Inbred strains of rats differ widely in their susceptibility to interstitial nephritis induced by rabbit renal tubular basement membrane (TBM) preparations. We now report that susceptibility is determined in part by an RT1-linked gene for effector cell responsiveness producing interstitial lesions. Furthermore, we also obtained evidence that the gene determining expression of the target TBM antigen is linked to the gene for albinism on the first linkage group. When non-susceptible rats lacking the TBM antigen but having the gene for cellular responsiveness were mated with non-susceptible rats which had the TBM antigen but lacked the gene for cellular responsiveness, the F1 hybrids were susceptible to the induction of interstitial nephritis. Although strains varied widely in the amount of anti-TBM antibody (alpha TBM-Ab) they produced, this variation does not appear to be controlled by RT1-linked genes, nor does the isotype or amount of antibody appear to be related to the susceptibility to infiltrating cellular lesions.

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Brown Norway rats immunized with renal tubular antigens in adjuvant develop a severe interstitial nephritis (1-3). The expression of disease is characterized by the appearance of anti-tubular basement membrane antibodies (aTBM-Ab) 1 followed by an intense mononuclear cell infiltrate. The cellular lesion is composed of several subsets of T lymphocytes, macrophages, and Ig + cells (4). Natural killer cells have also been observed in the murine form of disease (5). The relevant tubular antigen for disease is a glycoprotein expressed on cortical tubular basement membranes (Neilson and Kefalides, unpublished observations) by genes closely linked with albinism on the first linkage group (1). The most important immunologic response to this tubular antigen is cell mediated, and is largely determined by an RT 1-1inked gene. There are strain differences in the amount of aTBM-Ab produced, but the genes involved are not RT1 linked and the antibody titer seems to have little or no effect on disease susceptibility (1).If rats are pretreated with tubular antigen-reactive T lymphoblasts in adjuvant and then immunized to produce disease, they do not develop interstitial lesions (6). Protected animals show a decreased T cell proliferative response to tubular antigens, produce aTBM-Ab with a reduced binding affinity for tubular antigen, and develop antiidiotypic antibodies that bind to idiotypes within the antigenbinding variable region of monoclonal o~TBM-Ab. These results suggest that antiidiotypic immunity might have a modulating influence in this model both at

The gene for tubular basement membrane (Tbm) antigen in the rat has been mapped relative to other markers in the first linkage group, and a polymorphic locus for a submaxillary gland protease, Tamase-1, has been identified. The hair-loss mutation fuzzy has also been mapped and occupies a position which is similar to that of the frizzy gene in the mouse. There are now at least five, and possibly six, genetic loci distributed over more than 30 centimorgans in the first linkage group of the rat which map in positions of approximate homology on the seventh chromosome of the mouse.

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