Autoantibodies to protein-arginine deiminase (PAD) 4 in rheumatoid arthritis: immunological and clinical significance, and potential for precision medicine

Martinez-Prat, Laura; Palterer, Boaz; Vitiello, Gianfranco; Parronchi, Paola; Robinson, William H.; Mähler, Michael

doi:10.1080/1744666x.2020.1668778

Cited by 23 publications

(18 citation statements)

References 137 publications

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“…Peptidylarginine deiminases (PADs) are enzymes that catalyze the deimino production of arginine residues in protein peptide chains to produce citrulline residues, including 5 subtypes, of which only PAD4 can exist in the nucleus 54 and is closely related to the pathogenesis and susceptibility of RA. The study found that the level of PAD4 protein in serum, articular synovial F I G U R E 3 Abnormal activation of T cells and B cells, bone resorption, cartilage destruction and angiogenesis tissue, and peripheral blood neutrophils of RA patients is high, [55][56][57][58][59] and anti-PAD4 antibody can also be used as a clinical diagnostic indicator of RA, [60][61][62] and the level in patients can be maintained in long-term stability. 63 However, after TNF-α stimulated HL-60 cells to activate NF-κB, the expression of PAD4 decreased.…”

Section: Anti-inflammatory Pathologymentioning

confidence: 99%

Nuclear factor‐κB in rheumatoid arthritis

Tang

Shi

et al. 2020

Int J of Rheum Dis

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NF-κB (nuclear factor kappa light chain enhancer of activated B cells) signaling pathway is involved in the occurrence and development of various kinds of inflammation, including rheumatoid arthritis (RA). In this paper, the relationship between the activation or inhibition of NF-κB and the pathogenesis of RA is discussed. It is found that activated NF-κB operates a dual-aspect effect which can either promote or suppress inflammation. When NF-κB is inhibited, the symptoms of RA are significantly improved. The specific role of NF-κB is closely related to its upstream stimulator and downstream activator. Therefore, we review the research on NF-κB in RA over the past 20 years in order to have a clearer understanding of its mechanism.

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Section: Anti-inflammatory Pathologymentioning

confidence: 99%

Nuclear factor‐κB in rheumatoid arthritis

Tang

Shi

et al. 2020

Int J of Rheum Dis

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“…PADs and associated protein deimination are crucial players in cancer and autoimmune and neurodegenerative diseases (17,19,20,22,25). PADs have received particular attention due to roles in cancer (20,22,26,27), rheumatoid arthritis (28)(29)(30)(31)(32)(33), multiple sclerosis (34)(35)(36)(37)(38), as well as due to their contribution to skin physiology and diseases (39). PADs have furthermore been shown to play crucial roles in hypoxia and CNS regeneration (40)(41)(42)(43)(44), and roles for PAD2 in promotion of oligodendrocyte differentiation and myelination have been shown (45).…”

Section: Introductionmentioning

confidence: 99%

Deimination Protein Profiles in Alligator mississippiensis Reveal Plasma and Extracellular Vesicle-Specific Signatures Relating to Immunity, Metabolic Function, and Gene Regulation

et al. 2020

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Alligators are crocodilians and among few species that endured the Cretaceous-Paleogene extinction event. With long life spans, low metabolic rates, unusual immunological characteristics, including strong antibacterial and antiviral ability, and cancer resistance, crocodilians may hold information for molecular pathways underlying such physiological traits. Peptidylarginine deiminases (PADs) are a group of calcium-activated enzymes that cause posttranslational protein deimination/citrullination in a range of target proteins contributing to protein moonlighting functions in health and disease. PADs are phylogenetically conserved and are also a key regulator of extracellular vesicle (EV) release, a critical part of cellular communication. As little is known about PAD-mediated mechanisms in reptile immunology, this study was aimed at profiling EVs and protein deimination in Alligator mississippiensis. Alligator plasma EVs were found to be polydispersed in a 50-400-nm size range. Key immune, metabolic, and gene regulatory proteins were identified to be posttranslationally deiminated in plasma and plasma EVs, with some overlapping hits, while some were unique to either plasma or plasma EVs. In whole plasma, 112 target proteins were identified to be deiminated, while 77 proteins were found as deiminated protein hits in plasma EVs, whereof 31 were specific for EVs only, including proteins specific for gene regulatory functions (e.g., histones). Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis revealed KEGG pathways specific to deiminated proteins in whole plasma related to adipocytokine signaling, while KEGG pathways of deiminated proteins specific to EVs included ribosome, biosynthesis of amino acids, and glycolysis/gluconeogenesis pathways as well as core histones. This highlights roles for EV-mediated export of deiminated protein cargo with roles in metabolism and gene regulation, also related to cancer. The identification of posttranslational deimination and EV-mediated communication Criscitiello et al. Deimination and EV Signatures in Alligator in alligator plasma revealed here contributes to current understanding of protein moonlighting functions and EV-mediated communication in these ancient reptiles, providing novel insight into their unusual immune systems and physiological traits. In addition, our findings may shed light on pathways underlying cancer resistance, antibacterial and antiviral resistance, with translatable value to human pathologies.

