Autoimmune diseases affect 20 million Americans and comprise the third most prevalent form of disease in the U.S. Mouse models of autoimmunity have proven to be critically important for studying the immune cells involved in disease. Although it is known that B cells are an integral component of many autoimmune diseases, less is known about the subsets of B cells that may be involved. The marginal zone (MZ) B cell subset has been found to be activated and increased in number in mouse models of lupus. MZ B cells express high levels of the non-classical MHC molecule CD1d which activates NK T cells, a T cell subset that has a protective role against autoimmune disease in both humans and mice. Absence of CD1d expression prevents the development of NK T cells, and autoimmunity is exacerbated in CD1d-/- mice. Evidence suggests that MZ B cell interactions with NK T cells may be crucial for NK T cell-mediated tolerance to selfantigens. Currently however, there are no mouse models in which the importance of MZ B cell interactions with NK T cells can be analyzed. This proposal seeks to generate a new conditional knockout mouse strain in which B cells lack CD1d expression to facilitate analysis of the B cell/NK T cell interactions in the induction of autoimmunity. With guidance from Core B, B cell-GDI d conditional mutant mice will be generated using the Cre-lox system with Cre under the control of the CD19 promoter in B cells. The B cell-GDI d conditional knockout mice will have regulatory NK T cells which are absent in traditional CD1d-/- mice, but the NK T cells will not be able to interact with B cells through CD1d.
Aim 2 of the proposal will begin to phenotypically characterize the B cell-GDI d conditional knockout mouse using flow cytometry to quantitate NK T cells. To assess effects on infection-induced autoantibody production, mice will be experimentally infected with Borrelia hermsii, which we have previously shown enhances production of anti-dsDNA antibodies in CD1d-/- mice. The generation of the B cell-GDI d conditional knockout mouse strain will provide a new research tool allowing us to answer questions about the involvement of CD1d, B cells, and NK T cells in autoimmunity that cannot be answered with any of the currently available transgenic mouse strains. We have many drugs that treat the symptoms of autoimmunity but few that prevent the development of disease or permanently halt its progression. Novel immunomodulatory treatments, such as alpha-galactosyl-ceramide, that target NK T cells may provide new hope to the millions of Americans that suffer with autoimmune disease, but we must learn more about the mechanisms involved in NK T cell activation so that more selective immunomodulation can be attained.
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