Genes predisposing to autoimmunity augment constitutive major histocompatibility complex class II-associated presentation of the self-antigen IgG2a in vivo.
The self-antigen IgG2ab is poorly presented to a gamma2ab 435-451-reactive I-Ad-restricted T-cell hybridoma unless available in high concentrations or targeted to Fcgamma- or complement receptors. Environmental factors, probably the extent of microbial challenge, profoundly influence the constitutive gamma2ab/I-Ad presentation in IgCHb, H-2d mice. Here we report also a strong genetic impact. Constitutive presentation was highly efficient in spleen and thymus of (NZB x BXSB)F1 mice, which inherit a predisposition to develop lupus. Presentation correlated with disease progression and the serum levels of IgG2ab and IgG2ab complement factor 3 complexes. The finding that constitutive presentation was by far most efficient in males indicated that it was augmented by the Y chromosome-linked autoimmune acceleration Yaa gene. In line with previous data for healthy mice, constitutive gamma2ab/I-Ad presentation was most pronounced in the adherent spleen cell fraction and improved by further enrichment for dendritic cells. Notably, however, whereas in normal mice the gamma2ab determinant was undetectable on B cells lacking surface IgG2ab, such B cells contributed considerably to constitutive presentation in (NZB x BXSB)F1 hybrids. Presumably this resulted from complement receptor-mediated internalization of IgG2ab-containing immune complexes formed in lupus. These data add to the evidence that B cells with self-reactive receptors, known to exist in the mature repertoire, may present non-cognate foreign antigen to anti-foreign helper T lymphocytes and thus differentiate into autoantibody-secreting cells, and might likewise account for the polyclonal B-cell activation characteristic of several autoimmune syndromes.
Department of Immunology, Institute of Medical Biology, University of Tromso, School of Medicine, Tromso, Norway.
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Bartnes
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Li
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Iwamoto
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Izui
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Hannestad
D000818:Animals; D017951:Antigen Presentation / Q000235:genetics; D001324:Autoantigens / Q000276:immunology*; D001327:Autoimmune Diseases / Q000276:immunology; D015551:Autoimmunity / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D000949:Histocompatibility Antigens Class II / Q000276:immunology*; D007074:Immunoglobulin G / Q000276:immunology*; D008180:Lupus Erythematosus, Systemic / Q000235:genetics* / Q000276:immunology; D008297:Male; D051379:Mice; D008814:Mice, Inbred NZB; D008815:Mice, Inbred Strains; D013154:Spleen / Q000276:immunology
D001324:Autoantigens; D000949:Histocompatibility Antigens Class II; C111389:I-Ad antigen; D007074:Immunoglobulin G