Decay-accelerating factor 1 (Daf1) deficiency exacerbates xenobiotic-induced autoimmunity.
Absence of decay-accelerating factor 1 (Daf1) has been shown to enhance T-cell responses and autoimmunity via increased expression of specific cytokines, most notably interferon (IFN)-gamma. To determine if Daf1 deficiency can exacerbate IFN-gamma-dependent murine mercury-induced autoimmunity (mHgIA), C57/BL6 Daf1(+/+) and Daf1(-/-) mice were exposed to mercuric chloride (HgCl(2)) and examined for differences in cytokine expression, T-cell activation and features of humoral autoimmunity. In the absence of Daf1, mHgIA was exacerbated, with increased serum immunoglobulin G (IgG), anti-nuclear autoantibodies (ANAs) and anti-chromatin autoantibodies. This aggravated response could not be explained by increased T-cell activation but was associated with increased levels of IFN-gamma, interleukin (IL)-2, IL-4 and IL-10 but not IL-17 in Daf1-deficient mice. Anti-CD3/anti-CD28 costimulation of Daf1(-/-) CD4(+) T cells in vitro was also found to increase cytokine expression, but the profile was different from that of mHgIA, suggesting that the cytokine changes observed in Daf1 deficiency reflect a response to mercury. The role of Daf1 in influencing cytokine expression was further examined by stimulation of CD4(+) T cells in the presence of anti-CD3 and CD97, a molecular partner for Daf1. This resulted in increased IL-10, decreased IL-17 and IL-21 and decreased IFN-gamma. These findings demonstrate that the absence of Daf1 exacerbates mHgIA, with changes in the profile of expressed cytokines. Interaction between Daf1 and its molecular partner CD97 was found to modify expression of mHgIA-promoting cytokines, suggesting a possible approach for the suppression of overaggressive cytokine production in autoimmunity.
Toomey
Christopher B
CB
Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA 92037, USA.
Cauvi
David M
DM
Song
Wen-Chao
WC
Pollard
Kenneth M
KM
D000818:Animals; D001323:Autoantibodies / Q000097:blood*; D001327:Autoimmune Diseases / Q000139:chemically induced* / Q000235:genetics / Q000276:immunology; D015551:Autoimmunity / Q000187:drug effects / Q000276:immunology; D018958:CD55 Antigens / Q000235:genetics / Q000378:metabolism*; D016207:Cytokines / Q000378:metabolism*; D008213:Lymphocyte Activation / Q000276:immunology; D008627:Mercuric Chloride / Q000008:administration & dosage / Q000633:toxicity; D051379:Mice; D008810:Mice, Inbred C57BL; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology*
D001323:Autoantibodies; D018958:CD55 Antigens; D016207:Cytokines; C521184:decay-accelerating factor 1, mouse; D008627:Mercuric Chloride
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