Antibodies from patients with rheumatoid arthritis target citrullinated histone 4 contained in neutrophils extracellular traps

Pratesi, Federico; Dioni, Ilaria; Tommasi, Cristina; Alcaro, Maria C.; Paolini, Ilaria; Barbetti, Fabrizio; Boscaro, Francesca; Panza, Filomena; Puxeddu, Ilaria; Rovero, Paolo; Migliorini, Paola

doi:10.1136/annrheumdis-2012-202765

Cited by 196 publications

(154 citation statements)

References 39 publications

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“…Interestingly, some of these targets, such as citrullinated myeloid nuclear differentiation antigen or vimentin, were also generated during in vitro NETosis in our assay, thus further supporting the idea that NETs are a possible source for these citrullinated proteins in the joints. This is also consistent with other published work in which citrullinated proteins within NETs were described as targets of the autoimmune response both in RA and in Felty's syndrome 35, 36.…”

Section: Discussionsupporting

confidence: 93%

Release of Active Peptidyl Arginine Deiminases by Neutrophils Can Explain Production of Extracellular Citrullinated Autoantigens in Rheumatoid Arthritis Synovial Fluid

Spengler

Lugonja

Ytterberg

et al. 2015

Arthritis & Rheumatology

188

172

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ObjectiveIn the majority of patients with rheumatoid arthritis (RA), antibodies specifically recognize citrullinated autoantigens that are generated by peptidylarginine deiminases (PADs). Neutrophils express high levels of PAD and accumulate in the synovial fluid (SF) of RA patients during disease flares. This study was undertaken to test the hypothesis that neutrophil cell death, induced by either NETosis (extrusion of genomic DNA–protein complexes known as neutrophil extracellular traps [NETs]) or necrosis, can contribute to production of autoantigens in the inflamed joint.MethodsExtracellular DNA was quantified in the SF of patients with RA, patients with osteoarthritis (OA), and patients with psoriatic arthritis (PsA). Release of PAD from neutrophils was investigated by Western blotting, mass spectrometry, immunofluorescence staining, and PAD activity assays. PAD2 and PAD4 protein expression, as well as PAD enzymatic activity, were assessed in the SF of patients with RA and those with OA.ResultsExtracellular DNA was detected at significantly higher levels in RA SF than in OA SF (P < 0.001) or PsA SF (P < 0.05), and its expression levels correlated with neutrophil concentrations and PAD activity in RA SF. Necrotic neutrophils released less soluble extracellular DNA compared to NETotic cells in vitro (P < 0.05). Higher PAD activity was detected in RA SF than in OA SF (P < 0.05). The citrullinated proteins PAD2 and PAD4 were found attached to NETs and also freely diffused in the supernatant. PAD enzymatic activity was detected in supernatants of neutrophils undergoing either NETosis or necrosis.ConclusionRelease of active PAD isoforms into the SF by neutrophil cell death is a plausible explanation for the generation of extracellular autoantigens in RA.

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Section: Discussionsupporting

confidence: 93%

Release of Active Peptidyl Arginine Deiminases by Neutrophils Can Explain Production of Extracellular Citrullinated Autoantigens in Rheumatoid Arthritis Synovial Fluid

Spengler

Lugonja

Ytterberg

et al. 2015

Arthritis & Rheumatology

188

172

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“…29) NETs participate in the pathogenesis of autoimmune diseases; in patients with RA, NET formation stimulates synovial fibroblasts to produce pro-inflammatory mediators that participate in joint injury. 30) In this study and in other experimental models of inflammation, OLM reduced the expression of COX-2, which could result in tissue protection. 19,31) COX-2 is an enzyme induced in inflammatory processes; it is involved in the synthesis of prostaglandins and inflammatory cytokines, which promote local inflammation and tissue damage.…”

Section: Discussionsupporting

confidence: 50%

Olmesartan Prevented Intra-articular Inflammation Induced by Zymosan in Rats

Guerra

Menezes

Araújo

et al. 2016

Biological & Pharmaceutical Bulletin

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The objective of this study was to study the effect of olmesartan medoxomil (OLM), an antihypertensive drug, on intra-articular inflammation induced by zymosan (Zy) in Wistar rats. Intra-articular inflammation was induced in the right knees of rats by 1 mg Zy dissolved in saline. The animals were divided into the following groups: saline only (oral saline and intra-articular saline); Zy only (intra-articular Zy and oral saline), and intra-articular Zy and oral OLM (5, 15, or 30 mg/kg) or diclofenac sodium (SD; 100 mg/ kg). Twenty-four hours after Zy injection, synovial fluid was collected for total leukocyte counts, blood was collected for biochemical measurements, and synovial tissue was collected for histopathology, immunohistochemistry, immunofluorescence and myeloperoxidase (MPO), malonaldehyde (MDA), and non-protein sulphydryl (NPSH) assays. OLM doses of 15 and 30 mg/kg had protective effects, as evidenced by improved histopathological parameters of synovium, reduced total leukocyte counts, reduced MPO and MDA levels, and increased NPSH group levels compared with the Zy group. OLM reduced immunostaining for cyclooxygenase 2, tumour necrosis factor and interleukin 17 and increased immunostaining for superoxide dismutase and glutathione peroxidase. SD produced similar results. The drugs studied caused no change in biochemical parameters of the animals. OLM showed protective effects in this model of Zy-induced intra-articular inflammation.

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“…Ninety-three patients with RA, 25 with psoriatic arthritis, 15 with ankylosing spondylitis, and 48 healthy controls were recruited and ACPA were detected by using an ELISA with 4 synthetic peptides derived from viral proteins 6 (viral citrullinated peptide; VCP) or from histones 7 (histone citrullinated peptide; HCP). Peptides containing arginine were used as the control.…”

Section: To the Editormentioning

confidence: 99%

Immunoglobulin G Subclass Profile of Anticitrullinated Peptide Antibodies Specific for Epstein Barr Virus-derived and Histone-derived Citrullinated Peptides

Panza

Pratesi²,

Valoriani³

et al. 2014

J Rheumatol

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Antibodies from patients with rheumatoid arthritis target citrullinated histone 4 contained in neutrophils extracellular traps

Cited by 196 publications

References 39 publications

Release of Active Peptidyl Arginine Deiminases by Neutrophils Can Explain Production of Extracellular Citrullinated Autoantigens in Rheumatoid Arthritis Synovial Fluid

Release of Active Peptidyl Arginine Deiminases by Neutrophils Can Explain Production of Extracellular Citrullinated Autoantigens in Rheumatoid Arthritis Synovial Fluid

Olmesartan Prevented Intra-articular Inflammation Induced by Zymosan in Rats

Immunoglobulin G Subclass Profile of Anticitrullinated Peptide Antibodies Specific for Epstein Barr Virus-derived and Histone-derived Citrullinated Peptides

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