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Resistance to Xenobiotic-Induced Autoimmunity Maps to Chromosome 1¹

Dwight H. Kono^2,*, Miyo S. Park^*, Agnieszka Szydlik^*, Katarina M. Haraldsson^*, Jason D. Kuan^*, Deborah L. Pearson, Per Hultman and K. Michael Pollard

Departments of ^* Immunology and Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA 92037; and Division of Molecular and Immunological Pathology, Department of Health and Environment, Linköping University, Linköping, Sweden

Although evidence indicates that environmental factors play a major role in precipitating systemic autoimmunity 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 to be influenced by both MHC and non-MHC genes, as well as susceptibility to spontaneous lupus, in mice and other experimental animals. Among the various mouse strains examined to date, the DBA/2 appears to uniquely lack susceptibility to mercury-induced autoimmunity (HgIA), despite expressing a susceptible H-2 haplotype (H-2^d). To define the genetic basis for this trait, two genome-wide scans were conducted using F₂ intercrosses of the DBA/2 strain with either the SJL or NZB strains, both of which are highly susceptible to HgIA. A single major quantitative trait locus on chromosome 1, designated Hmr1, was shown to be common to both crosses and encompassed a region containing several lupus susceptibility loci. Hmr1 was linked to glomerular immune complex deposits and not autoantibody production, suggesting that DBA/2 resistance to HgIA may primarily involve the later stages of disease pathogenesis. Identification and characterization of susceptibility/resistance genes and mechanisms relevant to the immunopathogenesis of mercury-induced autoimmunity should provide important insights into the pathogenesis of autoimmunity and may reveal novel targets for intervention.

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