Characterization of estrogen-induced autoantibodies to cardiolipin in non-autoimmune mice.
Antibodies to cardiolipin, in humans, have been associated with a variety of autoimmune disorders including anti-phospholipid syndrome, systemic lupus erythematosus and Sjögren's syndrome. These antibodies have also been demonstrated in autoimmune-prone MRL-Mp-lpr/lpr (MRL/lpr), BXSB-Mp-(+yaa) (BXSB) and (NZW x BXSB)F1 mice. In previous work, we had shown that gonadectomized or intact male and female non-autoimmune C57BL/6 mice, upon treatment with estrogen, express autoantibodies to cardiolipin. In this study, we extend these findings and show that the expression of these antibodies persists for months even after the exposure to exogenous estrogen has been terminated. These antibodies are of IgM and IgG, but not IgA, isotypes, and the predominant IgG subisotype is IgG2b. Estrogen-induced antibodies to cardiolipin only minimally cross-reacted with DNA, actin or ovalbumin. The binding of antibodies to cardiolipin from autoimmune human patients in general has been shown to depend upon the presence of a cofactor, beta2-glycoprotein I. We found that in estrogen-treated C57BL/6 mice, as well as in SLE-prone MRL/lpr and BXSB mice, the binding of anti-cardiolipin antibodies to cardiolipin was not enhanced, but rather reduced, in the presence of human beta2-glycoprotein I. Further, addition of exogenous human beta2-glycoprotein I to purified immunoglobulin fractions containing anti-cardiolipin antibodies reduces, rather than enhances, the binding to cardiolipin. Together, these data show that persistent detectable levels of IgG and IgM autoantibodies specific for cardiolipin can be induced in normal mice by estrogen treatment alone (i.e. without administration of autoantigens). Further, we characterize these antibodies regarding their kinetics, cross-reactivity, isotype distribution and cofactor (beta2-glycoprotein I) requirements.
Verthelyi
D
D
Department of Biomedical Sciences and Pathobiology, Virginia-Maryland Regional College of Veterinary Medicine, Virginia Polytechnic Institute and State University, Blacksburg 24061, USA.
Ansar Ahmed
S
S
D000818:Animals; D017153:Antibodies, Anticardiolipin / Q000096:biosynthesis / Q000737:chemistry* / Q000378:metabolism; D001327:Autoimmune Diseases / Q000276:immunology*; D001666:Binding Sites, Antibody / Q000187:drug effects; D002308:Cardiolipins / Q000378:metabolism; D003429:Cross Reactions; D004958:Estradiol / Q000494:pharmacology*; D005260:Female; D006023:Glycoproteins / Q000494:pharmacology; D006801:Humans; D007132:Immunoglobulin Isotypes / Q000032:analysis; D007136:Immunoglobulins / Q000302:isolation & purification / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D019463:Mice, Inbred MRL lpr; D008817:Mice, Mutant Strains; D053482:beta 2-Glycoprotein I
D017153:Antibodies, Anticardiolipin; D002308:Cardiolipins; D006023:Glycoproteins; D007132:Immunoglobulin Isotypes; D007136:Immunoglobulins; D053482:beta 2-Glycoprotein I; D004958:Estradiol