This is a research project grant to study B lymphocyte tolerance. The investigator and others have shown that in the absence of T-cell help, B-cells can be efficiently tolerized. Although these studies have helped demonstrated that B-cell tolerance can and does occur by a number of mechanisms, this accumulating knowledge about B-cell tolerance has brought into focus a new set of questions. In contrast to the generalities concluded from recent tolerance studies, there also exists a body of evidence arguing that autoreactive B- cells cannot only persist in the periphery, particularly in the B-1 subset., but that self-reactivity can actually enhance their abundance. A further contradiction to the concept that multivalent antigens elicit B- cell deletion in the absence of T-cell help is the phenomenon of T- independent antibody responses, in which highly multivalent antigens that lack T-cell epitopes efficiently stimulate antibody responses. Finally, the investigator's information in B-cell tolerance does not really permit them to predict how the rules of B-cell tolerance change during challenge with cross reactive antigens. In other words, they do not know if B-cell autoreactivity during an immune response such as infection is the norm, nor is it known to what extent this autoreactivity is resolved after infection and if any of these mechanisms are defective in autoimmune-prone mice. It is important to understand the rules that distinguish positive from negative selection. In this application, the investigator's propose to characterize B-cell tolerance during and upon resolution of an immune response to foreign antigen. To accomplish this aim, they take advantage of a system in which the degeneracy of the antibody combining site presents a problem of antigenic mimicry to the immune system. How the immune system maintains the distinction between self and non-self will be addressed in this application. The long term goal of these studies is to understand how B-cell autoreactivity is avoided and to determine what goes wrong in autoimmunity.
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