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Part I. Genetics and Autoimmunity |
Nitric Oxide Signaling Triggered by the Rheumatoid Arthritis–Shared EpitopeA New Paradigm for MHC–Disease Association?
JOSEPH HOLOSHITZa AND
SONG LINGa
a Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA
Key Words: autoimmunity • MHC–disease association • signal transduction
Address for correspondence: Joseph Holoshitz, M.D., University of Michigan Medical Center, 5520 MSRB I, Ann Arbor, Michigan 48109-0680, USA. Voice: +734-764-5470; fax: +734-763-4151. jholo{at}umich.edu
Many immune-mediated diseases are associated with particular MHC class I or class II alleles. In rheumatoid arthritis (RA-shared), the vast majority of patients possess HLA-DRB1 alleles encoding a shared epitope, which is a five–amino acid sequence motif in positions 70–74 of the HLA-DR chain. The mechanistic basis for this association is unknown. Here we discuss recent evidence suggesting that the shared epitope may act as an allele-specific ligand that triggers increased nitric oxide (NO) production in opposite cells with resultant immune dysregulation. We propose that by doing that, the RA-shared shared epitope may form an unintended bridge between the innate and adaptive immune systems, thereby allowing aberrant signaling events that could trigger disease.
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