Peer Review Studies on Asea and if It Works
Clin Exp Immunol. 2008 Jun; 152(3): 415–422.
Redox signalling and the inflammatory response in rheumatoid arthritis
L I Filippin
*Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil
R Vercelino
*Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil
Northward P Marroni
†Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil
R Chiliad Xavier
*Universidade Federal exercise Rio Grande do Sul, Porto Alegre, Brazil
†Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil
Abstract
Reactive oxygen species (ROS) are produced mainly during oxidative phosphorylation and by activated phagocytic cells during oxidative burst. The excessive production of ROS can damage lipids, poly peptide, membrane and nucleic acids. They also serve equally important intracellular signalling that enhances the inflammatory response. Many studies have demonstrated a role of ROS in the pathogenesis of inflammatory chronic arthropathies, such as rheumatoid arthritis. It is known that ROS can function equally a second messenger to actuate nuclear factor kappa-B, which orchestrates the expression of a spectrum of genes involved in the inflammatory response. Therefore, an agreement of the complex interactions between these pathways might be useful for the development of novel therapeutic strategies for rheumatoid arthritis.
Keywords: anti-oxidant enzyme, inflammation, oxidative stress, rheumatoid arthritis, ROS
Introduction
Reactive oxygen species (ROS) are produced in cells by several physiological and environmental stimulations, such as infections, ultraviolet radiation and pollutants, known collectively as oxidants. Interestingly, ROS have also been considered equally take chances and enhancer factors for autoimmune diseases [1], every bit in that location is a significant relation between the oxidative stress and such diseases [two].
Rheumatoid arthritis (RA) is an inflammatory systemic and autoimmune disease, characterized past chronic, symmetric and erosive synovitis, mainly of peripheral joints. Most patients present rheumatoid factors, which are autoantibodies directed to the Fc fraction of immunoglobulin Thousand, and antibodies reactive with citrullinated peptides [3,four]. RA has a prevalence of approximately 1% in the earth population [5].
Rheumatoid arthritis aetiology is basically unknown, simply several studies have implicated a combination of a genetic background and environmental triggers, such as infections and smoking, leading to defects in immunoregulation and a host of inflammatory mechanisms involved in joint tissue damage, including a function for oxidative stress [6].
The definition of oxidative stress equally 'a disturbance in the prooxidant-anti-oxidant remainder in favour of the sometime'[7] implies that disturbance because of pro-oxidant atmospheric condition can exist corrected by the improver of advisable anti-oxidants. Even so, redox mechanisms accept been shown to influence intracellular signalling, and cells seem to exist very sensitive to the loss of these regulatory and control systems. These two concepts take been incorporated recently into a new definition of oxidative stress every bit 'an imbalance between oxidants and anti-oxidants in favour of the oxidants, leading to a disruption of redox signalling and control and/or molecular impairment'[viii–ten].
In this review we explore the role of oxidative stress, ROS and redox signalling in the physiopathology of RA.
Generation of ROS
Reactive oxygen species are produced during normal aerobic cell metabolism, have important physiological roles in maintaining prison cell redox status and are required for normal cellular functions, including cell proliferation, aggregation, chemotaxis and apoptosis, equally well equally regulation of intracellular signalling pathways and the action of transcription factors, such as nuclear cistron (NF)-κB, activator protein 1 and hypoxia-inducible factor-1α. ROS produced by phagocytes are critical for the protection confronting invading microorganisms and also seem to take important physiological roles in priming the allowed organisation [xi–13]. The functioning of T lymphocytes is influenced markedly past alterations in the intracellular redox balance. Exposure to ROS has been demonstrated to down-regulate the activity of T lymphocytes; ROS produced past phagocytes also seem to have essential physiological roles in priming the immune organisation every bit second messengers [9]. Hitchon and El-Gabalawy propose that the physiological production of ROS by phagocytes in response to antigen affects T cell–antigen interactions and possibly induces apoptosis of autoreactive arthritogenic T cells, thereby preventing autoimmune responses [xiv].
