The shared epitope hypothesis. an approach to understanding the molecular genetics of susceptibility to rheumatoid arthritis

Abstract

Understanding the inheritance of rheumatoid arthritis (RA) has been the quest of intense investigation over the last decade. One major focus of these efforts has been the attempt to identify genes within the class I1 region of the major histocompatibility complex (MHC) that confer susceptibility for disease. These studies have been based largely on finding associations between class I1 serologic specificities and disease. The results have not been simple to interpret, and lucid analysis is made more difficult by the highly complicated nomenclature that is used to describe the class I1 HLA system. The advent of recombinant DNA technology, however, has greatly expanded our knowledge of this system over the last few years and has offered alternative interpretations of disease association data. One such interpretation, the shared epitope hypothesis, has been described previously (1) and is the subject of this review.To understand the shared epitope hypothesis, one must have some knowledge of the genetic organization of the class I1 region and of the biochemical structure of class I1 molecules. Briefly, the human class I1 region (Figure 1) extends to nearly l , OOO, OOO base pairs, and includes at least 14 different genes. With the exception of DOp and DZa, these genes are generally found in 1 of 3 major subregions: DR, DQ, or DP.Each subregion contains at least 1 functional a Figure 2. Alpha and beta chains from the DQ subregion are polymorphic (i.e., there are multiple alleles at each locus in the population), and together they encode the DQ serologic specificities (DQwl-3).The DR subregion also contains 2 functional p chain genes, designated DRPI and DRPIII. These p chains are both polymorphic. The D W I gene encodes the classic DR specificities (DR1-14); the DRPIII gene encodes the DRw52 and DRw53 specificities. The genes within the DR and DQ subregions are very closely linked and are almost always inherited together as a unit. Therefore, DR and DQ subregion alleles form stable haplotypes in the population. For example, the DR4 allele (encoded by the D W I gene) is almost always found in association with DRw53 (encoded by DRpIII) and DQw3 (encoded by DQ a and P), thus forming the typical DR4,DRw53,DQw3 haplotype. As discussed herein, all the variability between different DR4 haplotypes is located in the DRPI gene. The other linked genes, namely DRPIII, DQa, and DQP, are identical in all DR4 haplotypes, with few exceptions (2,3).The structural features of class I1 molecules at the cell surface are shown in Figure 2 (top). For comparison, class I molecules are also shown. In the case of class I1 molecules, both a and P chain molecules are inserted into the membrane and associate with each other in a noncovalent fashion to form an alp heterodimer. The class I1 p chain contains 2 immunoglobulin-like external domains. The first, or N-terminal, domain (Figure 2) is the site of most of thevariability

Frequency of HLA-DRB1 alleles in rheumatoid arthritis patients in Zahedan, southeast Iran

“…HLA-DRB1*04 allele has frequently been found to be associated with RA susceptibility;41314 and the HLA-DRB1*0404 sub-allele, strongly related with high titers of anti–cyclic citrullinated peptide (CCP) antibodies 15. In contrast with these studies, no significant association was seen between DRB1*04 and RA in our subjects.…”

Molecular Genetic Analysis of HLA—DR and HLA—DQ Genes Among Anti—U1‐70‐kd Autoantibody Positive Connective Tissue Disease Patients

“…This finding is similar to findings in RA, in which disease susceptibility is associated with non-Dwl0 subtypes of DR4 and with DR1, and in Lyme arthritis, in which susceptibility is associated with DR2 and DR4 (42), as was found in the present study. A postulated explana-tion for these findings is the fact that disease susceptibility is primarily associated with "shared epitopes" within the HLA system which are not fixed to a single genotype (14,424). The "shared epitope" hypothesis of RA has also been supported by the identification of this same shared epitope among Japanese RA patients with the HLA-Dwl5 subtype of DR4 (41) and among Yakima Indian RA patients with the Dw16 subtype of DR6 (46).…”

“…The serologically detected HLA-DR4 molecule can be encoded by 1 of 8 polymorphic variants of HLA-DR4 genes: Dw4, DwlO, Dw13.1, Dw14.1, Dw15, DKT2, Dw13.2, and Dw14.2 (by the 1989 Nomenclature Committee for Factors of the HLA System, these are called HLA-DRB1*0401, DRB 1 *0402, DRB 1 *0403, DRB 1 *0404, DRB 1 *0405, DRB1*0406, DRB1*0407, and DRB1*0408, respectively) (12,13). In some DR4-associated autoimmune diseases, such as rheumatoid arthritis (RA) and pemphigus vulgaris, disease susceptibility has been shown to be associated with select subtypes of DR4 (14)(15)(16), while in another DRCassociated disease, type I diabetes mellitus, the primary genetic association has been shown to be with DRCassociated DQBl genes (17,18).…”

Therapy for Lyme arthritis: Strategies for the treatment of antibiotic‐refractory arthritis

“…The first suggestion that antibiotic-refractory Lyme arthritis may have an autoimmune component was the demonstration of its association with the HLA-DR4 and HLA-DR2 alleles (25) (27,28) and the DRB5*0101 allele linked to DRB1*1501 (the former DR2 allele) (26). Moreover, patients with antibiotic-refractory arthritis often have T cell recognition of OspA 163-175 (29)(30)(31)(32)(33).…”