Genes predisposing to autoimmunity augment constitutive major histocompatibility complex class II‐associated presentation of the self‐antigen IgG2abin vivo

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Abstract
Summary: The self‐antigen IgG2ab is poorly presented to a γ2ab 435–451‐reactive I‐Ad‐restricted T‐cell hybridoma unless available in high concentrations or targeted to Fcγ‐ or complement receptors. Environmental factors, probably the extent of microbial challenge, profoundly influence the constitutive γ2ab/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 × 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 γ2ab/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 γ2ab determinant was undetectable on B cells lacking surface IgG2ab, such B cells contributed considerably to constitutive presentation in (NZB × 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.

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