Phagocytic cells, such as macrophages and neutrophils, are known to be activated under oxidative conditions. This activation is mediated by the oxidase nicotinamide adenine dinucleotide phosphate (NADPH) arrangement and results in a noticeable increase in oxygen consumption and consequent superoxide anion production O2 •−) [fifteen]. The activation of oxidase NADPH may be induced by lipopolysaccharides, lipoproteins and cytokines, such equally interferon (IFN)-γ, interleukin (IL)-1β and tumour necrosis gene (TNF)-α[14–16] (meet Fig. i).
Germination of active oxygen and nitrogen species (upper left corner), targets of these reactive species (lower left corner), relation of reactive oxygen species (ROS) with the activation of NF-κB and transcription of pro-inflammatory cytokines (correct). O2 •−, superoxide anion radical; H2Oii, hydrogen peroxide; HO•, hydroxyl radical; SOD, superoxide dismutase endogenous enzyme; Cat, catalase endogenous enzyme; GPx, glutathione endogenous enzyme; L-arginine, precursory enzyme of nitric oxide; NO, nitric oxide; NOS, nitric oxide synthase; ONOO-, peroxynitrite; -SH, sulphydryl group; GSSH/GHS, oxidized/reduced glutathione ratio; IKK, inhibitor kappa kinase; IκBα, inhibitor kappa B; P, phosphorylation; cPLA2, cytosolic phospholipase A2; COX2, cyclooxyganase two; iNOS, inducible nitric oxide synthase; LPS, lipopolysaccharides; TNF-α, neoplasm necrosis factor alpha; IL-1β, interleukin 1 beta.
In the presence of iron ions (Iron2+) or other transition metals O2 •−and hydrogen peroxide (H2Oii) are converted, via the Fenton reaction, to highly reactive, aqueous soluble hydroxyl radicals (HO•), that are probably responsible for much of the cell toxicity associated with ROS [11]. Every bit soon equally HO• is formed it will react rapidly with the closest molecules, which may be lipids, proteins or DNA bases. It happens because the constant rate of hydroxyl radical reaction is very high if compared with the other reactive species (chiliad > 109 M−1 due south−ane) [11].
Besides ROS, reactive nitrogen species (RNS), such equally the peroxynitrite radical ONOO- generated by the reaction betwixt O2 •− and nitric oxide (NO), tin can likewise cause oxidative damage [17]. NO is a very reactive inorganic costless radical, with a half-life shorter than 10 southward because of its rapid oxidation to nitrites [xviii]. Information technology is produced past the deaimination of L-arginine past NO synthase in the presence of NADPH and O2, producing L-citrulline and NO [17]. The addition of ONOO– to body cells, tissues and fluids leads to fast protonation, which may result in the depletion of –SH groups and other anti-oxidants, oxidation and nitration of lipids, Dna disruption, nitration and deamination of DNA bases (mainly guanine) [11].
Amid the oxygen and nitrogen radicals, ONOO- can deplete –SH groupings and consequently change the redox balance in the glutathione towards oxidative stress. This unbalanced glutathione redox status induces, by redox regulation [19], the kappa-B inhibitor (IκB) kinase to phosphorylate IκB, enabling translocation of the transcription factor NF-κB to the nucleus, leading to the transcription of several inflammatory mediators (see Fig. one).
More recently ROS take been believed to office as 2nd messengers. Typically, second messengers are molecules generated at the time of activation of a receptor, are short-lived and act specifically on effectors to modify their activity transiently. Indeed, ROS and RNS tin exist generated at the time of receptor activation and are short-lived, equally are other second messengers, just the specificity of their action has been more difficult to assess, except for that of NO, which binds specifically to the haem of the regulatory domain of soluble guanylate cyclase, resulting in its activation [8,twenty].
Oxidant defence mechanisms
Despite of import physiological roles, an unbalanced redox condition presents potentially destructive effects on cellular biology. For this reason, several enzymatic and non-enzymatic anti-oxidant mechanisms are involved in the protection of cells and organisms in case of eventual impairment acquired by excessive amounts of such highly reactive mediators [17,21].
Superoxide is converted to HtwoO2either spontaneously or more rapidly when catalysed by the enzyme superoxide dismutase (SOD) [14]. There are three SOD isoforms: manganese-SOD resides in the mitochondria and is inducible by cytokines through the NF-κB pathway and other co-factors; copper–zinc-SOD is constitutive; and extracellular-SOD (EC-SOD or SOD3) [11].
