Human MHC-II with Shared Epitope Motifs Are Optimal Epstein-Barr Virus Glycoprotein 42 Ligands—Relation to Rheumatoid Arthritis

Abstract

Rheumatoid arthritis (RA) is a chronic systemic autoimmune disorder of unknown etiology, which is characterized by inflammation in the synovium and joint damage. Although the pathogenesis of RA remains to be determined, a combination of environmental (e.g., viral infections) and genetic factors influence disease onset. Especially genetic factors play a vital role in the onset of disease, as the heritability of RA is 50–60%, with the human leukocyte antigen (HLA) alleles accounting for at least 30% of the overall genetic risk. Some HLA-DR alleles encode a conserved sequence of amino acids, referred to as the shared epitope (SE) structure. By analyzing the structure of a HLA-DR molecule in complex with Epstein-Barr virus (EBV), the SE motif is suggested to play a vital role in the interaction of MHC II with the viral glycoprotein (gp) 42, an essential entry factor for EBV. EBV has been repeatedly linked to RA by several lines of evidence and, based on several findings, we suggest that EBV is able to induce the onset of RA in predisposed SE-positive individuals, by promoting entry of B-cells through direct contact between SE and gp42 in the entry complex.

Epstein-Barr Virus and Systemic Autoimmune Diseases

“…Presumably, EBNA2 and possibly also other EBV proteins become citrullinated by peptidyl arginine deiminase (PAD) enzymes during the inflammatory process in RA joints (121,122). RFs have been found to target cryptic epitopes of IgG heavy chains, presumably being released by lysis of EBV-infected B cells (123) and MHC-II molecules with SE motives (certain HLA-DRB1 alleles) have been found to be optimal ligands for EBV gP42, thus favoring EBV infection of B cells with these forms of MHC-II (31). Thus, the major characteristics of RA can be related to chronic EBV infection, and actually, serum EBV HLA-DRB1, C', multiple genes VitD, smoking, EBV, sunburn, silica dust Systemic sclerosis (SSc) HLA-DRB1, multiple genes Silica dust, solvents DNA has been found to correlate with disease activity (124).…”

“…The gH/gL interaction with integrins is mediated by a KGD motif on gH, and the interaction between gH/gL and EphA2 occurs through the receptor's ligand binding and fibronectin type III repeats and is mediated by the gP42 binding site on gH. Upon attachment and interaction with integrins or EphA2, a conformational change in gH/gL allows interaction with the trimeric gB, which in turn changes conformation and facilitates viral entry by acting as a fusogen (20,(28)(29)(30)(31)(32).…”

Association between variant alleles of major histocompatibility complex class II regulatory genes and nasopharyngeal carcinoma susceptibility

“…Recently, researchers have subscribed to the belief that class II MHC-restricted CD4+ T cell is also the most widely distributed contributory factor in effective anti-infection and antitumor immunity ( Lam et al , 2018 ). MHC class II molecule, an essential role for antigen presentation, has emerged as powerful immunoregulatory function in immune reaction and its deficiency may therefore engender autoimmune diseases, infectious diseases, and cancer ( Marty Pyke et al , 2018 ; Trier et al , 2018 ; Gameiro et al , 2019 ).…”

EBNA1 IgM-Based Discrimination Between Rheumatoid Arthritis Patients, Systemic Lupus Erythematosus Patients and Healthy Controls

“…RA is most prevalent in women and is caused by a combination of genetic and environmental factors [5,8]. Among multiple genetic factors, especially major histocompability complex (MHC) II alleles with specific amino acid motifs, collectively called the shared epitope (SE), strongly predispose to the disease, and especially in ACPA-positive individuals [8,9,10]. Among the environmental factors, vitamin D, smoking, obesity in adolescence and EBV infection are most influential.…”