HLA-DQB1 polymorphism determines incidence, onset, and severity of collagen-induced arthritis in transgenic mice. Implications in human rheumatoid arthritis.

Abstract

Certain HLA-DR alleles have been associated with predisposition to human rheumatoid arthritis (RA). There is also evidence that certain HLA-DQ alleles may also be important in determining susceptibility to RA. We have previously demonstrated that mice transgenic for HLA-DQ8, a DQ allele associated with susceptibility to RA, develop severe arthritis after type II collagen immunization. To investigate the influence of polymorphic difference at the DQ loci on susceptibility to arthritis, we generated mice transgenic for HLA-DQ6, an allele associated with a nonsusceptible haplotype. The DQ6 mice were found to be resistant to collagen-induced arthritis. We also assessed the combined effect of an RA-susceptible and an RA nonassociated DQ allele by producing double-transgenic mice expressing DQ6 and DQ8 molecules, representing the more prevalent condition found in humans where heterozygosity at the DQ allele is common. The double-transgenic mice developed moderate CIA when immunized with CII when compared with the severe arthritis observed in DQ8 transgenic mice, much like RA patients bearing both susceptible and nonsusceptible HLA haplotypes. These studies support a role for HLA-DQ polymorphism in human RA. (

An HLA-DRB1-Derived Peptide Associated with Protection Against Rheumatoid Arthritis Is Naturally Processed by Human APCs

“…The enhancing DRB1 alleles are DRB1*0401 and *0404, whereas DRB1 alleles such as DRB1*0402, *1301, and 1302, which all encode the amino acid sequence motif 70 DERAA 74 in the HV3 region of the protein, are dominantly protective (6). Consistent with this model, DQ8 transgenic mice, but not DQ6 (DQB1*0601/DQA1*0103) transgenic mice, develop collagen-induced arthritis (7). The DQ3-DR4 haplotypes have a stronger association with RA and predispose to a more severe disease than the DQ5-DR1 and DQ5-DR10 haplotypes (8,9).…”

A review of the MHC genetics of rheumatoid arthritis

“…In contrast, transfection with a non-RA-associated gene, HLA-DQ6, created a phenotype resistant to the development of inflammatory arthritis. [18][19][20][21][22] Some association studies in humans have suggested a direct role for DQ alleles in RA. 23 However, further larger studies have not supported this hypothesis.…”

HLA-DQ Determines the Response to Exogenous Wheat Proteins: A Model of Gluten Sensitivity in Transgenic Knockout Mice

“…Transgenic mice expressing human class II molecules (in the absence of endogenous mouse class II) have been used to study other autoimmune disorders, including rheumatoid arthritis and multiple sclerosis (15)(16)(17)(18). We have studied the effect of gluten in double transgenic mice expressing HLA-DQ and human CD4 genes in the absence of endogenous class II and CD4 genes.…”