Identification of Annexin 1 as a Novel Autoantigen in Acute Exacerbation of Idiopathic Pulmonary Fibrosis

Kurosu, Katsushi; Takiguchi, Yuichi; Okada, Osamu; Yumoto, Norio; Sakao, Seiichiro; Tada, Yuji; Kasahara, Yasunori; Tanabe, Nobuhiro; Tatsumi, Koichiro; Weiden, Michael D.; Rom, William N.; Kuriyama, Takayuki

doi:10.4049/jimmunol.181.1.756

Cited by 97 publications

(94 citation statements)

References 51 publications

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“…CD4+ T cells from IPF patients show characteristics of an autoreactive immune process, and an autoreactive T cell response, due to mutations in the autoimmune regulator gene, is associated with the development of interstitial lung disease [46][47]. Furthermore, an association was found between exacerbations of IPF and a reaction to auto-antigens [48]. Similar to several auto-immune diseases, a diminished number and T cellsuppressive function of CD4+CD25+FOXP3+ regulatory T cells was found in BAL and peripheral blood from patients with IPF [49].…”

Section: Cd28mentioning

confidence: 89%

Serum biomarkers in idiopathic pulmonary fibrosis

Blink

Wijsenbeek

Hoogsteden

2010

Pulmonary Pharmacology & Therapeutics

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Section: Cd28mentioning

confidence: 89%

Serum biomarkers in idiopathic pulmonary fibrosis

Blink

Wijsenbeek

Hoogsteden

2010

Pulmonary Pharmacology & Therapeutics

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“…A sizeable proportion of patients with IPF develop acute exacerbations that can result in very rapid progression of respiratory dysfunction and high mortality (40), and these sudden disease progressions have been recently linked to B cells (5,14,17,18). The patients with IPF in this cohort who were having acute exacerbations at presentation, or would do so within the next 6 months, also had significantly greater concentrations of CXCL13 ( Figure 4D).…”

Section: Ipfmentioning

confidence: 91%

“…The production of autoantibodies with specificities for varied autoantigens is a common feature of immunologic diseases (15). Several selfreactive antibodies have also been identified in IPF cohorts (12,14,(16)(17)(18)(19)(20)(21)(22)(23)(24). Moreover, some of these IPF autoantibodies have direct profibrotic, proinflammatory, or cytotoxic effects, and/or are highly associated with the clinical manifestations and outcomes of individual patients (14,(17)(18)(19)(20)(21).…”

mentioning

confidence: 99%

C-X-C Motif Chemokine 13 (CXCL13) Is a Prognostic Biomarker of Idiopathic Pulmonary Fibrosis

Vuga¹,

Tedrow²,

Pandit³

et al. 2014

Am J Respir Crit Care Med

163

115

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Rationale: C-X-C motif chemokine 13 (CXCL13) mediates B-cell trafficking and is increased, proportionately to disease activity, in many antibody-mediated syndromes. Dysregulated B cells have recently been implicated in idiopathic pulmonary fibrosis (IPF) pathogenesis.Objectives: To determine if CXCL13 is associated with IPF progression.Methods: CXCL13 was measured in lungs by DNA microarray and immunohistochemistry, and in plasma by ELISA.Measurements and Main Results: CXCL13 mRNA was threefold and eightfold greater in IPF lungs (n = 92) compared with chronic obstructive pulmonary disease (COPD) (n = 191) and normal (n = 108) specimens, respectively (P , 0.0001). IPF lungs also showed increased CXCL13 staining. Plasma CXCL13 concentrations (pg/ml) were greater in 95 patients with IPF (94 6 8) than in 128 subjects with COPD (53 6 9) and 57 normal subjects (35 6 3) (P , 0.0001). Circulating CXCL13 levels were highest in patients with IPF with pulmonary artery hypertension (P = 0.01) or acute exacerbations (P = 0.002). Six-month survival of patients with IPF in the highest quartile of plasma CXCL13 was 65 6 10% versus 93 6 10% in the others (hazard ratio, 5.5; 95% confidence interval, 1.8-16.9; P = 0.0008). CXCL13 increases by more than 50% in IPF serial assays, irrespective of initial values, also presaged respiratory failure (hazard ratio, 7.2; 95% confidence interval, 1.3-40.0; P = 0.008). In contrast, CXCL13 clinical associations in subjects with COPD were limited to modest correlations with FEV 1 (P = 0.05) and progression of radiographic emphysema (P = 0.05).Conclusions: CXCL13 is increased and is a prognostic biomarker in patients with IPF, and more so than in patients with COPD. This contrast indicates CXCL13 overexpressions are intrinsic to IPF, rather than an epiphenomenon of lung injury. The present data implicate CXCL13 and B cells in IPF pathogenesis, and support considerations for trials of specific B-cell-targeted therapies in patients with this intractable disease.