Glutathione peroxidase (GPx) and catalase (Cat) are responsible for HiiO2 degradation [xv]. True cat resides in the peroxisome matrix and therefore it tin degrade only the H2O2 produced in the matrix and non the H2Otwo produced in the peroxisome core. HiiO2 produced in the nucleus is transported to cytoplasm by tubules in the nuclear membrane, where GPx will perform the degradation [22]. The H2O2 GPx besides degrades other peroxides. This is the showtime mitochondrial protection from H2Oii and is regulated by p53 and hypoxia [fourteen].
Anti-oxidant mechanisms also have the participation of non-enzymatic anti-oxidants deriving from the nutrition, which include vitamin E, β-carotene, vitamin C and glutathione; the latter is considered the most of import hydrosoluble not-enzymatic anti-oxidant, as information technology participates in numerous ox-reduction reactions [11,13,21]. Glutathione acts as a co-factor of GPx and other enzymes and is involved in many other metabolic processes, including the metabolism of ascorbate, communication between cells, prevention of oxidation of thiol groups of proteins and radioprotection [eleven].
Oxidative stress evaluation
Currently, the use of oxidative stress biomarkers can help to explore the relation between oxidative damage to macromolecules (Dna, lipids and proteins) and several diseases. Evaluation, both in vivo and ex vivo, includes measurements of Dna oxidation, lipid peroxidation and protein oxidation [23] (encounter Table i).
Table ane
Biomarkers for oxidative stress status.
| Substrate of damage | Oxidative stress evaluation |
|---|---|
| DNA | eight-hydroxyl-deoxyguanosine (8-OHdG) |
| • The viii-OHdG is the end product of guanine oxidation through hydroxyl radicals [23] | |
| Comet assay | |
| • Very sensitive method for measuring DNA strand breaks in private cells | |
| • Used in environmental toxicology, cancer enquiry, and radiation biology to assess DNA harm | |
| • Damaged Deoxyribonucleic acid migrates during electrophoresis from the nucleus towards the anode, forming a shape of a 'comet' with a head (jail cell nucleus with intact DNA) and a tail (relaxed and broken Deoxyribonucleic acid) | |
| • The proportion of Dna in the tail is indicative of the frequency of breaks [23,24] | |
| 5-Hydroxyluracil (5-OHUra) | |
| • Presumed to form in Deoxyribonucleic acid via deamination and loss of water from the oxidative DNA lesion cytosine glycol | |
| • A modified pyrimidine, 5-OHUra is a substrate for hNTH1, accounting for an before observation of repair of this lesion in human cell extracts [25,26] | |
| Proteins | Protein carbonyls |
| • Conventional analysis: colorimetric procedure that involves dinitrophenylhydrazine | |
| • ELISA method: correlates well with the colorimetric assay for quantifying protein carbonyls in plasma samples [27] | |
| Lipids | Thiobarbituric acid-reactive substances (TBA-RS) |
| • Malondialdehyde (MDA) is a secondary production of lipid peroxidation by enzymatic via | |
| • It is a β-rupture byproduct of polyunsaturated fatty acids, such as linoleic, arachidonic and docosahexaenoic acids | |
| • Based on the reaction of TBA with MDA, i of the aldehyde products of lipid peroxidation | |
| • More than specific technique for MDA quantification is past high performance liquid chromatography (HPLC), where the particles are separated and but MDA is detected [28] | |
| Fii isoprostanes | |
| • Produced by free radical-related peroxidation of arachidonic acid [xvi] | |
| • Formed in phospholipids and are then cleaved and released into the circulation before excretion in the urine every bit free isoprostanes | |
| • Most abundant is eight-isoprostaglandin F 2α (8-iso-PGF2α), which has been suggested to be a promising marking for oxidation injury [29] | |
| Reduced/oxidized glutathione (GSH/GSSH) | |
| • Major anti-oxidant in man tissues that provides reducing equivalents for the glutathione peroxidase catalysed reduction of hydrogen peroxide and lipid hydroperoxides to h2o and the respective alcohol [21] | |
| • During this process GSH becomes oxidized glutathione. The GSSG is then recycled into GSH by gutathione reductase (GR) and NADPH | |
| • Mammalian cells are exposed to increased oxidative stress, the ratio of GSH/GSSG will decrease as a consequence of GSSG accumulation [11] | |
| • Measurement of the GSSG level and decision of the GSH/GSSG ratio are an useful indicators of oxidative stress and can exist used to monitor the effectiveness of anti-oxidant intervention strategies [30] |
Testify of oxidative stress in RA
