nature of he in vivo tolerance defects observed in HEL-Ig/sHEL double transgenic mice lacking CD5, and to fully evaluate CD5-/-Ig/sHEL mice that exhibit the very highest levels of serum antibody. Next the CD5 knockout alleles will be bred onto lupus-prone sle2 congenic and sle1/sle3 bi-congenic mice to determine whether CD5 deficiency will enhance autoimmunity in these models for systemic lupus erythematosus (SLE). Finally, the influence of CD5 on receptor editing and induction into the B-1 compartment will be explored. Together, the experiments proposed should significantly advance understanding of the role that CD5 plays in regulating immune responses. In addition, these experiments are likely to provide interesting new insights into the mechanisms that lead to autoimmunity, with potential therapeutic implications for patients with antibody-mediated autoimmune diseases such as SLE.