Autophagy generates citrullinated peptides in human synoviocytes: a possible trigger for anti-citrullinated peptide antibodies

Sorice, Maurizio; Iannuccelli, Cristina; Manganelli, Valeria; Capozzi, Antonella; Alessandri, Cristiano; Lococo, Emanuela; Garofalo, Tina; Franco, Manuela Di; Bombardieri, Michèle; Nerviani, Alessandra; Misasi, Roberta; Valesini, Guido

doi:10.1093/rheumatology/kew178

Cited by 62 publications

(61 citation statements)

References 41 publications

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“…In particular, autophagy regulates the citrullination and presentation of antigens by APCs as well as the presentation of citrullinated antigens by B cells (in the context of Bcellreceptor engagement), which leads to the activation of T cells 105,106 . Furthermore, recent data suggests that increased autophagy leads to the pro duction of citrullinated proteins in RA FLS, and that the level of LC3II (a readout for autophagy) in RA FLS pos itively correlates with the level of anticyclic citrullinated protein antibodies 107 . These observations suggest that autophagy has a vital role in the onset and progression of RA as a result of continued selfantigen production, presentation and recognition.…”

Section: Autophagy In Rheumatic Diseasesmentioning

confidence: 99%

Autophagy: controlling cell fate in rheumatic diseases

2016

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Autophagy, an endogenous process necessary for the turnover of organelles, maintains cellular homeostasis and directs cell fate. Alterations to the regulation of autophagy contribute to the progression of various rheumatic diseases, including systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), osteoarthritis (OA) and systemic sclerosis (SSc). Implicit in the progression of these diseases are cell-type-specific responses to surrounding factors that alter autophagy: chondrocytes within articular cartilage show decreased autophagy in OA, leading to rapid cell death and cartilage degeneration; fibroblasts from patients with SSc have restricted autophagy, similar to that seen in aged dermal fibroblasts; fibroblast-like synoviocytes from RA joints show altered autophagy, which contributes to synovial hyperplasia; and dysregulation of autophagy in haematopoietic lineage cells alters their function and maturation in SLE. Various upstream mechanisms also contribute to these diseases by regulating autophagy as part of their signalling cascades. In this Review, we discuss the links between autophagy, immune responses, fibrosis and cellular fates as they relate to pathologies associated with rheumatic diseases. Therapies in clinical use, and in preclinical or clinical development, are also discussed in relation to their effects on autophagy in rheumatic diseases.

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Section: Autophagy In Rheumatic Diseasesmentioning

confidence: 99%

Autophagy: controlling cell fate in rheumatic diseases

2016

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“…After autophagy induction via treatment with tunicamycin, the synoviocyte showed PAD4 activation, consequently resulting in protein cirtrullination. In the same vein, the positive correlation between levels of autophagy and anti-cyclic citrullinated peptide antibody was observed in treatment-naïve early RA patients [75].…”

Section: Rheumatoid Arthritis (Ra)mentioning

confidence: 73%

Pathogenic Role of Autophagy in Rheumatic Diseases

Choi

Yoo

2016

J Rheum Dis

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Autophagy is a principle catabolic process mediated by lysosomes in eukaryotic cells. This is an intracellular homeostatic mechanism crucial for degradation in acidic lysosomal compartments of waste components from the cytoplasm. Autophagy research was initially focused on its degradation mechanism, but focus is now shifting to its effects on immunity. It contributes to detection and removal of pathogens as well as regulation of inflammasomes and neutrophil extracellular traps. Moreover, it is pivotal in antigen presentation and immune cell maturation, survival and homeostasis. The importance of autophagic pathways in normal and dysregulated immunity has become increasingly recognized in the past several years. Dysregulation of the autophagic pathway is implicated in the pathogenesis of several rheumatic diseases. In this review, we summarize the immunological function of autophagy in innate and adaptive immunity, and the functions of autophagy in the pathogenesis of rheumatic diseases. (J Rheum Dis 2016;23:202-211)