Rheumatoid arthrities is an inflammatory disease characterized past chronic inflammation of the synovial joints associated with proliferation of synovial cells and infiltration of activated immunoinflammatory cells, including memory T cells, macrophages and plasma cells, leading to progressive devastation of cartilage and bone [14,31]. The perpetuation of this inflammatory process is considered to be mediated by a number of cytokines, such as TNF-α, IL-1β, IL-vi, IL-viii, IL-12, IL-17, IL-eighteen, IL-23 and IFN-γ[32]. Several cytokines, including TNF-α and IL-1β, are known initiators of the NF-κB activation cascade [1] and are under its transcriptional command, constituting a positive feedback loop (see Fig. ane). TNF-α participates positively in the phosphorylation of kinase kappa inhibitor, assuasive NF-κB dimers (p50 and p65 portions) to drift to the nucleus and so bind to promoters of proinflammatory genes [33] and stimulate the oxidase NADPH activation (see Fig. 2). Increased cytokine product driven past NF-κB can heighten expression of vascular adhesion molecules that attract leucocytes into the joint, as well as matrix metalloproteinases that help to degrade the extracellular matrix.
An overview of the signalling T-cells and oxidative stress. See text for details.
Another central characteristic of RA synovitis is the transformation of fibroblast-like synovial cells into autonomously proliferating cells with a tissue-infiltrating nature, forming hyperplastic tissue with potential for bone erosion and cartilage deposition known as pannus. These cells can proliferate in an anchorage-independent manner, lack contact inhibition and express several oncogenes characteristic of cells that have escaped normal growth-regulatory mechanisms [34]. Because NF-κB activation can induce cistron expression of cell growth-promoting factors such as cyclin D1 and c-Myc and physiological inhibitors of apoptosis such equally cIAPs, Bcl-10 and cFLIP, it can also have a role in RA synovial hyperproliferation, indicating that information technology is a crucial determinant to the disease pathogenesis [35].
There is a cracking deal of prove of the important role of oxidative stress in RA physiopathology.
Several groups have demonstrated increased oxidative enzyme activity, forth with decreased anti-oxidant levels in RA sera and synovial fluids (SF). Studies with SF and tissues in RA take demonstrated oxidative impairment of hyaluronic acid [36], lipoperoxidation products [37], oxidation of low-density lipoproteins [38] and carbonyl increment by protein oxidation [39]. Testify of oxidative harm in cartilage, extracellular collagen and DNA has likewise been reported. Peripheral blood lymphocyte Dna from RA patients contains significantly elevated levels of the promutagenic 8-oxohydrodeoxyguanosine [40]. Moreover, the levels of thioredoxine, a cellular reducing goad known to participate in the redox regulation of cellular proteins by reducing the redox-active cysteines through reversible oxidation of the active centre dithiol to disulphide, are higher in SF of RA patients [41]. The product of NO is likewise up-regulated in RA synovial tissue; there are too increased levels of nitrite in the SF, indicating an increased local production [42].
Jikimoto et al. [43] reported a correlation between the disease activity and the presence of oxidative stress in patients with RA. Other studies have plant not-significant correlations [3]. Information technology seems that the strongest correlation is between DNA damage and the oxidative stress index,i.e. the relation between the levels of oxidation and anti-oxidant capacity {OSI = [(TOS, μmol/l)/(TAS, mmol trolox equivalent/fifty]} × 100 [3].
Epidemiological studies have shown that RA occurs in previously healthy subjects who accept low levels of circulating anti-oxidants [44], implying a pathogenic role of increased oxidative stress in the development of RA. Patients with RA accept been reported to accept lower serum levels of a variety of anti-oxidants, including vitamin E, vitamin C, β-carotene, selenium and zinc, in comparison with controls [45], but these associations may be a issue of the affliction or its treatment [46]. In 2 nested case–control studies using serum obtained prior to diagnosis of RA, selenium, α-tocopherol, β-carotene and an overall anti-oxidant index were associated inversely with the later development of RA [47]. In a case–control study assessing dietary intake using a food frequency questionnaire, intake of vitamin C, only not intake of vitamin E, was associated weakly and inversely with RA [48].
