Contribution to Pathogenesis and Progression and Modulation by Natural Products. Department of Physics and Chemistry, School of Pharmaceutical Sciences of Ribeir. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Rheumatoid arthritis (RA) is a highly disabling disease that affects all structures of the joint and significantly impacts on morbidity and mortality in RA patients. RA is characterized by persistent inflammation of the synovial membrane lining the joint associated with infiltration of immune cells. Eighty to 9. 0% of the leukocytes infiltrating the synovia are neutrophils. The specific role that neutrophils play in the onset of RA is not clear, but recent studies have evidenced that they have an important participation in joint damage and disease progression through the release of proteolytic enzymes, reactive oxygen species (ROS), cytokines, and neutrophil extracellular traps, in particular during frustrated phagocytosis of immune complexes (ICs). ![]()
![]() ![]() ![]() ![]() ![]() Evidence-Based Complementary and Alternative Medicine Volume 2015 (2015), Article ID 429878, 22 pages http://dx.doi.org/10.1155/2015/429878. PubMed comprises more than 27 million citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links. ![]() In addition, the local and systemic activation of the complement system contributes to the pathogenesis of RA and other IC- mediated diseases. This review discusses (i) the participation of Fc. Introduction. Rheumatoid arthritis (RA) occurs in 0. Twenty to 3. 0% of the untreated RA patients become unable to work within three years of diagnosis . RA is a chronic inflammatory polyarthritis disease that affects multiple joints, and some types of RA also affect multiple organ systems. RA is characterized by synovial hyperplasia, swelling, pain, and neutrophil- rich infiltrates and can lead to bone erosion, cartilage destruction, and complete loss of joint integrity over time. This condition is classified as an autoimmune disorder because it involves the formation of antibodies against self- antigens causing immune complex (IC) deposits in synovial tissue of patients with RA . Studies have confirmed the key role of the major histocompatibility complex genes and identified other loci that warrant further exploration . The prevalence of RA in various populations has been associated with increased urbanization and other factors like cigarette smoking . Smokers usually exhibit augmented concentrations of rheumatoid factors and anti- cyclic citrullinated peptide (anti- CCP) antibodies, as well as disturbances of immune functions and redox balance . Autoantibodies are one immunologic factor that significantly participates in the etiology of RA. The rheumatoid factors—which are autoantibodies directed to the Fc fraction of immunoglobulin G (Ig. G)—and anti- CCP antibodies can be detected in the preclinical phase of the disease. The levels of these antibodies tend to increase as a function of the age at diagnosis of RA . Around 1. 0–5. 0% of RA patients have anti- collagen II antibodies, and some patients with very severe arthritis have anti- glucose- 6- phosphoisomerase antibodies . The DAS- 2. 8 score correlates with the extent of disease activity as follows: < 2. Other laboratory tests used to diagnose RA and follow disease progression include total and differential blood cell count, evaluation of renal and hepatic function, urinalysis, and measurement of plasma levels of complement, antinuclear antibody, anti- CCP antibody, and immunoglobulins . CD4+ T cells, B cells, macrophages, and neutrophils are present in synovial infiltrate, and these cells sometimes organize into discrete lymphoid aggregates with germinal centers . During the active phases of RA, 8. SF) are neutrophils; the neutrophil turnover can exceed 1. L joint effusion . Neutrophil production in the bone marrow is augmented in RA patients, and both mature and immature neutrophils are mobilized . The neutrophil- lymphocyte ratio and platelet- lymphocyte ratio are markers of systemic inflammation that correlate with DAS- 2. RA . The complex cross talk between neutrophils and immune cells is essential to drive and control the course of inflammatory and autoimmune diseases . Many researchers have recently reviewed the novel immunomodulatory functions of neutrophils . The oxidant status of neutrophils usually correlates with DAS- 2. RA . Deposition of ICs and complement proteins onto the joint surface impairs the complete phagosome closure, resulting in frustrated phagocytosis. Neutrophils then release high amounts of oxidant and cytotoxic agents into the microenvironment of the semiclosed phagosome, that is, the joint surface and SF. Massive neutrophil infiltration and activation can overwhelm the local antiprotease and antioxidant protective mechanisms and damage the surrounding tissues of patients with RA . This paper also discusses the future perspectives in the treatment of RA patients with plant extracts, dietary compounds, and isolated natural compounds to minimize the harmful effects of the overactivation of neutrophils and the complement system. Some types of receptors are not constitutive, but their expression can be induced by molecules of the inflammatory environment (see . Both soluble ICs and insoluble ICs deposited along the synovial membrane lining are recognized by cytokine- primed neutrophils in the inflammatory microenvironment. Therefore, the interaction among ICs, proteins of the complement system, and Fc. This scenario is depicted in Figure 1. Figure 1: Interaction among neutrophils, immune complexes, and the complement system in mediating joint damage in rheumatoid arthritis. Both soluble and deposited ICs activate the complement system (. The recruited neutrophils recognize