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.
Highlights
human leukocyte antigen (HLA)-DR was originally shown to interact with gp42 in an expression library screen for proteins binding to a soluble gp42Fc construct [127]
Subsequent studies demonstrated that the interaction between gp42 and HLA-DR is crucial for Epstein-Barr virus (EBV) infection in B-cells, since monoclonal antibodies to gp42 as well as HLA-DR inhibited B-cell infection in vitro [128]
The crystal structure of the gp42: HLA-DR1 complex reveals that E46 of HLA is directly in contact with R220 and Y107 of gp42 through a salt bridge and a hydrogen bond, respectively, whereas R72 interacts with T104 and Y107 of gp42 through hydrogen bonding [106]
Summary
Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease of unknown etiology. 70–80% of RA individuals are ACPA positive, and as with RF, these antibodies are present early in the course of the disease and precede clinical onset [12,13,14,15]. Through the identification and characterization of ACPAs, and by novel insights into RA-diagnosis and etiopathology, it has become clear that RA is of heterogeneous nature, consisting of clinical subsets of ACPA-positive and ACPA-negative RA. These subsets share many clinical features, but differ with respect to genetic background, predisposing environmental factors and clinical progression/remission [14,24,25,26]. Individuals with ACPA-positive RA typically have severe symptoms and disease course, whereas individuals with ACPA-negative RA often experience a mild disease course [24,27,28,29]
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