Genes predisposing to autoimmunity augment constitutive major histocompatibility complex class II-associated presentation of the self-antigen IgG2ab in vivo

The self-antigen IgG2a(b) is poorly presented to a gamma 2a(b) 435-451-reactive I-A(d)-restricted T-cell hybridoma unless available in high concentrations or targeted to Fc gamma- or complement receptors. Environmental factors, probably the extent of microbial challenge, profoundly influence the constitutive gamma 2a(b)/I-A(d) presentation in IgC(H)(b), H-2(d) mice. Here we report also a strong genetic impact. Constitutive presentation was highly efficient in spleen and thymus of (NZB x BXSB)F-1 mice, which inherit a predisposition to develop lupus. Presentation correlated with disease progression and the serum levels of IgG2a(b) and IgG2a(b) 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 gamma 2a(b)/I-A(d) 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 gamma 2a(b) determinant was undetectable on B cells lacking surface IgG2a(b), such B cells contributed considerably to constitutive presentation in (NZB x BXSB)F-1 hybrids. Presumably this resulted from complement receptor-mediated internalization of IgG2a(b)-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.