New insights into the functional role of the rheumatoid arthritis shared epitope

Abstract

The shared epitope (SE) - an HLA-DRB1-encoded 5-amino acid sequence motif carried by the vast majority of rheumatoid arthritis (RA) patients - is a risk factor for severe disease. The mechanistic basis of RA-SE association is unknown. This group has previously demonstrated that the SE acts as a signal transduction ligand that activates nitric oxide and reactive oxygen species production. SE-activated signaling depends on cell surface calreticulin, a known innate immunity receptor previously implicated in immune regulation, autoimmunity and angiogenesis. Recent evidence that the SE enhances the polarization of Th17 cells, which is a key mechanism in autoimmunity, is discussed highlighting one of several potential functional effects of the SE in RA.

Clinical Role of Human Leukocyte Antigen in Health and Disease

“…The SE motif consists of three homologous amino acid sequence variants: (1) QKRAA, the SE variant that is the most common motif among Caucasian, is coded primarily by the HLA-DRB1*0401 allele, (2) the second most common motif, QRRAA, is coded by several alleles, among them HLA-DRB1*0404, HLA-DRB1*0101 and HLA-DRB1*0405 and (3) the third motif, RRRAA, coded by allele HLA-DRB1*1001, is the rarest. In addition to increasing RA risk, SE-coding HLA-DRB1 alleles have been shown to associate with more severe disease and to exhibit allele-dose effect, that is patients with two SE-coding alleles tend to experience more severe disease than patients with one allele, who, in turn, have more severe RA than SE-negative patients [158,159].…”

MHC molecules in health and disease: At the cusp of a paradigm shift

“…[15][16][17][18] Our recent discovery of the ligand function of the SE [19][20][21][22][23][24][25][26] provides an important impetus to the MHC Cusp theory. The SE is a five amino acid sequence motif in the cusp region (residues 70-74 of the DRβ chain) coded by HLA-DRB1 alleles that are carried by the vast majority of RA patients.…”

“…18 Importantly, our group has recently discovered that the allelespecific RA-associated shared epitope (SE), which is located in the HLA-DR cusp region, is acting as a signaling ligand for calreticulin, an established innate immune system receptor. [19][20][21][22][23][24][25][26] Thus, there is growing evidence that the MHC cusp performs several allele-dependent, nonantigen presentation functions.…”

New Possibilities of Pharmacotherapy for Immunoinflammatory Rheumatic Diseases: A Focus on Inhibitors of Interleukin-17

“…Это исследование представляет большой интерес, поскольку имеются данные о функциональной роли HLA-DRB1*SE (характерный иммуногенетический маркер РА), определяющего поляризацию иммунного ответа при РА по Th17-типу [155]. В этом исследовании продемонстрирована более высокая эффективность СЕК по сравнению с ПЛ по ACR20 (87,1 и 25,0% соот-ветственно) и положительная динамика индекса DAS28 через 28 нед.…”