The Central Role of Acute Phase Proteins in Rheumatoid Arthritis: Involvement in Disease Autoimmunity, Inflammatory Responses, and the Heightened Risk of Cardiovascular Disease

Abstract

Rheumatoid arthritis (RA) is an autoimmune disease of complex etiopathogenic origin and traditionally characterized by chronic synovitis and articular erosions. Furthermore, there is strong evidence that infectious agents, including those that become dormant within the host, play a major role in much of the etiology of RA and its hallmark of inflammation. A combination of genetic predisposition, environmental exposure, and presence of infectious agents may therefore lead to a loss of immune tolerance to citrullinated proteins, which present as self-antigens to the human immune system. This results in generation of highly RA-specific autoantibodies, known as anti-citrullinated protein antibodies (ACPAs). Protein citrullination occurs via posttranslational deamination of arginine residues by peptidylarginine deiminase enzymes, which have confirmed sources of both endogenous and infectious origins. A recognized plasma protein target of citrullination and RA autoantibody generation is fibrin and its soluble precursor fibrinogen, both key components of hemostasis and acute phase reaction. Increased titers of ACPAs that accompany rapid progression to clinical RA disease have been shown to drive a variety of proinflammatory processes, and therefore results in aberrant fibrin clot formation and increased cardiovascular risk. However, the full extent to which hemostasis is affected in RA remains controversial, owing to the differential impact that citrullinated fibrin(ogen) and concurrent systemic inflammation may have on resulting hemostatic outcome. This review highlights key events in initiation of autoimmune-driven inflammatory events, including the role of bacterial infectious agents, which subsequently result in clinical RA disease and associated secondary cardiovascular disease risk, with specific focus on plasma proteins that are heavily involved throughout the immunopathological progression process.

2022 Eberhard F. Mammen Award Announcements: Part I—Most Popular Articles

“…Table 3 lists the top 25 downloaded “free to download” articles from STH (2020 and 2021 inclusive), as eligible for the “Open Access” award. 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 Table 4 lists the top 25 downloaded non-open access articles from STH (2020 and 2021 inclusive), as otherwise eligible for the “General category” award. 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51…”

LC-MS/MS-based serum proteomics reveals a distinctive signature in a rheumatoid arthritis mouse model after treatment with mesenchymal stem cells

“…In RA clinical patients, concentrations of several acute-phase proteins can provide useful diagnostic information. The most frequently used acute-phase proteins as RA biomarkers are erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), serum amyloid A protein (SAA), alpha-1-acid glycoprotein (AGP or ORM), haptoglobin (HP), and alpha-1-antitrypsin (AAT) [42,43]. These expression levels are usually correlated with clinical assessment of disease severity.…”

The Key Comorbidities in Patients with Rheumatoid Arthritis: A Narrative Review

“…Autoimmune mechanisms that drive RA progression have also been linked to abnormal fibrin clot formation and increased CVD risk. However, the extent to which haemostasis is affected in RA remains unclear (reviewed in detail by Bezuidenhout et al [52]). Targeted CVD risk management is an important part of the overall clinical management of patients with inflammatory joint disorders, including RA [53].…”

“…RA can be exacerbated by cytomegalovirus infection and is linked to coronary artery damage via cytotoxic T-cells [51]. The autoimmune mechanisms that drive RA have been linked to abnormal fibrin clot formation and increased CVD risk; however, the extent to which this is affected in RA remains unclear [52]. Grey bar indicates nonlocalised effects.…”