Clinical and immunological aspects of anti-peptidylarginine deiminase type 4 (anti-PAD4) autoantibodies in rheumatoid arthritis

Reyes-Castillo, Zyanya; Muñoz‐Valle, José Francisco; Llamas-Covarrubias, Mara Anaís

doi:10.1016/j.autrev.2017.11.023

Cited by 18 publications

(16 citation statements)

References 97 publications

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“…PADI4 plays a major role in the formation of neutrophil extracellular traps, which is an important source of antigenic nucleic acids in SLE [43]. AutoAbs targeting cyclic citrullinated peptide and PADI4 are prevalent in rheumatoid arthritis [44], [45], [46]. Our study is the first to reveal the presence of anti-PADI4 autoAb in SLE and its correlation with anti-dsDNA, suggesting a pathogenic role for this autoAb in SLE.…”

Section: Discussionmentioning

confidence: 55%

Novel Autoantibodies Related to Cell Death and DNA Repair Pathways in Systemic Lupus Erythematosus

Luo

Bao

Wang

et al. 2019

Genomics, Proteomics &Amp; Bioinformatics

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Systemic lupus erythematosus (SLE) is a complex autoimmune syndrome characterized by various co-existing autoantibodies (autoAbs) in patients’ blood. However, the full spectrum of autoAbs in SLE has not been comprehensively elucidated. In this study, a commercial platform bearing 9400 antigens (ProtoArray) was used to identify autoAbs that were significantly elevated in the sera of SLE patients. By comparing the autoAb profiles of SLE patients with those of healthy controls, we identified 437 IgG and 1213 IgM autoAbs that the expression levels were significantly increased in SLE (P < 0.05). Use of the ProtoArray platform uncovered over 300 novel autoAbs targeting a broad range of nuclear, cytoplasmic, and membrane antigens. Molecular interaction network analysis revealed that the antigens targeted by the autoAbs were most significantly enriched in cell death, cell cycle, and DNA repair pathways. A group of autoAbs associated with cell apoptosis and DNA repair function, including those targeting APEX1, AURKA, POLB, AGO1, HMGB1, IFIT5, MAPKAPK3, PADI4, RGS3, SRP19, UBE2S, and VRK1, were further validated by ELISA and Western blot in a larger cohort. In addition, the levels of autoAbs against APEX1, HMGB1, VRK1, AURKA, PADI4, and SRP19 were positively correlated with the level of anti-dsDNA in SLE patients. Comprehensive autoAb screening has identified novel autoAbs, which may shed light on potential pathogenic pathways leading to lupus.

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Section: Discussionmentioning

confidence: 55%

Novel Autoantibodies Related to Cell Death and DNA Repair Pathways in Systemic Lupus Erythematosus

Luo

Bao

Wang

et al. 2019

Genomics, Proteomics &Amp; Bioinformatics

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“…Peptidylarginine deiminase 4 (PAD4) is a nuclear citrullinating enzyme, which transforms protein l -arginine to l -citrulline and plays an important role in RA pathogenesis [33,34]. PAD4 is also a target of autoantibodies in a subgroup of RA patients and anti-PAD4 autoantibodies can serve as a severity biomarker of RA [35]. Immunostaining of RA mouse ankle joint tissue sections showed that PAD4 was up-regulated in RA mice and the AD treatment significantly reduced PAD4 expression (Figure 4A).…”

Section: Resultsmentioning

confidence: 99%

Andrographolide Ameliorates Rheumatoid Arthritis by Regulating the Apoptosis–NETosis Balance of Neutrophils

Yuan

Zhu

et al. 2019

IJMS

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Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by symmetric polyarthritis with swelling and pain at synovial joints. In RA patients, delayed neutrophil apoptosis amplifies the inflammatory response and massively released neutrophil extracellular traps (NETs) induce tissue damage and provide self-antigens. Andrographolide (AD) is the major active labdane diterpenoid derived from Andrographis paniculata, which has multiple pharmacological effects, including hepatoprotection, anti-angiogenesis, anti-thrombosis, and anti-inflammation. In the present study, we investigated the effect of AD on an adjuvant-induced arthritis (AA) murine model of RA and found that AD alleviated murine arthritis by reducing neutrophil infiltration and NETosis in the ankle joints and relieved the systematic inflammation. In vitro experiments showed that AD accelerated the apoptosis of lipopolysaccharide-activated neutrophils and inhibited autophagy-dependent extracellular traps formation of neutrophils. These findings suggest that AD has considerable potential for RA therapy.

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“…Therefore, an enzyme that is always located intracellularly in neutrophils will be exposed to the immune system following NET formation, suggesting PAD4 is an ideal neoantigen candidate. Indeed, anti-PAD4 antibodies are detected and well-characterized in RA [57][58][59][60][61]. Anti-PAD4 antibodies correlate with ACPA levels, longer disease duration and shared epitope alleles, but not with serum PAD4 concentration in RA [58,62,63].…”

Section: Discussionmentioning

confidence: 99%

Systemic levels of anti-PAD4 autoantibodies correlate with airway obstruction in cystic fibrosis

Yadav

Yoo

Kahlenberg

et al. 2019

Journal of Cystic Fibrosis

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Cystic fibrosis (CF) airway disease is characterized by the long-term presence of neutrophil granulocytes. Formation of neutrophil extracellular traps (NETs) and/or autoantibodies directed against extracellular components of NETs are possible contributors to neutrophil-mediated lung damage in CF. The goal of this study was to measure their levels in CF adults compared to healthy controls and subjects with rheumatologic diseases known to develop NET-related autoantibodies and pathologies, rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). Sera were analyzed from the following number of subjects: 37 CF, 23 healthy controls (HC), 20 RA, and 21 SLE. CF had elevated serum myeloperoxidase (MPO) concentrations (347.5±56.1 ng/ml, mean+/-S.E.M., p = .0132) compared to HC (144.5±14.6 ng/ml) but not of neutrophil elastase (NE) complexed with alpha-1-antitrypsin, cell-free DNA or NE-DNA complexes. The peptidylarginine deiminase 4 (PAD4) enzyme is required for NET formation and associated DNA release in neutrophils. Serum levels of anti-PAD4 antibodies (Ab) were elevated in CF (p = .0147) compared to HC and showed an inverse correlation with a measure of lung function, FEV1% predicted (r = −0.5020, p = .015), as did MPO levels (r = −0.4801, p = .0026). Anti-PAD4 Ab levels in CF sera associated with lung infection by P. aeruginosa, but not that by S. aureus, age, sex, CF-related diabetes or the presence of musculoskeletal pain. Serum levels of anti-citrullinated protein Abs (ACPAs) and anti-nucleosome Abs were not elevated in CF compared to HC (p = .7498, p = .0678). In summary, adult CF subjects develop an autoimmune response against NET components that correlates with worsening lung disease.

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Clinical and immunological aspects of anti-peptidylarginine deiminase type 4 (anti-PAD4) autoantibodies in rheumatoid arthritis

Cited by 18 publications

References 97 publications

Novel Autoantibodies Related to Cell Death and DNA Repair Pathways in Systemic Lupus Erythematosus

Novel Autoantibodies Related to Cell Death and DNA Repair Pathways in Systemic Lupus Erythematosus

Andrographolide Ameliorates Rheumatoid Arthritis by Regulating the Apoptosis–NETosis Balance of Neutrophils

Systemic levels of anti-PAD4 autoantibodies correlate with airway obstruction in cystic fibrosis

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