MULTIPLE LOCI GOVERN THE BONE-MARROW-DERIVED IMMUNOREGULATORY MECHANISM CONTROLLING DOMINANT RESISTANCE TO AUTOIMMUNE ORCHITIS

The existence of immunoregulatory genes conferring dominant resistance to autoimmunity is well documented, In an effort to better understand the nature and mechanisms of action of these genes, we utilized the m urine model of autoimmune orchitis as a prototype. When the orchitis-r esistant strain DBA/2J is crossed with the orchitis-susceptible strain BALB/cByJ, the F-1 hybrid is completely resistant to the disease, By; using reciprocal radiation bone marrow chimeras, the functional compo nent mediating this resistance was mapped to the bone marrow-derived c ompartment, Resistance is not a function of either low-dose irradiatio n- or cyclophosphamide (20 mg/kg)-sensitive immunoregulatory cells, bu t can be adoptively transferred by primed splenocytes. Genome exclusio n mapping identified three loci controlling the resistant phenotype. O rchil maps to chromosome 11, whereas Orch4 and Orch5 map to the telome ric and centromeric regions of chromosome 1, respectively, All three g enes are linked to a number of immunologically relevant candidate loci , Most significant, however, is the linkage of Orch3 to Idd4 and Orch5 to Idd5, two susceptibility genes which play a role in autoimmune ins ulin-dependent type 1 diabetes mellitus in the nonobese diabetic mouse .