Several factors could be involved in the generation of oxidative stress in the joints of RA patients. Intra-articular force per unit area is much higher in RA joints, probably because of decreased compliance of the articulation wall because of synovial membrane swelling and fibrosis of the capsule [49]. Together with the reduced capillary density and elevated tissular metabolic rate, this elevated force per unit area could subtract capillary menses rates and induce a repetitive ischaemia–reperfusion injury in the articulation. In fact, SF pO2levels are frequently below those detected in venous blood [xiv]. Tissue injury could release iron and copper ions, which are catalytic for gratuitous radical reactions. Recently, neutrophils from the SF of RA, but not from other arthritides, were found to exist activated and producing ROS intracellularly in RA, probably as a effect of active processing of endocytosed material [50].
Ecology factors appear to accept a role in the induction, magnitude and rate of progression of the disease, and could as well be involved in the generation of oxidative stress. Recent data implicate smoking strongly every bit an of import environmental risk factor for development of disease in human being leucocyte antigen D-related 4-positive individuals [51]. Smoking is a well-known source of ROS. Tobacco smoke presents several organic compounds, among which are the quinones, source of the semiquinone radical, which can generate Oii - and HtwoO2[52].
Free radicals take also been considered as mediators of tissue damage in RA, in conjunction with proinflammatory cytokines. The role of ROS and, in particular, of O2 - in the degradation of cartilage and bone is not unexpected. Cartilage is the only protein known to exist fragmented past the superoxide anion, and SOD inhibits this degradation strongly. ROS degrade SF and depolymerize hyaluronic acid, which leads to a loss of viscosity in the joint, inactivation of anti-proteinases and consecration of bone resorption [53]. O2 - is produced by osteoclasts during os resorption, and this formation occurs at the osteoclast–bone surface interface [54]. These furnishings are amplified several-fold in the presence of cytokines such equally IL-1β[55]. Experimentally, information technology has been verified that excessive production of ROS may lead to an accelerated damage to articulation cartilage and osteoclast activation [56,57] (meet Fig. ii).
Studies in SF and tissue accept demonstrated oxidative damage in hyaluronic acid, which has been shown to induce T cell hyporesponsiveness in RA through effects on proteins and proteosomal deposition with pregnant decrease of the intracellular reduced glutathione (GSH) levels, has also been correlated with the hyporesponsive state of these cells [58].
Likewise as the well-established damage to the lipid bilayer acquired by free radicals, Dna impairment, which is an of import target to oxidative injuries, has too been investigated. Studies evaluating the Deoxyribonucleic acid harm through the comet test in RA patients accept demonstrated elevated harm levels, which were related to increased oxidative stress and decreased total anti-oxidant capability [iii]. ROS-induced genotoxic events have also been linked to mutations of the tumour suppressor gene p53 observed in RA-derived fibroblast-similar synoviocytes, which could explain, at least in part, the transformed phenotype of these cells and their inadequate apoptosis [34].
In improver to active oxygen species, agile nitrogen species take also been investigated in RA. This link occurs because of the participation of RNS in the activation of NF-κB, as the formation of peroxynitrite interferes in the redox residue of glutathione. Studies indicate that RNS donors caused NF-κB activation and increased activation of proteolytic systems [19,59] (Fig. one). A positive effect of thioredoxin in NF-κB activation has also been suggested [60], as this transcription factor must be in a reduced state to demark to the κB Dna sequence of the target genes. Therefore, it is very likely that ROS are involved importantly in regulation of the NF-κB signalling.
Some observations derived from manipulation of the oxidative stress in creature models have too pointed to a role of ROS in RA pathogenesis. Administration of vitamin E prevented articular destruction in an animal model of RA, but vitamin E did not modify the inflammatory components of the disease (including TNF-α level and arthritis index score) or the oxidation condition of the animals [61].
Superoxide dismutase extracellular (SOD3) exert protective effects in beast models of ischaemia and inflammation [fourteen]. In mice that are genetically deficient in SOD3, both the severity of collagen-induced arthritis (CIA) and the production of proinflammatory cytokines are increased. SOD3 gene transfer via the subcutaneous route or into the articulatio genus decreases the severity of experimental arthritis in rodents [62,63].
