Risk Of RA Research Articles

The Importance of DR4Dw4 β Chain Residues 70, 71, and 86 in Peptide Binding and T Cell Recognition

The expression of specific alleles of the human HLA-DR locus is associated with increased risk for the development of rheumatoid arthritis. Examination of the amine acid sequence of the DR β chain has revealed that risk for RA correlates with a cluster of polymorphic residues located between positions 67 and 86, and in particular with the identity of residues 70, 71, and 86. To examine the contributions of these HLA-DR polymorphic residues to antigen-specific T cell responses, the DRB1*0401 gene was subjected to site-directed mutagenesis and forms possessing alanine in place of the naturally occurring amine acid at positions 70, 71, 86, and 70/71 were generated. The mutated genes were coexpressed with the DRA gene in Chinese hamster ovary cells and the transfectants were tested as stimulater cells for a panel of three human influenza virus hemagglutinin-specific T cell clones. Additionally, soluble forms of the mutant DR molecules were examined for their ability to bind peptide. All of the mutants had a modest loss of affinity for the peptide relative to the wild type, but there were no significant differences in peptide binding ability among the substituted molecules. In contrast to the relatively uniform influence on peptide binding, the impact of these mutations on T cell stimulation was heterogeneous. Specifically, these studies indicate that residue 71 plays a critical role in T cell stimulation either through direct contact with the T cell receptor or by changing the orientation or conformation of the peptide--MHC complex. Replacement of residue 71 with alanine abrogated stimulation of all of the T cell clones. Two of three clones were affected by changes at residue 70 while none lost recognition when amino acid 86 was converted from Val to Ala. These data emphasize that subtle alterations in structure can have a profound impact on T cell recognition.

INCIDENCE OF RHEUMATOID ARTHRITIS IN A 10-YEAR FOLLOW-UP STUDY OF EXTENDED PEDIGREE MULTICASE FAMILIES

A 10-year follow-up study was undertaken of 17 multicase RA families with extended pedigrees to (i) determine the incidence of RA in the previously unaffected members and (ii) to assess the stability of diagnosis as defined by the 1958 and 1987 ARA criteria. In all, eight individuals developed RA. Of these, six were surviving at 10 years--four first degree (FDR), one second degree (SDR) and one non-blood relative (NBR) of the proband equivalent to incidence densities of 9, 3, and 3 per 1000 person years of observation respectively. These are substantially greater than estimates for both the general population and a DR1/4 positive population. The risk of RA is greatest in FDR and this is likely to be due to both shared inherited and environmental factors. The risk in NBR, who share no genetic material is of similar magnitude to more distant blood relatives. Definite/classical RA is a stable diagnosis over time in the majority of cases unlike probable RA which may herald definite RA but usually does not.

The molecular basis for HLA class II associations with rheumatoid arthritis.

The association of HLA-DR4 with rheumatoid arthritis strongly implicates genes of the major histocompatibility complex (MHC) as contributing to disease susceptibility. Molecular analysis of MHC genes expressed on haplotypes in association with HLA-DR4 reveals that at least six different alleles of the DR beta 1 locus and at least three different alleles of the DQ beta locus occur on different DR4+ haplotypes. Some of these allelic differences are quite substantial, and others are rather subtle, involving as few as two amino acids. The analysis of individual DR and DQ alleles in rheumatoid arthritis identifies some DR4+ genes strongly associated with disease susceptibility and some DR4+ genes which are not. The Dw4(DR4) and Dw14(DR4) DR beta 1 genes appear to represent specific alleles which confer disease risk in RA; other DR beta 1 genes, such as Dw10(DR4), may represent DR beta genes altered during evolution which have lost their contribution to RA susceptibility. DQ beta 3.1(DQw3) and DQ beta 3.2(DQw3) DQ beta genes, which are present on DR4+ haplotypes, represent discrete variable alleles not directly implicated in RA, but which account for HLA-DR4 associations with other diseases, such as the association of DQ beta 3.2(DQw3) with Type I diabetes.

The frequency of rheumatoid arthritis among relatives of probands with definite ankylosing spondylitis.

We studied families of 23 unrelated HLA-B27 positive probands with definite ankylosing spondylitis to investigate the occurrence of rheumatoid arthritis. The prevalence of RA among these relatives was significant higher (2.91%; 0.02 less than p less than 0.05) than in the control group of 28 healthy individuals (1.02%). These data suggest an increased relative risk of RA in relatives of patients with AS.