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“…Increased levels of MPs have been reported in patients with autoimmune diseases, such as Rheumatoid Arthritis (RA) (1) which is characterized by an accelerated atherosclerosis. TNF, a key cytokine involved in the pathogenesis of RA, has been associated to RA atherosclerosis (2). Moreover, MPs could also have a role in endothelial dysfunction contributing to atherosclerosis in RA patients.…”

Section: Discussionmentioning

confidence: 99%

FRI0027 Tnf expression on microparticles from rheumatoid arthritis patients mediates endothelial cell fate in vitro

Barbati

Vomero

Colasanti

et al. 2017

Poster Presentations

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BackgroundMicroparticles (MPs) are small membrane vesicles released by many cell types under physiological conditions or pathological situations. Increased levels of MPs have been reported in patients with autoimmune diseases, such as Rheumatoid Arthritis (RA) (1) which is characterized by an accelerated atherosclerosis. TNF, a key cytokine involved in the pathogenesis of RA, has been associated to RA atherosclerosis (2). Moreover, MPs could also have a role in endothelial dysfunction contributing to atherosclerosis in RA patients.ObjectivesThe aim of this study was: 1) to evaluate TNF expression on RA-MPs. 2) to estimate the effects of serum RA-MPs on endothelial apoptosis and autophagy before and after in vivo and in vitro treatment with Etanercept.Methods15 RA patients were recruited from the Department of Rheumatology Sapienza University of Rome at baseline (T0) and after three months of therapy (T3) with Etanercept. A fasting blood sample was collected and centrifuged two times to obtain platelet-poor plasma rich in MPs. The resulting plasma was stained with Ab anti-TNF and analized by flow cytometry. In vitro effects of serum RA-MPs on endothelium were evaluated using human umbilical vein cell line EA.hy926. Cells were treated with RA-MPs purified at T0 and T3 and with RA-MPs in vitro treated with Etanercept. At the end of experiments apoptosis and autophagy were evaluated. Apoptosis was analyzed by flow cytometry using a FITC-conjugated annexin V and propidium iodide apoptosis detection kit; autophagy was analyzed by western blot for the expression level of the autophagic marker LC3-II.ResultsOur results showed that MPs purified from RA patients at T0 expressed TNF on their surface and this expression decreased after three months of treatment with Etanercept (p=0.04). Moreover, serum RA-MPs at T0 significantly increased, in a dose-dependent manner, both apoptosis and autophagy levels in the human umbilical vein cell line EA. hy926 (p=0.005 and p=0.02, respectively versus untreated cells). After three months of treatment with Etanercept, RA-MPs were not able to significantly change these parameters.Finally, in vitro studies showed that RA-MPs treated with Etanercept significantly decreased surface expression of TNF and were no longer able to modulate apoptosis and autophagy in EA.hy926 cells.ConclusionsOur data demonstrate that serum RA-MPs express TNF on their surface. Moreover, both in vivo and in vitro treatment with Etanercept interfere with the ability of MPs to significantly modulate apoptosis and autophagy of endothelial cells by decreasing surface expression of TNF.References Beyer C and Pisetsky DS.The role of microparticles in the pathogenesis of rheumatic diseases. Nat. Rev. Rheumatol. 2010;6:21–9.Feldmann M, Brennan FM, Foxwell BM and Maini RN.The role of TNF alpha and IL-1 in rheumatoid arthritis Curr. Dir. Autoimmun. 2001;3:188–99. Disclosure of InterestNone declared

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Autophagy generates citrullinated peptides in human synoviocytes: a possible trigger for anti-citrullinated peptide antibodies

Abstract: These findings support the view that the processing of proteins in autophagy generates citrullinated peptides recognized by the immune system in RA.

Cited by 62 publications

References 41 publications

Autophagy: controlling cell fate in rheumatic diseases

Autophagy: controlling cell fate in rheumatic diseases

Pathogenic Role of Autophagy in Rheumatic Diseases

FRI0027 Tnf expression on microparticles from rheumatoid arthritis patients mediates endothelial cell fate in vitro

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