Citrullination Controls Dendritic Cell Transdifferentiation into Osteoclasts

Krishnamurthy, Akilan; Ytterberg, A. Jimmy; Sun, Meng; Sakuraba, Koji; Stéen, Johanna; Joshua, Vijay; Tarasova, Nataliya K.; Malmström, Vivianne; Wähämaa, Heidi; Réthi, Bence; Catrina, Anca I.

doi:10.4049/jimmunol.1800534

Cited by 43 publications

(43 citation statements)

References 23 publications

(32 reference statements)

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“…Anti-citrullinated protein antibodies (ACPAs) are present in a majority of patients with rheumatoid arthritis (RA) and are specific for this disease 1. They consist of a group of antibodies with different specificities towards citrullinated antigens that might cross-react with other protein modifications but not with the native proteins2–4 and have been suggested to contribute to joint pain and bone loss already before onset of joint inflammation in RA 5–8. In line with this, we and others have shown that polyclonal ACPAs bind to the surface of developing osteoclasts (OC) and suggested that reactivity to citrullinated targets increase OC differentiation and bone loss 9 10.…”

Section: Introductionmentioning

confidence: 72%

Anticitrullinated protein antibodies facilitate migration of synovial tissue-derived fibroblasts

et al. 2019

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ObjectivesRheumatoid arthritis (RA)-specific anti-citrullinated protein/peptide antibodies (ACPAs) might contribute to bone loss and arthralgia before the onset of joint inflammation. We aimed to dissect additional mechanisms by which ACPAs might contribute to development of joint pathology.MethodsFibroblast-like synoviocytes (FLS) were isolated from the synovial membrane of patients with RA. The FLS cultures were stimulated with polyclonal ACPAs (anti-CCP-2 antibodies) purified from the peripheral blood of patients with RA or with monoclonal ACPAs derived from single synovial fluid B cells. We analysed how ACPAs modulate FLS by measuring cell adhesion and mobility as well as cytokine production. Expression of protein arginine deiminase (PAD) enzymes and protein citrullination were analysed by immunofluorescence, and signal transduction was studied using immunoblotting.ResultsChallenge of FLS by starvation-induced stress or by exposure to the chemokine interleukin-8 was essential to sensitise the cells to ACPAs. These challenges led to an increased PAD expression and protein citrullination and an ACPA-mediated induction of FLS migration through a mechanism involving phosphoinositide 3-kinase activation. Inhibition of the PAD enzymes or competition with soluble citrullinated proteins or peptides completely abolished the ACPA-induced FLS migration. Different monoclonal ACPAs triggered distinct cellular effects in either fibroblasts or osteoclasts, suggesting unique roles for individual ACPA clones in disease pathogenesis.ConclusionWe propose that transient synovial insults in the presence of a certain pre-existing ACPA repertoire might result in an ACPA-mediated increase of FLS migration.

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Section: Introductionmentioning

confidence: 72%

Anticitrullinated protein antibodies facilitate migration of synovial tissue-derived fibroblasts

et al. 2019

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“…In support of this concept, several RA-associated symptoms, in particular joint pain (arthralgia) and bone loss, have been described in ACPA-and RFpositive individuals years before onset of joint inflammation [177,181,182]. Additional studies have demonstrated that antibodies, including ACPAs derived from RA patients, may induce bone loss as well as pain when transferred to mice [183][184][185][186][187]. As has been discussed in previous reviews [178,179], some of these effects are suggested to be due to an activation and chemokine production from osteoclasts after exposure to ACPA [184][185]187].…”

Section: Gene-environment Interactionsmentioning

confidence: 90%

“…Additional studies have demonstrated that antibodies, including ACPAs derived from RA patients, may induce bone loss as well as pain when transferred to mice [183][184][185][186][187]. As has been discussed in previous reviews [178,179], some of these effects are suggested to be due to an activation and chemokine production from osteoclasts after exposure to ACPA [184][185]187].…”

Section: Gene-environment Interactionsmentioning

confidence: 99%

The importance of differences; On environment and its interactions with genes and immunity in the causation of rheumatoid arthritis

et al. 2020

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“…In RA, ACPA is associated with arthralgia before the onset of inflammation and a more aggressive disease ensues, suggesting potential pathogenic effects of the ACPA response [185]. Binding of ACPAs to osteoclasts released IL-8, leading to bone erosion [186] and also enhanced osteoclast differentiation from monocyte-derived or circulating CD1c + DCs by increasing the release of IL-8 [187]. Upon binding to its target antigens, ACPAs also induced joint pain by activating sensory neurons via CXCL1/IL-8, released from CD68 + osteoclasts in an autoantibody-dependent manner, and blocking the chemokine receptors for CXCL1/2 attenuated ACPA-induced hypersensitivity [188].…”

Section: Natural and Pathogenic Autoantibodiesmentioning

confidence: 99%

Autoantibodies as Diagnostic Markers and Mediator of Joint Inflammation in Arthritis

Fang

Nandakumar

2019

Mediators of Inflammation

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Rheumatoid arthritis is a systemic, polygenic, and multifactorial syndrome characterized by erosive polyarthritis, damage to joint architecture, and presence of autoantibodies against several self-structures in the serum and synovial fluid. These autoantibodies (anticitrullinated protein/peptide antibodies (ACPAs), rheumatoid factors (RF), anticollagen type II antibodies, antiglucose-6 phosphate isomerase antibodies, anticarbamylated protein antibodies, and antiacetylated protein antibodies) have different characteristics, diagnostic/prognostic value, and pathological significance in RA patients. Some of these antibodies are present in the patients' serum several years before the onset of clinical disease. Various genetic and environmental factors are associated with autoantibody production against different autoantigenic targets. Both the activating and inhibitory FcγRs and the activation of different complement cascades contribute to the downstream effector functions in the antibody-mediated disease pathology. Interplay between several molecules (cytokines, chemokines, proteases, and inflammatory mediators) culminates in causing damage to the articular cartilage and bones. In addition, autoantibodies are proven to be useful disease markers for RA, and different diagnostic tools are being developed for early diagnosis of the clinical disease. Recently, a direct link was proposed between the presence of autoantibodies and bone erosion as well as in the induction of pain. In this review, the diagnostic value of autoantibodies, their synthesis and function as a mediator of joint inflammation, and the significance of IgG-Fc glycosylation are discussed.

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Citrullination Controls Dendritic Cell Transdifferentiation into Osteoclasts

Cited by 43 publications

References 23 publications

Anticitrullinated protein antibodies facilitate migration of synovial tissue-derived fibroblasts

Anticitrullinated protein antibodies facilitate migration of synovial tissue-derived fibroblasts

The importance of differences; On environment and its interactions with genes and immunity in the causation of rheumatoid arthritis

Autoantibodies as Diagnostic Markers and Mediator of Joint Inflammation in Arthritis

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