ANTIGEN NONSPECIFIC EFFECT OF MAJOR HISTOCOMPATIBILITY COMPLEX HAPLOTYPE ON AUTOANTIBODY LEVELS IN SYSTEMIC LUPUS-ERYTHEMATOSUS PRONE LPR MICE

MHC-linked genes strongly influence susceptibility to autoimmune disea ses and also regulate responses to exogenous antigens. To begin to und erstand the mechanism of this MHC effect on disease, we have investiga ted MHC-congenic mouse strains that develop spontaneous autoimmunity b ecause of the lpr gene. C57BL6/lpr (B6/lpr) mice (H-2b) are known to h ave substantial levels of autoantibodies to chromatin, single stranded DNA (ssDNA3), and IgG of different murine subclasses (rheumatoid fact or). We have crossed the H-2d and the H-2bm12 (la mutant) haplotypes o nto the B6/lpr background. Surprisingly, levels of all of the autoanti bodies were markedly lower in B6/lpr.H-2d, but levels in B6/lpr.H-2bm1 2 were no different from those in B6 / lpr mice. The downregulating in fluence of the H-2d allele was dominant, and there was no effect on au toantibody fine specificities. The genetics of the H-2d effect and its diffuse influence on multiple autoantibody specificities, in addition to the lack of effect of the bml2 mutation, which modifies the peptid e-binding groove of I-A, together raise the question of whether MHC-li nked genes other than classical (IR) genes may be responsible for MHC disease associations in this model.