Heavy Metal-Induced Autoimmunity

Scripps Research Institute, La Jolla CA

Investigators

Linked publications & trials

Abstract

DESCRIPTION (Applicant's Abstract): Although evidence indicates that environmental factors play a major role in precipitating systemic in genetically susceptible individuals, little is known about the mechanisms involved. Certain heavy metals, such as mercury, are potent environmental immunostimulants that produce a number of immunopathologic sequelae including lymphoproliferation, hypergammaglobulinemia and overt systemic autoimmunity. Predisposition to such metal-induced immunopathology has been shown, in mice and other experimental animals, to be influenced by both MHC and non-MHC genes, as well susceptibility to spontaneous lupus. Among the various mouse strains examined thus far, the DBA/2 appears to be the only background that is not susceptible to mercury-induced autoimmunity (HgIA) despite expressing a susceptible H-2 haplotype (H-2d). To define the genetic basis for this trait, two genome-wide scans were conducted in F2 intercrosses of the DBA/2 strain with either the SJL or NZB strains, both of which are susceptible to HgIA. A single major quantitative trait locus (QTL) on chromosome 1, designated Hmr1, was the only region identified in common in both crosses. The aims of this proposal are to define the role of Hmr1 in heavy metal-induced and spontaneous autoimmunity using reciprocal interval-specific congenic strains and to dissect the Hmr1 interval by more precisely mapping linked traits. Mapping studies will determine whether Hmr1 represents one or more genetic alterations, examine the relationship of Hmr1 to a previously defined NZB QTL on chromosome I (Lbw7) and reduce the interval containing Hmr1 to less than one centimorgan (cM). Identification and characterization of susceptibility/resistance genes and mechanisms relevant to the immunopathogenesis of mercury induced autoimmunity should provide important insights on the pathogenesis of autoimmunity and may reveal novel targets for intervention.