Ig. G and some complement fragments contained in the ICs via their Fc. This process is termed “frustrated phagocytosis.” The cytotoxic products can overwhelm the local antiprotease and antioxidant protective mechanisms and degrade components of articular cartilage. CR1/CR3, complement receptors types 1 and 3; IC, immune complex; Ig. G, immunoglobulin G; MPO, myeloperoxidase; ROS, reactive oxygen species. This illustration was adapted from the review article published by Wright et al . The role that these components of the immune system play in animal models of arthritis has been reviewed elsewhere . ICs present in the SF, in the superficial layers of the cartilage, and circulating in the periphery interact primarily with Fc. The levels of circulating ICs correlate positively with DAS- 2. RA patients . Priming neutrophils with cytokines regulates their functional responses to these ICs. Soluble ICs that exist in the SF elicit a rapid, intense, and transient ROS generation in GM- CSF- primed neutrophils, but not in unprimed neutrophils. Resting neutrophils are efficiently stimulated in vitro by large immunoglobulin aggregates and insoluble ICs . Neutrophil activation via Fc. Human neutrophils constitutively express the low- affinity Fc. Activation of human neutrophils by ICs requires synergistic ligation of both activating receptors . Peripheral blood neutrophils from RA patients with active disease express elevated levels of Fc. This receptor is constantly shed from the surface of activated neutrophils by metalloproteases and replaced by new receptors stored in intracellular granules . Binding of soluble ICs to Fc. In a murine model of antibody- mediated arthritis, only neutrophils that expressed the activating Fc. Polymorphisms in the activating Fc. RA patients’ SF neutrophils that express Fc. Defective Fc. The Complement System. The complement system is an essential component of the innate immune system that participates in microbial killing, clearance of apoptotic cells and ICs, recruitment of inflammatory cells, and regulation of immune responses and inflammatory processes . In addition, the complement system constitutes a network connected to other systems such as the kallikrein- kinin system and the blood coagulation system . The classical pathway is activated when C1q recognizes the Fc portion of ICs and clustered Ig. G and/or Ig. M antibodies bound to their targets. The alternative pathway is initiated by cleavage of the unstable complement factor C3—that can occur spontaneously or after its interaction with pathogen’s cell surfaces—and subsequent deposition of C3b on microbial cell surfaces . Under certain circumstances, the alternative pathway seems to be activated by properdin and ICs composed of Ig. G and Ig. A . The lectin pathway is triggered by the binding of microbial polysaccharides to circulating lectins, such as plasma mannan- binding lectins or ficolins, structurally similar to C1q. The alternative and lectin pathways are activated in the absence of antibodies . These pathways of complement activation lead to cleavage of the complement proteins C2, C3, C4, and C5 as well as to production of the anaphylatoxins C3a and C5a and the opsonins C3b, C3d, and i. C3b. They also culminate in the assembly of the complement components C5b, C6, C7, and C8 and multiple copies of C9 to form the C5b- 9(n) complex called “terminal complement complex” or “membrane attack complex” (MAC). When assembly occurs on a target cell membrane, MAC inserts into and through the bilayer to create a pore and induce cell lysis . The complement system participates in the pathogenesis of human IC- mediated diseases, such as systemic lupus erythematosus (SLE), vasculitis, glomerulonephritis, and RA (see . In RA, the complement system is activated by circulating and deposited ICs, rheumatoid factors, anti- CCP antibodies, Ig. G molecules with altered glycosylation patterns, C- reactive protein, and surface molecules exposed after cartilage damage . The rheumatoid synovia of patients with RA and osteoarthritis usually exhibits reduced levels of complement proteins C3, C4, and factor B, associated with increased levels of complement metabolites and the soluble form of MAC (s. MAC or s. C5b- 9(n)) . Synovial complement activation positively correlates with the intensity of joint inflammation and disease activity in patients with RA . Welcome. Abstract. Inflammasomes are high- molecular- weight cytosolic complexes that mediate the activation of caspases. There are many inflammasomes, and each is influenced by a unique pattern- recognition receptor response. Two signals are typically involved in the inflammasome pathways. Signal one involves recognition of pathogen- associated molecular patterns (PAMPs), such as LPS or other colonizing/invading microbes, that interact with TLRs, which induce the downstream production of pro–IL- 1. This is followed by signal two, which involves recognition of PAMPs or damage- associated molecular patterns (DAMPs), such as uric acid or ATP, via NLRP3, which leads to caspase- 1–dependent cleavage of pro–IL- 1. Ultimately, these two signals cause the release of multiple proinflammatory cytokines. Both PAMPs and DAMPs can be liberated by early insults to the allograft, including ischemia/reperfusion injury, infections, and rejection. The consequence of inflammasome activation and IL- 1 expression is the upregulation of adhesion molecules and chemokines, which leads to allograft neutrophil sequestration, mononuclear phagocyte recruitment, and T cell activation, all of which are key steps in the continuum from allograft insult to chronic allograft dysfunction. Authors. S. Samuel Weigt, Vyacheslav Palchevskiy, John A.
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