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 Snijders, A. Articles by Zanelli, E. H. Search for Related Content PubMed PubMed Citation Articles by Snijders, A. Articles by Zanelli, E. H.

An HLA-DRB1-Derived Peptide Associated with Protection Against Rheumatoid Arthritis Is Naturally Processed by Human APCs¹

Alies Snijders^2,*, Diënne G. Elferink^*, Annemieke Geluk^*, A. Linda van der Zanden^*, Koen Vos, Geziena M. T. Schreuder^*, Ferdinand C. Breedveld, René R. P. de Vries^* and Eric H. Zanelli^*

^* Immunohematology and Blood Transfusion and Department of Rheumatology, Leiden University Medical Center, Leiden, The Netherlands

Predisposition to rheumatoid arthritis (RA) is thought to be associated with HLA-DR1, -DR4, and -DR10. However, many epidemiological observations are better explained by a model in which the DQ alleles that are linked to these DR alleles, i.e., DQ5, DQ7, and DQ8, predispose to RA, while certain DR alleles have a dominant protective effect. All protective DRB1 alleles, e.g., *0402, *1301, and *1302, encode a unique motif, ⁷⁰DERAA⁷⁴. The protection may be explained by the presentation of DRB1-derived peptides by DQ to immunoregulatory T cells, because it was demonstrated in various autoimmune disease models that T cell responses to certain self-Ags can be involved in disease suppression. The aim of this study was to analyze whether peptides carrying the DERAA motif are naturally processed by human APC and presented in the context of the RA-predisposing DQ. Using a synthetic peptide carrying the DRB1*0402-derived sequence ⁶⁵KDILEDERAAVDTYC⁷⁹, we generated DERAA peptide-specific DQ-restricted T cell clones (TCC) from a DQ8 homozygous individual carrying DERAA-negative DR4 alleles. By analyzing the proliferation of these TCC, we demonstrated natural processing and presentation of the DERAA sequence by the APC of all the individuals (n = 12) carrying a DERAA-positive DRB1 allele and either DQ8 or the DQ8-related DQ7. Using a panel of truncated synthetic peptides, we identified the sequence ⁶⁷(I)LEDERAAVD(TY)⁷⁸ as the minimal determinant for binding to DQ8 and for recognition by the TCC. These findings support a model in which self-MHC-derived peptide can modulate predisposition to autoimmune disease in humans.

This article has been cited by other articles:

				A L Feitsma, A H M van der Helm-van Mil, T W J Huizinga, R R P de Vries, and R E M Toes Protection against rheumatoid arthritis by HLA: nature and nurture Ann Rheum Dis, December 1, 2008; 67(Suppl_3): iii61 - iii63. [Abstract] [Full Text] [PDF]

				V. Taneja, M. Behrens, E. Basal, J. Sparks, M. M. Griffiths, H. Luthra, and C. S. David Delineating the Role of the HLA-DR4 "Shared Epitope" in Susceptibility versus Resistance to Develop Arthritis J. Immunol., August 15, 2008; 181(4): 2869 - 2877. [Abstract] [Full Text] [PDF]

				A. L. Feitsma, J. Worthington, A. H. M. van der Helm-van Mil, D. Plant, W. Thomson, J. Ursum, D. van Schaardenburg, I. E. van der Horst-Bruinsma, J. J. van Rood, T. W. J. Huizinga, et al. Protective effect of noninherited maternal HLA-DR antigens on rheumatoid arthritis development PNAS, December 11, 2007; 104(50): 19966 - 19970. [Abstract] [Full Text] [PDF]

				V. Taneja, N. Taneja, M. Behrens, S. Pan, T. Trejo, M. Griffiths, H. Luthra, and C. S. David HLA-DRB1*0402 (DW10) Transgene Protects Collagen- Induced Arthritis-Susceptible H2Aq and DRB1*0401 (DW4) Transgenic Mice from Arthritis J. Immunol., October 15, 2003; 171(8): 4431 - 4438. [Abstract] [Full Text] [PDF]