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Organ-Specific Autoimmune Disease : A Deficiency of Tolerogenic Stimulation

Journal of Experimental Medicine
The Rockefeller University Press
Publication Date
  • Commentary
  • Medicine


011158 J. Exp. Med.  The Rockefeller University Press • 0022-1007/2001/09/F31/06 $5.00 Volume 194, Number 5, September 3, 2001 F31–F36 Commentary F31 Organ-specific Autoimmune Disease: A Deficiency of Tolerogenic Stimulation Sylvie Lesage and Christopher C. Goodnow Australian Cancer Research Foundation Genetics Lab, Medical Genome Centre, John Curtin School of Medical Research, Canberra ACT 2601, Australia It is well appreciated that organ-specific autoimmune diseases run in families, but that within a family one mem- ber 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 co- stimulatory 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-spe- cific autoimmune disease, and illustrates the caution that will be needed as new immunological interventions are ap- plied in the clinic. The inheritance of susceptibility to organ-specific au- toimmunity is extraordinarily complex. Particular haplo- types of the major histocompatibility complex, such as HLA-DR3-DQB1 * 0201, are strongly associated with hu- man 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. Inde- pendent of HLA-type, mutations in a non-MHC gene, AIRE, cause a Mendelian syndrome, APECED, character- ized by autoimmune manifestations ranging from Addison’s, thyroid, and

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