Resistance to xenobiotic-induced autoimmunity maps to chromosome 1.
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-2d). 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.
Kono
D H
DH
Department of Immunology, The Scripps Research Institute, La Jolla, CA 92037, USA. dkono@scripps.edu
Park
M S
MS
Szydlik
A
A
Haraldsson
K M
KM
Kuan
J D
JD
Pearson
D L
DL
Hultman
P
P
Pollard
K M
KM
D000818:Animals; D001327:Autoimmune Diseases / Q000139:chemically induced / Q000235:genetics* / Q000276:immunology; D002874:Chromosome Mapping / Q000379:methods; D003433:Crosses, Genetic; D005260:Female; D008040:Genetic Linkage / Q000276:immunology; D005819:Genetic Markers / Q000276:immunology; D020022:Genetic Predisposition to Disease / Q000235:genetics; D007113:Immunity, Innate / Q000235:genetics*; D008627:Mercuric Chloride / Q000276:immunology*; D051379:Mice; D008811:Mice, Inbred DBA; D008814:Mice, Inbred NZB; D008815:Mice, Inbred Strains; D019655:Quantitative Trait, Heritable; D013045:Species Specificity; D015262:Xenobiotics / Q000276:immunology*
D005819:Genetic Markers; D015262:Xenobiotics; D008627:Mercuric Chloride