Genetic basis of collagen diseases in MRL mice with a deficit in Fas- mediated apoptosis: Dissection of the complex pathological manifestations

The lpr and the gld gene are a Fas deletion mutant and a Fas ligand (Fas-L) mutant, respectively. These genes induce a deficit in Fas-mediated apoptosis of activated T and B cells and macrophages in a result of an incapacity for Fas/Fas-L interaction, and have been thought to generate subsequently autoimmune disease. An MRL/MpJ-lpr/lpr (MRL/lpr) strain develop various forms of collagen disease, including polyarteritis, glomerulonephritis (GN), sialoadenitis and arthritis, associated with autoimmune traits. A newly established MRL recombinant congenic strain of mice bearing the gld gene, MRL/MpTn-gld/gld (MRL/gld), also developed similar diseases as those in MRL/lpr mice. The treatment of MRL/gld mice with anti- Fas antibodies was successful in the prevention and amelioration of these diseases. These findings might indicate that collagen diseases in these mice are a single gene disease, associated with the complex pathological manifestations as pleiotropy. However, comparative studies with C3H/HeJ and C57BL/6J strains bearing lpr or gld revealed that these diseases developed only in mice with an MRL background. Moreover, the complex pathological manifestations of collagen diseases were genetically segregated among MRL/lpr x (MRL/lpr x C3H/lpr)Fl mice. This indicates that an MRL genetic background has particular susceptible gene(s) for the development of each disease. Several MRL recombinant congenic strains of mice derived from the hybrid mice between MRL/lpr and C3H/lpr strains, were established, one of which McH5- lpr/lpr (McH5/lpr) developed only polyarteritis, but not glomerulonephritis, arthritis and sialoadenitis. In the association studies of each disease with polymorphic microsatellite markers using the backcross mice, furthermore, responsible gene loci for arteritis were mapped on chromosomes 3 and 4. These loci were not associated with other collagen diseases. Thus, it is likely that complex pathological manifestations of collagen diseases are under the control of different combinations of host polygenes.