View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Crossref Hindawi Publishing Corporation Evidence-Based Complementary and Alternative Medicine Volume 2015, Article ID 429878, 22 pages http://dx.doi.org/10.1155/2015/429878 Review Article Fc and Complement Receptors and Complement Proteins in Neutrophil Activation in Rheumatoid Arthritis: Contribution to Pathogenesis and Progression and Modulation by Natural Products Adriana Balbina Paoliello-Paschoalato,1,2 Larissa Fávaro Marchi,1 Micássio Fernandes de Andrade,1,3 Luciana Mariko Kabeya,1 Eduardo Antônio Donadi,2 and Yara Maria Lucisano-Valim1 1 Department of Physics and Chemistry, School of Pharmaceutical Sciences of Ribeirao˜ Preto, University of Sao˜ Paulo, Avenida Cafe´ s/n, 14040-903 Ribeirao˜ Preto, SP, Brazil 2Department of Internal Medicine, Ribeirao˜ Preto Medical School, University of Sao˜ Paulo, Avenida Bandeirantes 3900, 14049-900 Ribeirao˜ Preto, SP, Brazil 3Department of Biochemistry and Immunology, Ribeirao˜ Preto Medical School, University of Sao˜ Paulo, Avenida Bandeirantes 3900, 14049-900 Ribeirao˜ Preto, SP, Brazil Correspondence should be addressed to Adriana Balbina Paoliello-Paschoalato; [email protected] Received 1 April 2015; Revised 30 June 2015; Accepted 5 July 2015 Academic Editor: Kamal D. Moudgil Copyright © 2015 Adriana Balbina Paoliello-Paschoalato et al. 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 90% 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). 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 and complement receptors in mediating the effector functions of neutrophils in RA; (ii) the contribution of the complement system and ROS-dependent and ROS-independent mechanisms to joint damage in RA; and (iii) the use of plant extracts, dietary compounds, and isolated natural compounds in the treatment of RA, focusing on modulation of the effector functions of neutrophils and the complement system activity and/or activation. 1. Introduction RA is characterized by synovial hyperplasia, swelling, pain, and neutrophil-rich infiltrates and can lead to bone erosion, Rheumatoid arthritis (RA) occurs in 0.5–1.0% of the adult cartilage destruction, and complete loss of joint integrity over population worldwide and accounts for around 250,000 time. This condition is classified as an autoimmune disorder hospitalizations and 9 million doctor visits per year [1]. because it involves the formation of antibodies against self- Twenty to 30% of the untreated RA patients become unable antigens causing immune complex (IC) deposits in synovial to work within three years of diagnosis [2]. RA is a chronic tissue of patients with RA [3, 4]. inflammatory polyarthritis disease that affects multiple joints, RA is a multifactorial disease in which genetic, envi- and some types of RA also affect multiple organ systems. ronmental, and immunologic factors contribute to disease 2 Evidence-Based Complementary and Alternative Medicine outcome and progression [5]. Studies have confirmed the researchers have recently reviewed the novel immunomod- key role of the major histocompatibility complex genes and ulatory functions of neutrophils [19–21]. identified other loci that warrant further exploration [6]. The Neutrophils are important players in promoting systemic prevalence of RA in various populations has been associated andlocal(inthesynovia)oxidativestressinpatientswithRA with increased urbanization and other factors like cigarette [22–24]. The oxidant status of neutrophils usually correlates smoking [6–8]. Smokers usually exhibit augmented concen- with DAS-28 scores and the level of oxidative stress markers trations of rheumatoid factors and anti-cyclic citrullinated andtissuedamageinpatientswithRA[25, 26]. Deposition of peptide (anti-CCP) antibodies, as well as disturbances of ICs and complement proteins onto the joint surface impairs immune functions and redox balance [5]. Autoantibodies the complete phagosome closure, resulting in frustrated are one immunologic factor that significantly participates phagocytosis. Neutrophils then release high amounts of in the etiology of RA. The rheumatoid factors—which are oxidant and cytotoxic agents into the microenvironment of autoantibodies directed to the Fc fraction of immunoglobulin