TY - JOUR
T1 - β2-microglobulin is required for the full expression of xenobiotic-induced systemic autoimmunity
AU - Pollard, Kenneth M.
AU - Hultman, Per
AU - Toomey, Christopher B.
AU - Cauvi, David M.
AU - Konoc, Dwight H.
N1 - Funding Information:
ThispublicationwasmadepossiblebyNationalInstitutes of Health grant numbers ES007511 and ES014847 to KMP, ES08666, AR053731, and AR42242 to DHK, and Swedish Research Council, Branch of Medicine grant number 09453 to PH, and the Stein Endowment of the Department of Molecular and Experimental Medicine. M-L Eskilsson provided expert help in the preparation of the tissue immunopathology. This is publication 17325-MEM from The Scripps Research Institute (La Jolla, CA).
PY - 2011/7
Y1 - 2011/7
N2 - Mercury exposure in both humans and mice is associated with features of systemic autoimmunity. Murine HgCl2-induced autoimmunity (mHgIA) requires MHC Class II, CD4 + T-cells, co-stimulatory molecules, and interferon-γ (IFN-γ), similar to spontaneous models of systemic lupus erythematosus (SLE). β2-microglobulin (B2m) is required for functional MHC Class I molecules and the neonatal Fc receptor (FcRn). Deficiency of B2m in lupus-prone strains is consistently associated with reduced IgG levels, but with variable effects on other manifestations. Herein, we examined the role of B2m in mHgIA and show that in the absence of B2m, mercury-exposed mice failed to exhibit hypergammaglobulinemia, had reduced anti-nucleolar autoantibodies (ANoA), and had a lower incidence of immune complex deposits in splenic blood vessels, whereas IgG anti-chromatin autoantibodies and renal immune deposits were largely unaffected. Subclass analysis of the IgG anti-chromatin, however, revealed a significant reduction in the IgG1 subtype. Examination of IFNγ, IL-4, and IL-2 in exposed skin, draining lymph nodes, and spleen following mercury exposure showed reduced IL-4 in the spleen and skin in B2m-deficient mice, consistent with the lower IgG1 anti-chromatin levels, and reduced IFNγ expression in the skin. These findings demonstrate how a single genetic alteration can partially but significantly modify the clinical manifestations of systemic autoimmunity induced by exposure to xenobiotics.
AB - Mercury exposure in both humans and mice is associated with features of systemic autoimmunity. Murine HgCl2-induced autoimmunity (mHgIA) requires MHC Class II, CD4 + T-cells, co-stimulatory molecules, and interferon-γ (IFN-γ), similar to spontaneous models of systemic lupus erythematosus (SLE). β2-microglobulin (B2m) is required for functional MHC Class I molecules and the neonatal Fc receptor (FcRn). Deficiency of B2m in lupus-prone strains is consistently associated with reduced IgG levels, but with variable effects on other manifestations. Herein, we examined the role of B2m in mHgIA and show that in the absence of B2m, mercury-exposed mice failed to exhibit hypergammaglobulinemia, had reduced anti-nucleolar autoantibodies (ANoA), and had a lower incidence of immune complex deposits in splenic blood vessels, whereas IgG anti-chromatin autoantibodies and renal immune deposits were largely unaffected. Subclass analysis of the IgG anti-chromatin, however, revealed a significant reduction in the IgG1 subtype. Examination of IFNγ, IL-4, and IL-2 in exposed skin, draining lymph nodes, and spleen following mercury exposure showed reduced IL-4 in the spleen and skin in B2m-deficient mice, consistent with the lower IgG1 anti-chromatin levels, and reduced IFNγ expression in the skin. These findings demonstrate how a single genetic alteration can partially but significantly modify the clinical manifestations of systemic autoimmunity induced by exposure to xenobiotics.
KW - Autoantibodies
KW - autoimmunity
KW - cytokines
KW - immune deposits
KW - mercury
KW - mouse
KW - xenobiotic
KW - β2-microglobulin
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U2 - 10.3109/1547691X.2011.583614
DO - 10.3109/1547691X.2011.583614
M3 - Article
C2 - 21793797
AN - SCOPUS:79960988419
SN - 1547-691X
VL - 8
SP - 228
EP - 237
JO - Journal of Immunotoxicology
JF - Journal of Immunotoxicology
IS - 3
ER -