Citrullination: A Target for Disease Intervention in Multiple Sclerosis and other Inflammatory Diseases?

Chirivi, Renato G. S.

doi:10.4172/2155-9899.1000146

Cited by 31 publications

(38 citation statements)

References 83 publications

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“…Since PAD activity is highly Ca 2+ dependent, changes in Ca 2+ fluxes induced in cytokine-exposed b-cells might play a role. The present findings, together with the recent report on posttranslationally modified GAD65 (15), add type 1 diabetes to the list of autoimmune diseases involving citrullination, i.e., RA, multiple sclerosis, and systemic erhythematosus (32). This suggests that citrullination is not a specific diseaserelated event but rather an inflammation-dependent process occurring preferentially in autoimmune target tissues.…”

Section: Discussionsupporting

confidence: 66%

Citrullinated Glucose-Regulated Protein 78 Is an Autoantigen in Type 1 Diabetes

et al. 2014

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Posttranslational modifications of self-proteins play a substantial role in the initiation or propagation of the autoimmune attack in several autoimmune diseases, but their contribution to type 1 diabetes is only recently emerging. In the current study, we demonstrate that inflammatory stress, induced by the cytokines interleukin-1β and interferon-γ, leads to citrullination of GRP78 in β-cells. This is coupled with translocation of this endoplasmic reticulum chaperone to the β-cell plasma membrane and subsequent secretion. Importantly, expression and activity of peptidylarginine deiminase 2, one of the five enzymes responsible for citrullination and a candidate gene for type 1 diabetes in mice, is increased in islets from diabetes-prone nonobese diabetic (NOD) mice. Finally, (pre)diabetic NOD mice have autoantibodies and effector T cells that react against citrullinated GRP78, indicating that inflammation-induced citrullination of GRP78 in β-cells generates a novel autoantigen in type 1 diabetes, opening new avenues for biomarker development and therapeutic intervention.

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Section: Discussionsupporting

confidence: 66%

Citrullinated Glucose-Regulated Protein 78 Is an Autoantigen in Type 1 Diabetes

et al. 2014

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“…51 There is growing evidence of the pathological role of NETs in the development and progression of multiple acute and chronic inflammatory diseases. [5][6][7][8][9]52 First, NETs act as a source of autoantigens that break immunological tolerance in autoimmune diseases, including RA, SLE, APS, and ANCA-associated vasculitis. 53 Second, the cytotoxicity of NETs results in local inflammation that leads to tissue damage, organ failure and severe morbidity.…”

Section: Discussionmentioning

confidence: 99%

Therapeutic ACPA inhibits NET formation: a potential therapy for neutrophil-mediated inflammatory diseases

Chirivi¹,

Rosmalen²,

Linden³

et al. 2020

Cell Mol Immunol

107

100

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Excessive release of neutrophil extracellular traps (NETs) is associated with disease severity and contributes to tissue injury, followed by severe organ damage. Pharmacological or genetic inhibition of NET release reduces pathology in multiple inflammatory disease models, indicating that NETs are potential therapeutic targets. Here, we demonstrate using a preclinical basket approach that our therapeutic anti-citrullinated protein antibody (tACPA) has broad therapeutic potential. Treatment with tACPA prevents disease symptoms in various mouse models with plausible NET-mediated pathology, including inflammatory arthritis (IA), pulmonary fibrosis, inflammatory bowel disease and sepsis. We show that citrulline residues in the N-termini of histones 2A and 4 are specific targets for therapeutic intervention, whereas antibodies against other N-terminal post-translational histone modifications have no therapeutic effects. Because citrullinated histones are generated during NET release, we investigated the ability of tACPA to inhibit NET formation. tACPA suppressed NET release from human neutrophils triggered with physiologically relevant human diseaserelated stimuli. Moreover, tACPA diminished NET release and potentially initiated NET uptake by macrophages in vivo, which was associated with reduced tissue damage in the joints of a chronic arthritis mouse model of IA. To our knowledge, we are the first to describe an antibody with NET-inhibiting properties and thereby propose tACPA as a drug candidate for NET-mediated inflammatory diseases, as it eliminates the noxious triggers that lead to continued inflammation and tissue damage in a multidimensional manner.

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“…Citrullination of proteins is understood to be an important post-translational modification with systemic implications (Chirivi et al, 2013). Previous studies have shown that up-regulation of peptidyl arginine deiminase (PAD) expression and the associated increase in citrullinated proteins were found in patients with rheumatoid arthritis (Foulquier et al, 2007).…”

Section: Proteome Associated With Microbe-host Interactionmentioning

confidence: 99%

Filifactor alocis: The Newly Discovered Kid on the Block with Special Talents

2014

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Infection-induced periodontal disease has been primarily focused on a small group of periodontal pathogens. A paradigm shift, based on data emerging from the oral microbiome project, now suggests the involvement of as-yet-unculturable and fastidious organisms. Collectively, these studies have demonstrated that there are changes in the periodontal status associated with shifts in the composition of the bacterial community in the periodontal pocket. In addition, it is likely that the emerging new pathogens may play a more significant role in the disease. One of the organisms previously unrecognized is Filifactor alocis. While this Gram-positive anaerobic rod has been identified in peri-implantitis, in endodontic infections, and in patients with localized aggressive periodontitis, its presence is now observed at significantly higher levels in patients with adult periodontitis or refractory periodontitis. Its colonization properties and its potential virulence attributes support the proposal that F. alocis should be included as a diagnostic indicator of periodontal disease. Moreover, these emerging characteristics would be consistent with the polymicrobial synergy and dysbiosis (PSD) periodontal pathogenesis model. Here, unique characteristics of F. alocis are discussed. F. alocis has specific factors that can modulate multiple changes in the microbial community and host cell proteome. It is likely that such variations at the molecular level are responsible for the functional changes required to mediate the pathogenic process.

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Citrullination: A Target for Disease Intervention in Multiple Sclerosis and other Inflammatory Diseases?

Cited by 31 publications

References 83 publications

Citrullinated Glucose-Regulated Protein 78 Is an Autoantigen in Type 1 Diabetes

Citrullinated Glucose-Regulated Protein 78 Is an Autoantigen in Type 1 Diabetes

Therapeutic ACPA inhibits NET formation: a potential therapy for neutrophil-mediated inflammatory diseases

Filifactor alocis: The Newly Discovered Kid on the Block with Special Talents

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