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The Journal of Immunology, 2003, 171: 538-541.
Copyright © 2003 by The American Association of Immunologists


CUTTING EDGE

Cutting Edge: The Conversion of Arginine to Citrulline Allows for a High-Affinity Peptide Interaction with the Rheumatoid Arthritis-Associated HLA-DRB1*0401 MHC Class II Molecule1

Jonathan A. Hill*,{dagger},{ddagger}, Scott Southwood, Alessandro Sette||, Anthony M. Jevnikar*,{dagger},§, David A. Bell2,*,{dagger},{ddagger} and Ewa Cairns2,3,*,{dagger},{ddagger}

Departments of * Medicine and {dagger} Microbiology and Immunology, University of Western Ontario, and Divisions of {ddagger} Rheumatology and § Nephrology, London Health Sciences Center, London, Ontario, Canada; and Epimmune, Inc., and || La Jolla Institute for Allergy and Immunology, San Diego, CA 92121

Rheumatoid arthritis (RA) is genetically associated with MHC class II molecules that contain the shared epitope. These MHC molecules may participate in disease pathogenesis by selectively binding arthritogenic peptides for presentation to autoreactive CD4+ T cells. The nature of the arthritogenic Ag is not known, but recent work has identified posttranslationally modified proteins containing citrulline (deiminated arginine) as specific targets of the IgG Ab response in RA patients. To understand how citrulline might evoke an autoimmune reaction, we have studied T cell responses to citrulline-containing peptides in HLA-DRB1*0401 transgenic (DR4-IE tg) mice. In this study, we demonstrate that the conversion of arginine to citrulline at the peptide side-chain position interacting with the shared epitope significantly increases peptide-MHC affinity and leads to the activation CD4+ T cells in DR4-IE tg mice. These results reveal how DRB1 alleles with the shared epitope could initiate an autoimmune response to citrullinated self-Ags in RA patients.




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