Recently, information technology has demonstrated that M40403, a new SOD mimetic (SODm) that removes O2 - catalytically equally effectively as the native enzyme, exerts a benign effect in the type II collagen (CII)-CIA, which suggests the possible use of an SODm as a affliction-modifying therapeutic agent in chronic diseases such as RA [64].
Studies accept shown that the utilize of alpha-lipoic acid (LA) − a co-factor for mitochondrial α-keto dehydrogenase complexes and which participates in S–O transfer reactions − tin attenuate the development of CIA in mice. Lee et al. evaluated clinical, histological and biochemical parameters in mice with arthritis induced by bovine CII [65]. Amelioration of joint disease by LA was associated with reduction in oxidative stress, every bit well as inhibition of inflammatory cytokine activation and NF-κB Deoxyribonucleic acid bounden activity. Moreover, LA inhibited os destruction in vivo and osteoclastogenesis in vitro[65].
Rheumatoid arthritis pharmacological treatments and oxidative stress
Today, methotrexate, a folate antagonist adult initially to treat malignant neoplasias, is the first-choice drug for RA treatment. In RA, the doses utilized are much lower than oncological doses, and it is not believed that its efficacy in disease control is related to this anti-proliferative action. Other mechanisms accept been proposed, including the synthesis inhibition of toxic compounds spermine and spermidine and the extracellular accumulation of adenosine, which has a known anti-inflammatory action mediated by the adenosine receptors [66]. In addition, it has already been demonstrated that methotrexate tin can suppress straight or indirectly the generation of active oxygen metabolites induced past IL-6, which in plough is produced afterwards stimulation with TNF-α in synovial cells of RA [67], too as in polymorphonuclear cells [68]. However, studies suggest that low doses of methotrexate induce more accentuated ROS-mediated apoptosis in lineages of lymphocyte T cells than in monocytes [69].
More recently, biological agents (monoclonal antibodies or recombinant proteins) with adversary action of TNF-α accept been shown to be efficacious in the control of phlogistic signs and radiological progression of RA. These agents do not seem to human activity directly on the production of oxygen radicals, but lead to inhibition of the activation and chemotaxis of neutrophils to the synovial tissue, with consequent reduced generation of such radicals [seventy].
Studies with TNF-α inhibitors etanercept and infliximab accept demonstrated a reduction of oxidative stress markers in patients with RA. This study evaluated 22 patients with RA, besides the oxidative stress parameters, every bit well as laboratory and clinical parameters. This study demonstrated that etanercept acts equally a regulator against pentosidine formation, oxidative DNA damage and lipid peroxidation in RA patients [71].
Contempo epidemiological studies have shown an inverse clan between dietary intake of anti-oxidants and RA incidence, analysed through a standardized questionnaire including demographic data, reproduction and medical history, utilization of hormonal therapy, smoking and other lifestyle factors. Such remarks strengthen the hypothesis that a balanced nutrition and anti-oxidant supplementation may protect against affliction development or aggravation, as patients with RA have reported lower levels of anti-oxidants, including vitamin C, vitamin E, β-carotene, selenium and zinc compared with control patients [44,45,72].
Determination
Chronic inflammatory arthropathies, such as RA, are characterized by a complex progressive and chronic inflammatory process which involves numerous factors of transcription and molecular signallers. Oxygen metabolism has an important role in the pathogenesis of RA.
Several studies accept observed that there is a relation between the oxidative damage caused to lipids, proteins and Dna and the maintenance of the inflammatory process in RA, also equally the inhibiting effects of medications with anti-rheumatic activity on oxidative processes. However, the nature of this relation, notably whether it represents a direct or indirect effect, has not been well adamant and requires additional studies. This information has important potential, as it enables understanding of the action mechanisms of current therapies and in detail the development of new therapeutic strategies.
Acknowledgments
This study was supported by Coordenação de Aperfeiçoamento de Pessoal de Ensino Superior and Fundo de Incentivo a Pesquisa due east Eventos.
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Articles from Clinical and Experimental Immunology are provided here courtesy of British Society for Immunology
Source: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2453196/
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