HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Roth, S. Articles by Melchers, I. Search for Related Content PubMed PubMed Citation Articles by Roth, S. Articles by Melchers, I. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Hazardous Substances DB (L)-ARGININE L-LYSINE Medline Plus Health Information Joint Disorders Rheumatoid Arthritis

Major Differences in Antigen-Processing Correlate with a Single Arg⁷¹Lys Substitution in HLA-DR Molecules Predisposing to Rheumatoid Arthritis and with Their Selective Interactions with 70-kDa Heat Shock Protein Chaperones¹

Sabine Roth^*, Nicholas Willcox, Rita Rzepka^*, Matthias P. Mayer and Inga Melchers^2,*

^* Clinical Research Unit for Rheumatology and Institute of Biochemistry and Molecular Biology, Albert Ludwigs University, Freiburg, Germany; and Neurosciences Group, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford, United Kingdom

Several HLA-DR alleles are genetically associated with rheumatoid arthritis. DRB1*0401 predominates in Northern Europe and has a characteristic ⁷⁰QKRAA motif. This sequence contacts bound peptides and the TCR. Further interactions have been suggested with additional proteins during Ag loading. We explored the much stronger processing/presentation of full-length recombinant human acetylcholine receptor subunit to a specific T cell clone by APC from DRB1*0401⁺ than *0408⁺ donors. Using DR*04 transfectants, we show that this difference results largely from the single Lys⁷¹Arg interchange (04010408), which scarcely affects epitope binding, rather than from any other associated polymorphism. Furthermore, we proved our recombinant polypeptides to contain the Escherichia coli 70-kDa heat shock protein molecule DnaK and its requirement for efficient processing and presentation of the epitope by DRB1*0401⁺ cells. According to a recent report, 70-kDa heat shock protein chaperones preferentially bind to the QKRAA, rather than the QRRAA, motif. Variations between the shared epitope motifs QKRAA and QRRAA are emphasized by underlining. We propose that such interactions enhance the intracellular epitope loading of *0401 molecules. They may thus broaden immune responses to pathogens and at least partially explain the distinct contributions of DRB1*0401 and other alleles to disease predisposition.

This article has been cited by other articles:

				I. Auger, C. Roudier, S. Guis, N. Balandraud, and J. Roudier HLA-DRB1*0404 is strongly associated with anticalpastatin antibodies in rheumatoid arthritis Ann Rheum Dis, December 1, 2007; 66(12): 1588 - 1593. [Abstract] [Full Text] [PDF]

				M. P. Mycko, H. Cwiklinska, J. Szymanski, B. Szymanska, G. Kudla, L. Kilianek, A. Odyniec, C. F. Brosnan, and K. W. Selmaj Inducible Heat Shock Protein 70 Promotes Myelin Autoantigen Presentation by the HLA Class II J. Immunol., January 1, 2004; 172(1): 202 - 213. [Abstract] [Full Text] [PDF]