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 Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Sospedra, M. Articles by Martin, R. Search for Related Content PubMed PubMed Citation Articles by Sospedra, M. Articles by Martin, R.

Redundancy in Antigen-Presenting Function of the HLA-DR and -DQ Molecules in the Multiple Sclerosis-Associated HLA-DR2 Haplotype¹

Mireia Sospedra^2,*, Paolo A. Muraro^*, Irena Stefanová, Yingdong Zhao, Katherine Chung^*, Yili Li, Marc Giulianotti^¶, Richard Simon, Roy Mariuzza, Clemencia Pinilla^¶,|| and Roland Martin^3,*

^* Cellular Immunology Section, Neuroimmunology Branch, National Institute of Neurological Disorders and Stroke, and Lymphocyte Biology Section, Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892; Computational and System Biology Group, Biometric Research Branch, National Cancer Institute, National Institutes of Health, Rockville, MD 20852; Center for Advanced Research in Biotechnology, University of Maryland, Rockville, MD 20850; and ^¶ Mixture Sciences and ^|| Torrey Pines Institute for Molecular Studies, San Diego, CA 92121

The three HLA class II alleles of the DR2 haplotype, DRB1*1501, DRB5*0101, and DQB1*0602, are in strong linkage disequilibrium and confer most of the genetic risk to multiple sclerosis. Functional redundancy in Ag presentation by these class II molecules would allow recognition by a single TCR of identical peptides with the different restriction elements, facilitating T cell activation and providing one explanation how a disease-associated HLA haplotype could be linked to a CD4⁺ T cell-mediated autoimmune disease. Using combinatorial peptide libraries and B cell lines expressing single HLA-DR/DQ molecules, we show that two of five in vivo-expanded and likely disease-relevant, cross-reactive cerebrospinal fluid-infiltrating T cell clones use multiple disease-associated HLA class II molecules as restriction elements. One of these T cell clones recognizes >30 identical foreign and human peptides using all DR and DQ molecules of the multiple sclerosis-associated DR2 haplotype. A T cell signaling machinery tuned for efficient responses to weak ligands together with structural features of the TCR-HLA/peptide complex result in this promiscuous HLA class II restriction.

This article has been cited by other articles:

				S. J. Caillier, F. Briggs, B. A. C. Cree, S. E. Baranzini, M. Fernandez-Vina, P. P. Ramsay, O. Khan, W. Royal III, S. L. Hauser, L. F. Barcellos, et al. Uncoupling the Roles of HLA-DRB1 and HLA-DRB5 Genes in Multiple Sclerosis J. Immunol., October 15, 2008; 181(8): 5473 - 5480. [Abstract] [Full Text] [PDF]

				P. Kudela, B. Janjic, J. Fourcade, F. Castelli, P. Andrade, J. M. Kirkwood, T. El-Hefnawy, M. Amicosante, B. Maillere, and H. M. Zarour Cross-Reactive CD4+ T Cells against One Immunodominant Tumor-Derived Epitope in Melanoma Patients J. Immunol., December 1, 2007; 179(11): 7932 - 7940. [Abstract] [Full Text] [PDF]