CD74/DQA1 dimers predispose to the development of arthritis in humanized mice

Luckey David, Ameya Gokhale, Seetharama Jois, Aaron Johnson, Marshall Behrens, Harvinder Luthra, Veena Taneja

Research output: Contribution to journalArticle

4 Scopus citations

Abstract

Rheumatoid arthritis (RA) is associated with the presence of certain HLA class II genes. However, why some individuals carrying RA non-associated alleles develop arthritis is still unexplained. The trans-heterodimer between two RA non-associated HLA genes can render susceptibility to develop arthritis in humanized mice, DQA1*0103/DQB1*0604, suggesting a role for DQ α chains in pathogenesis. In this study we determined the role of DQA1 in arthritis by using mice expressing DQA1*0103 and lacking endogenous class II molecules. Proximity ligation assay showed that DQA1*0103 is expressed on the cell surface as a dimer with CD74. Upon immunization with type II collagen, DQA1*0103 mice generated an antigen-specific cellular and humoral response and developed severe arthritis. Structural modelling suggests that DQA1*0103/CD74 form a pocket with similarity to the antigen binding pocket. DQA1*0103 mice present type II collagen-derived peptides that are not presented by an arthritis-resistant DQA1*0103/DQB1*0601 allele, suggesting that the DQA1*0103/CD74 dimer may result in presentation of unique antigens and susceptibility to develop arthritis. The present data provide a possible explanation by which the DQA1 molecule contributes to susceptibility to develop arthritis.

Original languageEnglish (US)
Pages (from-to)204-211
Number of pages8
JournalImmunology
Volume147
Issue number2
DOIs
StatePublished - Feb 1 2016

Keywords

  • 0103
  • CD74
  • DQA1
  • Heterodimer
  • Humanized mice
  • Rheumatoid arthritis

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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