RA is a chronic autoimmune disease characterized by the activation of the immune system and secretion of autoantibodies. It is characterized by joint inflammation, leading to cartilage and bone damage, which may lead to disability if not treated in time. In most patients, rheumatoid arthritis is a chronic, lifelong disease, and the goal of treatment is to achieve and maintain low disease activity, or ideal remission (i.e. no disease activity).
Many reports have reported the glycosylation of immunoglobulin G (IgG) related to RA. In its Fc region, IgG has an N-linked polysaccharide, which is mainly double-antenna and exists on asparagine 297 (Asn 297) in each heavy chain. It is reported that the change of N-linked Fc glycan on Asn 297 will affect the structural stability and functional activity of IgG, and then affect the immune response. Abnormal N-glycosylation of IgG has been observed in diseases driven by autoantibodies, especially in RA, and the pathogenicity of autoantibodies is mainly affected by their glycosylation characteristics. The abnormal structure of oligosaccharide with a single sialic acid molecule transforms inflammatory IgG into an anti-inflammatory mediator, and the abnormal structure of the FC part of IgG with a core fucose residue reduces the cytotoxicity (ADCC) of antibody-dependent cells by blocking its binding with FcγRIIIα receptor. Therefore, it is of great significance to determine whether IgG glycosylation is related to clinical outcomes for understanding the pathogenesis of autoimmune diseases (such as RA).
Fig.1 Pro-inflammatory and osteoclastogenic roles of autoantibodies in rheumatoid arthritis. (Bugatti, et al., 2018)
It is the most famous autoantibody in RA. Rheumatoid factor (RF) is defined as a kind of immunoglobulin (Ig-s) against the FC region of IgG. Different RF isoforms can be detected, among which IgM is the most common. The detection of RF is traditionally used in clinical settings to distinguish RA from other diseases with similar symptoms. Although various RF titers and isoforms can be seen in a wide range of different diseases, high titers of IgM and IgA are considered high indicators of RA.
Although RF has been known for decades, its role in the pathogenesis of RA is still unclear. However, RF may exert its pathogenic characteristics through the formation of immune complexes. In healthy conditions, RF can form a complex with IgG bound to the antigen to promote an immune response. However, in RA, RF showed signs of affinity maturity, which was not observed in healthy individuals. The high drop and high-affinity RF found in the synovial fluid of RA patients may lead to derailment-promoting function, thus making inflammation persist. RF immune complex is thought to promote inflammation by stimulating the production of pro-inflammatory cytokines, such as tumor necrosis factor (TNF) α.
ACPAhas been the focus of autoantibody research because of its high specificity for RA. These autoantibodies target citrulline residues on protein or peptides. Citrullination (or deiminase) is an irreversible post-translational modification of arginine, which is mediated by an enzyme called peptide arginine deiminase (PAD).
ACPA usually occurs simultaneously with RF and exists in about 50%-60% of patients with early RA and 60%-90% of patients with diagnosed diseases. Only 1%-3% of healthy people are positive for ACPA, and most of them are at a low level. The specificity of RF(ACPA to RA is significantly higher than that of RF (95% for ACPA and 85% for RF), which makes them important biomarkers of RA. On the one hand, ACPA can be observed in asymptomatic individuals for many years, which does not necessarily lead to RA development. On the other hand, in individuals suffering from musculoskeletal symptoms including arthralgia (arthralgia), the existence of ACPA indicates the development of RA: more than 60% of positive predictive values were observed in individuals clinically suspected of recent onset of arthralgia. In addition, ACPA is a marker of positive RA in serum, which is related to higher disease severity, radiological joint injuries, and the occurrence of extra-joint manifestations (such as cardiovascular and pulmonary involvement). Interestingly, even in the absence of RA, ACPA has been shown to be associated with cardiovascular mortality.
Glycosylation malfunction is closely related to rheumatoid arthritis. CD BioGlyco provides comprehensive glycosylation-related services, including but are not limited to Characterization of Glycosylation in Fc-Fusion Protein Drugs, Characterization of Glycosylation in Protein Drugs, and Characterization of Glycosylation in Antibody Drugs. If you are interested in our services, please contact us for more details without any hesitation.
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