A common immunoregulatory locus controls susceptibility to actively induced experimental allergic encephalomyelitis...

Previous studies have shown that differential susceptibility to actively induced experimental allergic encephalomyelitis (EAE) and experimental allergic orchitis (EAO) exists among various BALB/c substrains. Of eight substrains studied for EAE and 13 for EAO, BALB/cJ mice are phenotypically the most resistant to disease induction. Resistance to both diseases is controlled by single recessive mutations unlinked to any of the known alleles distinguishing BALB/cJ mice. In this study, segregation analysis employing a second generation backcross population shows that resistance to both EAE and EAO is due to a mutation in a common immunoregulatory gene. The role of immunoregulatory cells in controlling EAE resistance was examined using adoptive transfer protocols. BALB/cJ mice immunized with spinal cord homogenate plus adjuvants generate immunoregulatory spleen cells (SpC) that, when transferred to naive BALB/cByJ recipients, reduce the incidence and severity of EAE. Treatment of such cells with either cytotoxic monoclonal anti-Thy1.2 or anti-CD4 plus C' before transfer abrogates the ability of BALB/cJ SpC to inhibit disease. In contrast, neither SpC from adjuvant-immunized BALB/cJ nor spinal cord homogenate- plus adjuvant-primed BALB/cByJ donors influences the incidence or severity of disease observed in recipients. In addition, the role of environment in influencing susceptibility to EAE and EAO in BALB/c mice is documented. Taken together, these results support the existence of a common disease susceptibility locus in the pathways leading to two autoantigenically distinct CD4+ T cell-mediated, organ-specific, autoimmune diseases.