Genetic Factors in Rheumatoid Arthritis

GENETIC FACTORS IN RHEUMATOID ARTHRITIS

A. HLA Associations

The incidence of familial rheumatoid arthritis is low, and only 15% of the identical twins are concordant for the disease. However, 70–90% of Caucasians with rheumatoid arthritis express the HLA DR4 antigen that is found in about 15–25% of the normal population. In-dividuals expressing this antigen are 6–12 times more at risk of having RA, but HLA-DR1 was also found to increase susceptibility to RA and wide fluctuations in the frequency of these markers are seen between different patient populations.

B. HLA-DR4 Subtypes

DNA sequencing of the β chain of the DR4 and DR1 molecules defined five HLA-DR4 subtypes: Dw4, Dw10, Dw13, Dw14, and Dw15. While Dw4, Dw10, Dw13, and Dw15 dif-fer from each other in amino acid sequence at positions 67, 70, and 74 of the third hyper-variable region of the β1 domain of the β chain, Dw4 and Dw14 have identical amino acid sequences at these positions and are associated with RA. The same amino acids are present in the Dw1 subtype of HLA-DR1. The prevalence of Dw4, Dw14, or Dw1 in the general population is 42%. Of these individuals, 2.2% develop RA. In contrast, the frequency of RA in individuals negative for these markers is only 0.17%, a 12.9-fold difference. Since most humans are heterozygous, a given individual may inherit more than one susceptibil-ity allele. Individuals having both Dw4 and Dw14 have a much higher risk (seven to one) of developing severe RA. In contrast, individuals with the Dw10 and Dw13 markers, whose sequence differs in the critical residues (Table 19.2), seem protected against RA.

The interpretation of these findings hinges on the fact that amino acids 67 to 74 are located on the third hypervariable region of the DR4 and DR1 β chains. This region is part of a helical region of the peptide-binding pouch of the DR βchain  that in-teracts both with the side chains of antigenic peptides and with the TcR. Its configuration, rather than the configuration of any other of the hypervariable regions of the DR4 and DR1β chains, seems to determine susceptibility or resistance to RA, depending on the charge of amino acids located on critical positions. In the case of Dw1 and DW14 the sequence of the 70–74 motif is identical (QRRAA), while the homologous sequence in Dw4 (QKRAA) shows one single substitution (a basic arginine by an equally basic lysine). In contrast, the sequence of the same stretch of amino acids in protective alleles shows a higher degree of divergence. In Dw10 aspartic acid and glutamic acid replace the first two amino acids (glu-tamine and arginine or lysine), resulting in a total change in the charge and affinity of the peptide-binding pouch. In the case of Dw13, glutamic acid replaces alanine at position 74, again resulting in a marked charge difference relatively to Dw1, 4, and 14.

It has been postulated that the structure of those DR4 and DR1 molecules associated with increased risk for the development of RA is such that they bind very strongly an “arthritogenic epitope” derived from an as yet unidentified agent. Bacterial antigens, in-cluding heat shock proteins, microbial proteins from Proteus mirabilis, Epstein-Barr virus, or retroviruses, as well as autologous proteins such as type II collagen or cartilage glyco-protein gp39 have been proposed as candidate sources for these peptides. The consequence of the binding of immunogenic peptides would be a strong and prolonged immune response that would be the basis of the inflammatory response in the joints. Obviously, the predom-inant localization of the inflammatory reaction to the peri-articular tissues implies that the level of expression of the peptides in question must be higher in those tissues. The reverse would be the case for those DR4 molecules associated with protection against the devel-opment of RA.

Supporting this interpretation are several observations concerning the severity of the disease in patients bearing those HLA antigens and subtypes. For example, DR4 positivity reaches 96% in patients suffering from Felty’s syndrome, the most severe form of the dis-ease. More recent studies showed that RA patients who are DR4-Dw14 positive have a faster progression to the stages of pannus formation and bone erosion.

The most significant discrepancy in this apparent consensus sequence between DR sequence and RA susceptibility was found in African Americans with RA; in this group,only 20% are DR4+ . In this ethnic group predisposition and severity appear independent of the presence and dose of the “arthritogenic” DR alleles identified in Caucasians.