thesemiclosedphagosome,thatis,thejointsurfaceandSF. G (IgG)—and anti-CCP antibodies can be detected in the Massive neutrophil infiltration and activation can overwhelm preclinicalphaseofthedisease.Thelevelsoftheseantibodies the local antiprotease and antioxidant protective mechanisms tend to increase as a function of the age at diagnosis of RA and damage the surrounding tissues of patients with RA [9]. Around 10–50% of RA patients have anti-collagen II [19, 22–24, 27, 28]. antibodies, and some patients with very severe arthritis have Given the importance of ICs deposited in the RA patients’ anti-glucose-6-phosphoisomerase antibodies [10]. synovia to elicit the effector functions of neutrophils via The disease progression and the therapeutic efficacy of Fc and complement receptors (FcR and CR, resp.), the RA treatment can be monitored using the disease activity present paper aims to discuss the participation of these score of 28 joints (DAS-28), which is calculated from (i) the receptors and complement proteins in the production of number of painful joints (hands, arms, and knees); (ii) the ROS and release of granule components by neutrophils in number of swollen joints (hands, arms, and knees); (iii) the the inflamed synovia and in peripheral blood. This paper visual analogue scale of patients’ assessment of their general also discusses the future perspectives in the treatment of RA health; (iv) the erythrocyte sedimentation rate in the first patients with plant extracts, dietary compounds, and isolated hour and/or the blood level of C-reactive protein to measure natural compounds to minimize the harmful effects of the the degree of inflammation. The DAS-28 score correlates overactivation of neutrophils and the complement system. with the extent of disease activity as follows: <2.6: disease remission; >2.6 and <3.2: low disease activity; >3.2 and <5.1: moderate disease activity; >5.1: high disease activity [11]. 2. Fc Rs and CRs and the Complement System Other laboratory tests used to diagnose RA and follow disease in Neutrophil Activation: Contribution to progression include total and differential blood cell count, Pathogenesis and Progression of RA evaluation of renal and hepatic function, urinalysis, and measurement of plasma levels of complement, antinuclear Neutrophils express many types of cell surface recep- antibody, anti-CCP antibody, and immunoglobulins [12]. tors, including Fc R, CR, G-protein-coupled chemokine The pathogenesis of RA remains unclear but it is known and chemoattractant receptors, adhesion receptors, Toll-like that the cellular and humoral components of the immune receptors, and C-type lectins. Some types of receptors are not system are activated and they coordinately contribute to constitutive, but their expression can be induced by molecules + disease pathology (see [13] for review). CD4 Tcells,B of the inflammatory environment (see [29]forreview). cells, macrophages, and neutrophils are present in synovial In the inflamed synovia, the neutrophil surface Fc Rs and infiltrate, and these cells sometimes organize into discrete CRs cooperate to recognize ICs opsonized with complement lymphoid aggregates with germinal centers [4]. During system proteins and further activate the cellular effector theactivephasesofRA,80to90%oftheimmunecells functions.BothsolubleICsandinsolubleICsdepositedalong infiltrating the synovial fluid (SF) are neutrophils; the neu- the synovial membrane lining are recognized by cytokine- 9 trophil turnover can exceed 10 cells per day in a 30 mL primed neutrophils in the inflammatory microenvironment. Therefore, the interaction among ICs, proteins of the com- joint effusion13 [ –15]. Neutrophil production in the bone marrow is augmented in RA patients, and both mature and plement system, and Fc Rs and CRs to activate the oxygen- immature neutrophils are mobilized [16, 17]. The neutrophil- dependent and oxygen-independent functional responses of lymphocyte ratio and platelet-lymphocyte ratio are markers neutrophils markedly contributes to the pathogenesis and of systemic inflammation that correlate with DAS-28 scores progression of RA [13, 21, 30, 31]. This scenario is depicted in patients with RA [18]. in Figure 1. This paper will mainly discuss how the complement