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.
Highlights
Rheumatoid arthritis (RA) is an autoimmune disease of complex etiopathogenic origin and traditionally characterized by chronic synovitis and articular erosions
Citrullination of Aβ1–40 resulted in an increased fraction of soluble amyloid oligomers, and citrullination of Aβ1–42 caused in an increased fraction of β-sheet rich oligomers.[137]. These findings suggest that citrullination causes structural changes bearing implication for the aggregative nature of amyloid proteins and providing some compelling additional research questions
Human synovial fibroblasts express intercellular adhesion molecule-1 (ICAM-1) and inflammatory chemokines under the influence of fibrinogen.[180]. These findings indicate that fibrin(ogen), which is present in high amounts within RA articular spaces, may fulfil a pronounced role in mediating various RA-related inflammatory processes
Summary
Together with the immunopathogenic profile in RA, there is evidence for increased cardiovascular disease (CVD) risk in these patients.[29,30,31] Conventional risk factors (age, sex, obesity, hypertension, and hypercholesterolemia) do not fully account for premature development of CVD in RA, indicating a prominent role for chronic systemic inflammation in alterations of hemostatic and thrombotic function.[32]. Neutrophils express multiple cell surface receptors, and NETosis is induced by proinflammatory mediators such as bacterial LPS,[202] platelet TLR-4,203 and cytokines such as TNFα, IL-1β, and IL-8.204 Enhanced NETosis is associated with local and peripheral presence of ACPAs, with NETs prominent sources of citrullinated autoantigens that express high levels of PAD2 and PAD4 enzymes.[205] NETs along with their individual components (DNA and histones) have been shown to possess significant prothrombotic and antifibrinolytic properties, and have been discussed at length in a recent review by Varjú and Kolev.[206] NETs provide a platform for the accumulation of integral hemostatic components such as platelets, erythrocytes, von Willebrand factor, and fibrinogen.[207] Histones promote fibrin deposition through its ability to bind to and inactivate antithrombin.[208] This protective mechanism against the inhibitory effects of antithrombin is achieved by the citrullination of antithrombin by PAD4.209 Integration of DNA–histone complexes into fibrin networks results in thicker fibrin fibers that improve clot stability and rigidity but decreases clot permeability.[208,210] The presence of these NET-derived complexes within the fibrin network impedes fibrinolysis, through the ability of both histones and DNA to bind large fibrin degradation products (such as plasminogen) and inhibit its activity.[208,210]
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