Understanding the connection between exposure to mercury, auto-immunity and tolerance in B cells

Wayne State University, Detroit MI

Investigators

Abstract

ABSTRACT Mercury (Hg) is a xenobiotic that is widespread in the environment. Hg is also a potent immunomodulator that has been implicated as a factor contributing to autoimmune disease in animal models and humans. A recent epidemiological study has now convincingly shown that in otherwise healthy individuals who were only exposed to low levels of mercury through typical environmental exposures, that there is a correlation between mercury blood levels and the appearance in the blood of antibodies to double stranded DNA. This indicates that under the proper circumstances exposure to environmental mercury promotes autoimmunity, a precursor to autoimmune disease. Since the discovery of B cells it has been appreciated by immunologists that in light of the Clonal Selection Theory, during the normal course of B cell development, large numbers of immature B cells must be generated that produce immunoglobulin reactive to many self- antigens (auto-antibodies). However, in the course of normal development, the vast majority of immature auto-reactive B cells are prevented from maturing by processes collectively known as tolerance. Autoimmune disease arises when these mechanisms of tolerance are disrupted. In B cells, it is firmly established that tolerance depends upon signals generated by the B Cell Receptor (BCR). Our preliminary experiments have shown that Hg interferes with signal generation by the BCR through mechanisms that may involve the tyrosine kinase Lyn, and the tyrosine phosphatases SHP-1 and CD45. It is our hypothesis that exposure to low, environmentally relevant levels of Hg, disrupts the development of tolerance in immature B cells by interfering with BCR signaling, leading to the appearance of mature auto-reactive B cells which have the potential to cause auto-immune disease. We propose to test this hypothesis through the utilization of anti-hen egg lysozyme (HEL)/hen egg lysozyme double transgenic mice. We also propose to expand upon our preliminary experiments in order to elucidate molecular mechanisms behind the ability of Hg to interfere with BCR signaling. We will utilize mouse strains with different, but well defined genetic susceptibilities to Hg intoxication, and employ complementary proteomic and multicolor phosphoflow cytometric approaches to directly investigate the ability of Hg to interfere with the function of Lyn, SHP-1 and CD45 during BCR signaling.