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-

How To Bolster Your Immune System

How To Bolster Your Immune System

All Natural Immune Boosters Proven To Fight Infection, Disease And More. Discover A Natural, Safe Effective Way To Boost Your Immune System Using Ingredients From Your Kitchen Cupboard. The only common sense, no holds barred guide to hit the market today no gimmicks, no pills, just old fashioned common sense remedies to cure colds, influenza, viral infections and more.

Get My Free Audio Book

Post a comment