title: Trans heterodimer between two non-arthritis-associated HLA alleles can predispose to arthritis in humanized mice.
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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Immunology, Mayo Clinic, Rochester, Minnesota 55905, USA.
authors.forename: Marshall
authors.initials: M
authors.lastname: Behrens
authors.forename: George K
authors.initials: GK
authors.lastname: Papadopoulos
authors.forename: Antonis
authors.initials: A
authors.lastname: Moustakas
authors.forename: Michele
authors.initials: M
authors.lastname: Smart
authors.forename: Harvinder
authors.initials: H
authors.lastname: Luthra
authors.forename: Chella S
authors.initials: CS
authors.lastname: David
authors.forename: Veena
authors.initials: V
authors.lastname: Taneja
mesh_terms: D000818:Animals; D001168:Arthritis / Q000235:genetics* / Q000276:immunology*; D024043:Collagen Type II / Q000276:immunology / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D020022:Genetic Predisposition to Disease; D006683:HLA-DQ Antigens / Q000235:genetics*; D059866:HLA-DQ beta-Chains; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics*; D051379:Mice; D008822:Mice, Transgenic; D008958:Models, Molecular; D012720:Severity of Illness Index
chemical_list: D024043:Collagen Type II; D006683:HLA-DQ Antigens; D059866:HLA-DQ beta-Chains; C069051:HLA-DQB1 antigen; D008562:Membrane Glycoproteins