Regulation of anti -dsDNA B lymphocytes in autoimmunity: Molecular mimicry and hormone modulation of tolerance
Michael, Daniel J.
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Anti-double stranded (ds) DNA antibodies are responsible for much of the pathology of systemic lupus erythematosus. Two mouse models in which anti-dsDNA B cells escape tolerance were used to study their regulation.;A peptide mimic of dsDNA can induce an anti-dsDNA immune response in non-autoimmune BALB/c mice. To track the responding B cells, an avidity enhanced tetrameric probe was developed. The peptide-reactive B cells were found to develop into a recently discovered B220- memory population and show evidence of receptor revision.;Immune responses differ depending on the type of lymphoid tissue in which they occur. We compared the anti-dsDNA peptide-induced response in lymph nodes and spleen. While the peptide-reactive B cells were found primarily in the red pulp or in the T cell zone of the spleen, in the lymph nodes the peptide-reactive cells were found in the B cell follicles, including germinal centers, as well as in the T cell zone.;Anti-dsDNA antibodies can also be induced by increased levels of female sex hormones. Previously, our laboratory has shown that estrogen breaks tolerance in mice transgenic for the heavy chain of an anti-dsDNA antibody. We studied the changes in regulation and loss of tolerance of anti-dsDNA B cells caused by estrogen and by prolactin, the pituitary hormone induced by estrogen.;Estrogen was found to activate transgene expressing B cells and severely alter the proportions of B cells in different splenic B cell subsets. Estrogen appeared to block negative selection in the peripheral immature B cell population. The majority of anti-dsDNA B cells activated by estrogen were marginal zone B cells. The estrogen-induced expansion of transgene expressing B cells, not their activation, occurred in T cell depleted mice and was, therefore, not T cell dependent.;Prolactin treatment was also found to break tolerance in R4A transgenic mice. As had been found in estrogen treated mice, prolactin treatment rescued transgene expressing B cells. Mice displayed anti-dsDNA antibody titers and IgG deposition in the glomeruli. Prolactin also altered the development of B cells resulting in a reduced immature population. In contrast to estrogen, prolactin led to an expansion of transgene expressing B cells only in the presence of T cells. Tolerance was lost by exposure to estrogen and prolactin in BALB/c, but not C57Bl/6 mice indicating a role for genetic background in the hormonal regulation of immune tolerance.