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.
| Pollard, Kenneth M; Hultman, Per; Toomey, Christopher B et al. (2011) ?2-microglobulin is required for the full expression of xenobiotic-induced systemic autoimmunity. J Immunotoxicol 8:228-37 |
| Pollard, K Michael; Hultman, Per; Kono, Dwight H (2010) Toxicology of autoimmune diseases. Chem Res Toxicol 23:455-66 |
| Hultman, P; Taylor, A; Yang, J M et al. (2006) The effect of xenobiotic exposure on spontaneous autoimmunity in (SWR x SJL)F1 hybrid mice. J Toxicol Environ Health A 69:505-23 |
| Kono, Dwight H; Theofilopoulos, Argyrios N (2006) Genetics of SLE in mice. Springer Semin Immunopathol 28:83-96 |
| Pollard, K Michael; Hultman, Per; Kono, Dwight H (2005) Immunology and genetics of induced systemic autoimmunity. Autoimmun Rev 4:282-8 |
| Pollard, K Michael; Arnush, Marc; Hultman, Per et al. (2004) Costimulation requirements of induced murine systemic autoimmune disease. J Immunol 173:5880-7 |
| Kono, Dwight H; Park, Miyo S; Theofilopoulos, Argyrios N (2003) Genetic complementation in female (BXSB x NZW)F2 mice. J Immunol 171:6442-7 |
| Pollard, K Michael; Hultman, Per; Kono, Dwight H (2003) Using single-gene deletions to identify checkpoints in the progression of systemic autoimmunity. Ann N Y Acad Sci 987:236-9 |
| Theofilopoulos, A N; Kono, D H (2002) A genetic analysis of lupus. Allergy 57 Suppl 72:67-74 |
| Pollard, K M; Pearson, D L; Hultman, P et al. (2001) Xenobiotic acceleration of idiopathic systemic autoimmunity in lupus-prone bxsb mice. Environ Health Perspect 109:27-33 |
Showing the most recent 10 out of 14 publications
