Organ-Specific Autoimmune Disease

It is well appreciated that organ-specific autoimmune diseases run in families, but that within a family one member may have type 1 diabetes, another autoimmune thyroid disease, and another multiple sclerosis (1). What causes clustering of different autoimmune diseases along genetic lines, and what logic causes the immune system to take aim at different organ targets? In this issue, Salomon et al. make the paradoxical finding that interference with a single costimulatory molecule, B7-2, shifts the aim of autoimmunity in the NOD mouse strain away from the pancreatic islet cell and onto the peripheral nerves (2). The finding adds an important molecular clue to the pathogenesis of organ-specific autoimmune disease, and illustrates the caution that will be needed as new immunological interventions are applied in the clinic. The inheritance of susceptibility to organ-specific autoimmunity is extraordinarily complex. Particular haplotypes of the major histocompatibility complex, such as HLA-DR3-DQB1 * 0201, are strongly associated with human susceptibility to multiple organ-specific autoimmune disorders (3). HLA-type nevertheless accounts for only a fraction of inherited susceptibility, and heterozygosity for different HLA alleles can either raise or lower the risk. Independent of HLA-type, mutations in a non-MHC gene, AIRE, cause a Mendelian syndrome, APECED, characterized by autoimmune manifestations ranging from Addison’s, thyroid, and parathyroid disease to type 1 diabetes (4, 5). The AIRE gene product appears to be a nucleic acid binding protein present in some thymic epithelial and dendritic cells. Its connection to organ-specific autoimmunity can only be speculated, perhaps related to presentation of organ specific antigens for tolerance induction in the thymus. The unpredictable interactions between MHC and nonMHC genetic loci have been most clearly illuminated by the genetic analysis of organ-specific autoimmunity in the NOD mouse, where it has been possible to create numerous congenic substrains differing at one or more of the 20 or so loci currently shown to contribute to susceptibility (6). The NOD mouse is an inbred strain derived in Japan from a mixture of outbred strains (7). A high proportion of NOD mice spontaneously develop type 1 diabetes due to destruction of pancreatic islets by T cells. NOD carries a unique MHC class II allele, I-A g7 , which makes a major contribution to diabetes susceptibility (Table I). The I-A g7