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We generated transgenic mice with DRB1*0401 gene with mutation in the beta2 domain (aa 110 and 139) for better interaction with mCD4. The DR4 transgene was introduced into H2-Aq (B10RQB3) and H2-Af (B10RFB3) to examine the role of DR4 in collagen arthritis. The HLA-DR molecules in these mice were found to be functional on the basis of their positive/negative selection of the Vbeta T cell repertoire. H2-Aq mice are resistant to porcine CII-induced arthritis. The RQB3/DR4 mice (H2Aq/DR4) developed severe collagen induced arthritis (CIA) when immunized with Porcine type II collagen while the negative littermates were resistant. RQB3.DR4 mice were also highly susceptible to CIA induced by Human CII while negative littermates got only mild disease. However, RFB3/DR4 mice (H2Af/ DR4) did not get CIA with any type II collagen. Therefore, the DR4 gene in the context of H2-Aq predisposes to severe arthritis but not in the context of H2-Af. Antibodies to renatured cyanogen bromide (CB) cleaved fragments of PII in RQB3/DR4 mice and negative littermates suggest that the presence of DR4 does not result in any differences in specificity of antibody response to CB fragments. These results indicate that a specific gene complementation occurring between DR4 and H2.Aq but not DR4 and H2Af promotes the induction of arthritis with PII and HII in these mice. A similar interaction may be involved between DR and DQ molecules in human RA.

On the basis of our studies with HLA class II transgenic mice, we had proposed that complementation of HLA-DQ and HLA-DR alleles may determine both disease susceptibility and severity in rheumatoid arthritis (RA). According to our model, certain HLA-DQ alleles, such as HLA-DQ8, predispose individuals to RA, while a self-peptide derived from the third hypervariable region (HV3 65-79) of HLA-DR alleles, such as DRB1∗0402, can protect from disease if presented by the DQ molecule. To test this hypothesis, we examined the immunomodulatory effects of the DRB1∗0402 derived peptide (HV3 65-79) on collagen-induced arthritis (CIA) in HLA-DQ8 mice. Co-immunization of the DRB1∗0402 peptide significantly reduced the severity of arthritis (mean score = 1.5 ± 0.6 vs 5.2 ± 1.4 in controls), whereas multiple doses of the peptide reduced the incidence of disease (3.5% vs 35–60% in controls). Subsequent analysis revealed that the DRB1∗0402 peptide mediated protection may be due to the generation of a subset of regulatory cells, which down-regulate collagen-specific pro-inflammatory responses. These results provide additional insights towards understanding the role of MHC class II molecules in RA predisposition.

HLA-B27 is highly linked with a group of human diseases called spondyloarthropathies (SpA). Many of these disorders begin after an infection with an enterobacteria. The symptoms seen in patients with spondyloarthropathies are inflammatory pain in the spine and asymmetrical arthritis of lower limbs. Additional symptoms related to SpA include inflammation in the eyes, bowel, and skin. The autoantigen(s) in SpA are not known. Proteins such as collagen and proteoglycans have been thought to be potent autoantigens in arthritidis including B27-associated human diseases. Type II collagen is a common denominator among eyes and joints, affected tissues in B27-linked diseases. Moreover, a few reports indicated CII specific T cells and antibodies in patients with spondyloarthropathies. We and others have previously described development of spontaneous arthritis and nail disease in HLA-B27 transgenic animals. To determine whether CII may be a target antigen in the B27-linked diseases, B27 + mβ 2 m o/o (HLA-B27 transgenic mice lacking mouse β 2 m with and without human β 2 m) mice were immunized with type II collagen inside the barrier facility. Male HLA-B27 transgenic mice developed collagen-induced arthritis compared to transgene negative littermates or female counterparts. There was no difference in the incidence of arthritis in HLA-B27 transgenic mice with and without human β 2 m. Our data suggest that β 2 m free heavy chain of HLA-B27 may present soluble antigens such as type II collagen to trigger specific T cells contributing in the development of arthritis. Our data also suggest that CII may be a potential target antigen in the cartilage during the disease process.

A strong correlation exists between susceptibility to RA in humans and some DRB1 alleles of the MHC region, such as DRB1*0401 and DRB1*0101. Meanwhile, incidences of other DR specificities, such as DR2, DR5, or DR7 have often been found reduced among RA patients. Like RA, susceptibility to mouse CIA is influenced by the MHC class II loci. To analyze the effect of a DRB1 molecule associated with low incidence of RA on mouse CIA, a human DRB1*1502 (DR2Dw12) transgene was introduced into CIA-susceptible B10.RQB3 (H2Aq) mice. Transgene-positive DRB1*1502 mice showed a significant reduction in the incidence and severity of arthritis. Moreover, the clinical reduction of arthritis correlated with the T-cell proliferative response of B10.RQB3-DRB1*1502 mice against a self-derived DRB1 peptide from the third hypervariable region. Our results suggest that the DRB1*1502-mediated protection against CIA can be explained by the DRB1 molecule acting as a source of self-antigenic peptide which interferes with the T-cell response against immunodominant regions(s) of the arthritogenic type II collagen molecule. By analogy, a similar mechanism might play a critical role in influencing the class II-associated predisposition to RA.