The strong association with the MHC (major histocompatibility complex) is the most important known genetic predisposition factor of ankylosing spondylitis (AS) and rheumatoid arthritis (RA). The MHC association alone, however, seems to be insufficient for the induction of these autoimmune diseases. Current genetic studies of siblings indicate the existence of MHC-independent genes which are involved in the pathological mechanisms of RA, and probably in AS as well. The complexity and polygenic nature of autoimmune diseases, however, make genetic studies extremely difficult in humans, especially due to the """"""""outbred"""""""" character of the population, where the incidence is very low. Proteoglycan (aggrecan)-induced progressive polyarthritis (PGIA) is a novel autoimmune animal model which shares many similarities with human RA, as indicated by clinical assessments, laboratory tests and histopathologic studies of diarthrodial joints. The development of arthritis is based upon cross-reactive immune responses between the immunizing human and the mouse self PGs in genetically susceptible BALB/c mice, where the incidence is close to 100%. Other murine strains, including DBA/2 with the same H2d haplotype as BALB/c mice, or F1 hybrids of BALB/c and DBA/2 parents, are resistant to arthritis. The susceptibility for PGIA """"""""returns"""""""" in F2 hybrid, i.e., the inheritance of susceptibility is recessive. Although intercross experiments followed the expected Mendelian ratio and suggested a monogenic character of the disease, the initial chromosome mapping revealed three non-MHC loci on chromosomes 9, 11 and 15 (narrowest region between 30-34 cM of chromosome 9), which may be involved in disease processes. At least one locus, potentially more, however has not been identified yet in the mouse genome. Consequently, the investigators now propose to identify additional loci, narrow the intervals of localized disease-associated loci and identify candidate genes that may control autoimmune processes in arthritis susceptible BALB/c mice. They propose to perform extended high resolution genetic linkage analysis to identify arthritis-associated loci in the mouse genome, and construct a physical map of the disease-associated locus on chromosome 9 to identify candidate genes by positional cloning.