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“…Lung epithelial cells are down-regulated by ANXA1 and its mimetic Ac2-26 (Croxtall et al, 1993(Croxtall et al, , 1998b. On the other hand, Kurosu et al (2008) reported that the N-terminal derivative of ANXA1 (peptide 18-26) induced a marked proliferative response of CD4-positive cells from 3 out of 15 patients showing acute exacerbation of idiopathic pulmonary fibrosis. It has been demonstrated that the constituents of ANXA1, required for FPR1 receptor activation, are shown to be within the 2-12 pharmacophore region of the molecule (Perretti et al, 2001), which indicates that the length of the ANXA1…”

Section: Discussionmentioning

confidence: 99%

“…Lung epithelial cells are down-regulated by ANXA1 and its mimetic Ac2-26 (Croxtall et al, 1993, 1998b. On the other hand, Kurosu et al (2008) …”

Section: Discussionmentioning

confidence: 99%

Annexin A1 mimetic peptide controls the inflammatory and fibrotic effects of silica particles in mice

Trentin

Ferreira

Arantes

et al. 2015

British J Pharmacology

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BACKGROUND AND PURPOSEEndogenous glucocorticoids are pro-resolving mediators, an example of which is the endogenous glucocorticoid-regulated protein annexin A1 (ANXA1). Because silicosis is an occupational lung disease characterized by unabated inflammation and fibrosis, in this study we tested the therapeutic properties of the N-terminal ANXA1-derived peptide annexin 1-(2-26) (Ac2-26) on experimental silicosis. EXPERIMENTAL APPROACHSwiss-Webster mice were administered silica particles intranasally and were subsequently treated with intranasal peptide Ac2-26 (200 μg per mouse) or dexamethasone (25 μg per mouse) for 7 days, starting 6 h post-challenge. Ac2-26 abolished the leukocyte infiltration, collagen deposition, granuloma formation and generation of pro-inflammatory cytokines evoked by silica; these variables were only partially inhibited by dexamethasone. KEY RESULTSA clear exacerbation of the silica-induced pathological changes was observed in ANXA1 knockout mice as compared with their wild-type (WT) littermate controls. Incubation of lung fibroblasts from WT mice with Ac2-26 in vitro reduced IL-13 or TGF-β-induced production of CCL2 (MCP-1) and collagen, but this peptide did not affect the production of CCL2 (MCP-1) by stimulated fibroblasts from formyl peptide receptor type 1 (FPR1) knockout mice. Ac2-26 also inhibited the production of CCL2 (MCP-1) from fibroblasts of FPR2 knockout mice. CONCLUSIONS AND IMPLICATIONSCollectively, our findings reveal novel protective properties of the ANXA1 derived peptide Ac2-26 on the inflammatory and fibrotic responses induced by silica, and suggest that ANXA1 mimetic agents might be a promising strategy as innovative anti-fibrotic approaches for the treatment of silicosis. IntroductionSilicosis is a lung occupational disease caused by inhalation of free crystalline silica particles over a prolonged period of time. This disease mainly affects workers in the ceramic industry, glass manufacturing, sandblasting, mining, quarrying and civil construction (Leung et al., 2012;Singer et al., 2012). Silicosis is a problem worldwide, but it is prevalent in countries of low and middle income. China had more than 500 000 cases recorded between 1991 and 1995, and 6000 new cases and more than 24 000 deaths are reported annually (Leung et al., 2012). In Brazil more than 4500 workers were reported to have silicosis between 1978 and 1998, especially in the gold-mining area in Minas Gerais (Carneiro et al., 2006). The irritative action of silica in the lungs results in the formation of nodular lesions, which may coalesce resulting in massive areas of fibrous tissue and reduction of lung elasticity (Davis, 1986). Because of its surface properties, crystalline silica leads to activation of alveolar macrophages [acting on 'scavenger' receptors such as the MARCO (macrophage receptor with collagenous structure)], epithelial cells and fibroblasts (Mossman and Churg, 1998;Fubini and Hubbard, 2003;Huaux, 2007). The granulomatous inflammation induced by silica is characterized by the accumulati...

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Identification of Annexin 1 as a Novel Autoantigen in Acute Exacerbation of Idiopathic Pulmonary Fibrosis

Cited by 97 publications

References 51 publications

Serum biomarkers in idiopathic pulmonary fibrosis

Serum biomarkers in idiopathic pulmonary fibrosis

C-X-C Motif Chemokine 13 (CXCL13) Is a Prognostic Biomarker of Idiopathic Pulmonary Fibrosis

Annexin A1 mimetic peptide controls the inflammatory and fibrotic effects of silica particles in mice

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