As an alternate hypothesis to the role of the HLA-DR in mediating susceptibility to RA, Zanelli et al. proposed that HLA-DQ8, and not DR1 or DR4, directly mediates the immunopathogenesis in RA . Although the role of DQ8 in RA is still in dispute [36, 37], human population studies have indicated that there is linkage disequilibrium between HLA-DQ8 and DR4 , suggesting a potential role of DQ8 in RA. To address this possibility, DBA/1-DQ8 transgenic mice in which murine Class II genes were deleted were generated for studying the function of DQ8 . Immunization of these DQ8 transgenic mice with CII induced an autoimmune arthritis similar to the other CIA models, and immunodominant epitopes of CII presented by
DQ8 in these mice were also identified. In contrast to the DR1- or DR4-restricted T-cell responses to CII in which only two determinants were identified, the DQ8 mice generated T-cell responses to 15 immunogenic epitopes of CII  and none of them overlapped with the DR-specific CII epitopes. While these data clearly indicate the differences between DR and DQ in specificity of peptide binding, perhaps the most interesting aspect of the DQ hypothesis is its incorporation of a functional role for the shared epitope of DR alleles associated with RA susceptibility. Sequence analysis of RA-associated HLA-DRB1 alleles revealed that these alleles share a common motif, a 'shared epitope' at residues 70-74, that is not present in other DR alleles . The amino acid sequence for the shared epitope is Q/R-K/R-R-A-A, and at least a few of these residues of the shared epitope are involved in pep-tide binding within the P4 binding pocket of the DR molecules . However, what exact role the shared epitope plays in RA has remained a mystery, although a number of hypotheses have been proposed. [43-48]. Zanelli et al. have proposed that the polymorphic region of DRB1 that encodes the shared epitope is a source of an antigenic peptide that regulates the function of the DQ8 molecule by binding to the DQ peptide binding site . This hypothesis is supported by their own studies in the DQ8 mice indicating that peptides from this region derived from DR alleles not associated with RA generate DQ8-restricted T-cell responses, while peptides from RA alleles do not . Their conclusion is that the peptide from non-RA alleles binds to DQ8 and regulates its function, whereas the analogous peptide derived from RA alleles lacks this ability. These data were supported by the fact that the susceptibility of DQ8 transgenic mice to CII immunization can also be blocked by introducing an RA-resistant DRB1*0402 transgene. The presence of this non-susceptibility allele also switches the cytokine profile of T-cells responding to CII immunization to the Th2 phenotype . Whether or not this intriguing hypothesis is correct, these studies demonstrate the utility of humanized mouse strains in testing novel hypotheses for the immunopathogenesis of RA.
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