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“…While the bulk of research on PADs and associated post-translational deimination and downstream effects has hitherto focussed on human pathologies, roles in normal physiology are receiving increasing attention -including in a range of taxa throughout the phylogenetic tree (Magnadottir et al, 2018a(Magnadottir et al, , 2019a(Magnadottir et al, ,b, 2020aPhillips et al, 2020;Pamenter et al, 2019;Criscitiello et al, 2019Criscitiello et al, ,2020a. Hitherto, no studies have been carried out on PAD/ADI protein function or physiological relevance for PAD/ADI-mediated post-translational deimination in Merostomata. In relation to pathological responses, PADs and associated protein deimination are recognized as crucial players in cancer, inflammatory, autoimmune, and neurodegenerative diseases (Mohanan et al, 2012;Witalison et al, 2015;Lange et al, 2017;Uysal-Onganer et al, 2020;Darrah and Andrade, 2018;Tilvawala et al, 2018;Ruiz-Romero et al, 2019;Fert-Bober et al, 2020;Martinez-Prat et al, 2019;Svärd et al, 2019;Mastronardi et al, 2006;Moscarello et al, 2013;Wei et al, 2013;Yang et al, 2016;Faigle et al, 2019;Méchin et al, 2020;) as well as in relation to ageing (Ding et al, 2017;Wong and Wagner, 2018). There is also a considerable interest in roles for PADs in tissue regeneration, including in the CNS and in response to hypoxia (Lange et al, 2011;Lange et al, 2014;Lange, 2016;Sase et al, 2017;Yu et al, 2018), as well as in wound healing (Wong et al, 2015;Fadini et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

Post-translational protein deimination signatures and extracellular vesicles (EVs) in the Atlantic horseshoe crab (Limulus polyphemus)

Bowden

Kraev

Lange

2020

Developmental & Comparative Immunology

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The horseshoe crab is a living fossil and a species of marine arthropod with unusual immune system properties which are also exploited commercially. Given its ancient status dating to the Ordovician period (450 million years ago), its standing in phylogeny and unusual immunological characteristics, the horseshoe crab may hold valuable information for comparative immunology studies.Peptidylarginine deiminases (PADs) are calcium dependent enzymes that are phylogenetically conserved and cause protein deimination via conversion of arginine to citrulline. This posttranslational modification can lead to structural and functional protein changes contributing to protein moonlighting in health and disease. PAD-mediated regulation of extracellular vesicle (EV) release, a critical component of cellular communication, has furthermore been identified to be a phylogenetically conserved mechanism. PADs, protein deimination and EVs have hitherto not been studied in the horseshoe crab and were assessed in the current study. Horseshoe crab haemolymph serum-EVs were found to be a poly-dispersed population in the 20-400 nm size range, with the majority of EVs falling within 40-123 nm. Key immune proteins were identified to be posttranslationally deiminated in horseshoe crab haemolymph serum, providing insights into protein moonlighting function of Limulus and phylogenetically conserved immune proteins. KEGG (Kyoto encyclopaedia of genes and genomes) and GO (gene ontology) enrichment analysis of deiminated proteins identified in Limulus revealed KEGG pathways relating to complement and coagulation pathways, Staphylococcus aureus infection, glycolysis/gluconeogenesis and carbon metabolism, while GO pathways of biological and molecular pathways related to a range of immune and metabolic functions, as well as developmental processes. The characterisation of EVs, and posttranslational deimination signatures, revealed here in horseshoe crab, contributes to current understanding of protein moonlighting functions and EV-mediated communication in this ancient arthropod and throughout phylogeny.

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Autoantibodies to protein-arginine deiminase (PAD) 4 in rheumatoid arthritis: immunological and clinical significance, and potential for precision medicine

Cited by 23 publications

References 137 publications

Nuclear factor‐κB in rheumatoid arthritis

Nuclear factor‐κB in rheumatoid arthritis

Deimination Protein Profiles in Alligator mississippiensis Reveal Plasma and Extracellular Vesicle-Specific Signatures Relating to Immunity, Metabolic Function, and Gene Regulation

Post-translational protein deimination signatures and extracellular vesicles (EVs) in the Atlantic horseshoe crab (Limulus polyphemus)

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