Trans heterodimer between two non-arthritis-associated HLA alleles can predispose to arthritis in humanized mice

Marshall Behrens, George K. Papadopoulos, Antonis Moustakas, Michele Smart, Harvinder Luthra, Chella S. David, Veena Taneja

Research output: Contribution to journalArticle

4 Scopus citations

Abstract

Objective Certain HLA class II alleles are associated with susceptibility to the development of arthritis. However, the development of arthritis in some persons carrying non-rheumatoid arthritis (RA)-associated alleles remains unexplained. An individual who is heterozygous for the DQA1 and DQB1 genes can express the DQ molecule in cis or trans heterodimers. In a cis heterodimer, the α-chain interacts with the β-chain coded by the same chromosome, while in a trans heterodimer it interacts with the β-chain on the other chromosome. In this study, we used a humanized mouse model of arthritis in an attempt to determine whether a trans heterodimer of 2 nonassociated alleles, DQB1*0601 and DQB1*0604, can predispose to arthritis. Methods DQB1*0601 and*0604 occur in linkage with DQA1*0103 and*0102, respectively. To understand the role of trans heterodimers, we generated DQB1*0604/DQA1*0103-transgenic mice lacking endogenous HLA class II molecules. Results Severe arthritis developed in the DQB1*0604/A1*0103-trangenic mice, and an antigen-specific response was generated in vitro. DQB1*0604/DQA1*0103 presented type II collagen-derived peptides that were not presented by the arthritis-resistant DQB1*0601 allele, suggesting that trans heterodimer molecules between 2 DQB1 and DQA1 molecules may result in the presentation of unique antigens and susceptibility to the development of arthritis. Molecular modeling of type II collagen peptides showed that DQB1*0604/DQA1*0103 shares a p4 pocket with the arthritis-susceptible DQB1*0302 allele, suggesting a critical role of the p4 and p9 pockets in susceptibility to arthritis. Conclusion These results provide a possible explanation for the parental inheritance of nonsusceptibility alleles in some patients with RA and a mechanism by which they can predispose to the development of arthritis.

Original languageEnglish (US)
Pages (from-to)1552-1561
Number of pages10
JournalArthritis and rheumatism
Volume63
Issue number6
DOIs
StatePublished - Jun 1 2011

ASJC Scopus subject areas

  • Immunology and Allergy
  • Rheumatology
  • Immunology
  • Pharmacology (medical)

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