Mercury (Hg) is a potent immunomodulator that has been implicated as a factor contributing to autoimmune disease in animal models as well as in humans. In animal models, susceptibility to Hg is genetically restricted, but genetic restriction i humans has been difficult to establish because of the heterogeneous nature of human populations. Nevertheless, because Hg is widely distributed in the environment, Hg is an excellent example of where exposure to an environmental agent has been associated with the development of autoimmune disease, and where an extrinsic agent interacts with selective genetic backgrounds to cause immunologic disease. Unfortunately at this time a mechanistic understanding of how Hg disrupts immune function remains elusive. Furthermore, while studies clearly demonstrate an association between Hg exposures and increased risk of autoimmune disease, there are currently no molecular biomarkers that can be utilized as an exposure signature to identify Hg involvement across the broad spectrum of the over 80 individually characterized autoimmune diseases which affect humans. Recently there has been increased appreciation of the involvement of B cells in autoimmune disease. Defects in the B Cell Receptor (BCR) signaling pathway are known to disrupt central tolerance and consequently to be associated with autoimmune disease. Lyn is a Src family protein tyrosine kinase which has been shown to be intimately involved in the initiation and regulation of the BCR signaling pathway. Lyn functionality is controlled through the phosphorylation of several different tyrosine residues. In preliminary experiments the investigators have employed advanced proteomic and multicolor phosphoflow cytometric approaches to investigate the interaction of Hg with mouse B cells. Results from these experiments have led them to hypothesize that an altered Lyn phosphorylation profile and functionality consequent to Hg exposure may be key interrelated phenomena mediating immuntoxicity of B cells which have been exposed to Hg, and the emergence of an autoimmune B cell repertoire in mercury intoxicated individuals. This being the case, the expression of specific Lyn phosphorylation profiles in B cells may be a useful exposure signature of Hg-induced autoimmunity in Hg exposed individuals. The investigators now propose to expand upon preliminary experiments. They 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 exposures to alter Lyn phosphophorylation profiles and functionality, so as to interfere with BCR signal transduction, and ultimately disrupt central tolerance in splenic B cells.
Previous studies show that when some, but not all, mouse strains are exposed to low levels of mercury they develop an autoimmune disease. The investigators'previous work shows that mercury may interfere with signal transduction mediated by the B Cell Receptor (BCR). Interference with BCR signaling would be expected to lead to disruption of central tolerance, which would explain the connection of autoimmune disease with mercury exposure in mercury susceptible strains. The purpose of this research is to investigate whether mercury affects the BCR signaling pathway differently in strains which develop autoimmunity upon mercury exposure, from those which do not.
|Caruso, Joseph A; Carruthers, Nicholas; Shin, Namhee et al. (2017) Mercury alters endogenous phosphorylation profiles of SYK in murine B cells. BMC Immunol 18:37|
|Gill, R; McCabe Jr, M J; Rosenspire, A J (2017) Low level exposure to inorganic mercury interferes with B cell receptor signaling in transitional type 1 B cells. Toxicol Appl Pharmacol 330:22-29|
|Rosenspire, Allen J; Chen, Kang (2015) Anergic B Cells: Precarious On-Call Warriors at the Nexus of Autoimmunity and False-Flagged Pathogens. Front Immunol 6:580|