HLAtransgenic mice new models for human RA

Genetic studies have linked predisposition in RA in humans to the MHC class II HLA-DRB1 locus. Analysis of HLA-DR alleles associated with RA have revealed that DRB1ยป0401 (Dw4) and DRB 1*0404 (Dwl4) confer genetic predisposition to RA, while DRB1 *0402 (Dw10) does not. In addition, these alleles bear a similar amino acid sequence within the HV3 region (amino acids 67-74) of the DRB1 molecule, which prompted the 'shared epitope' hypothesis of RA susceptibility. The hypothesis states that a critical element in conferring an increased risk for RA susceptibility is possession of this common epitope within the DRB1 molecule. Linkage disequilibrium between certain DQ and DR genes has revealed a much stronger association at the DQ and DR locus in some autoimmune disorders. In RA, the DQ7 allele has been shown to be associated with a majority of DR4 alleles (in Caucasoid populations), whereas in Asian populations, DQ8 is in linkage disequilibrium with DR4. The above data support a role of HLA-DQ alleles in genetic predisposition to RA.

Based on these findings and studies on the role of H-2E in CIA, we had proposed that an extended DQ/DR haplotype is responsible for RA predisposition and that polymorphism of the HI.A-DRB1 alleles dictates disease protection. The molecular basis of this protection is through the presentation of a DRB1 HV3 peptide by RA-associated DQ molecules. It should be noted that HLA class II-derived peptides indeed constitute a major fraction of naturally processed peptides bound to class II molecules. According to our hypothesis, the negative association of DQ8/DRB1 *0402 haplotype with RA should be reflected in the capacity of the DQ8 molecule to present the HV3 peptide from the DRB1*0402 chain during thymic education and induce a T cell response (Figure 1). Alternatively, the lack of DQ8 restriction of HV3 peptides derived from DRB1*0401, i;"0404, or *1402 allele should correlate with the RA association of the respective Dw4, Dwl4, or Dwl6 subtypes.

To test this hypothesis, we used H1.A-DQ8 transgenic mice which express a functional DQB1 * 0302/Al*0301 dimeric molecule in the absence of endogenous mouse class II molecules. HLA-DQ8 molecule expression in the peripheral blood lymphocyte (PBL) population is approximately 25%. These ra-

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