Identification of Periplakin as a New Target for Autoreactivity in Idiopathic Pulmonary Fibrosis

Taillé, Camille; Grootenboer‐Mignot, Sabine; Boursier, Céline; Michel, Laurence; Debray, Marie‐Pierre; Fagart, Jérôme; Barrientos, Lorena; Mailleux, Arnaud; Cigna, Natacha; Tubach, Florence; Marchal-Sommé, Joëlle; Stolzmann, Paul; Chollet‐Martin, Sylvie; Crestani, Bruno

doi:10.1164/rccm.201001-0076oc

Cited by 103 publications

(95 citation statements)

References 38 publications

(36 reference statements)

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“…The prognosis of IPF is poor, with median survival ∼ 3 y, and the only currently approved medications have modest efficacy. Autoimmunity has been implicated in the development and/or progression of IPF, although many details of these immune responses remain enigmatic (2)(3)(4)(5)(6)(7)(8).…”

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confidence: 99%

Autoimmunity to Vimentin Is Associated with Outcomes of Patients with Idiopathic Pulmonary Fibrosis

Surolia

et al. 2017

The Journal of Immunology

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Autoimmunity has been implicated in the pathogenesis of idiopathic pulmonary fibrosis (IPF); however, the repertoire of autoantigens involved in this disease and the clinical relevance of these autoimmune responses are still being explored. Our initial discovery assays demonstrated that circulating and intrapulmonary vimentin levels are increased in IPF patients. Subsequent studies showed native vimentin induced HLA-DR–dependent in vitro proliferation of CD4 T cells from IPF patients and enhanced the production of IL-4, IL-17, and TGF-β1 by these lymphocytes in contrast to normal control specimens. Vimentin supplementation of IPF PBMC cultures also resulted in HLA-DR–dependent production of IgG with anti-vimentin specificities. Circulating anti-vimentin IgG autoantibody levels were much greater in IPF subjects from the University of Alabama at Birmingham (n = 102) and the University of Pittsburgh (U. Pitt., n = 70) than in normal controls. Anti-vimentin autoantibody levels in IPF patients were HLA biased and inversely correlated with physiological measurements of lung function (i.e., forced expiratory volumes and diffusing capacities). Despite considerable intergroup differences in transplant-free survival between these two independent IPF cohorts, serious adverse outcomes were most frequent among the patients within each population that had the highest anti-vimentin autoantibody levels (University of Alabama at Birmingham: hazard ratio 2.5, 95% confidence interval 1.2–5.3, p = 0.012; University of Pittsburgh: hazard ratio 2.7, 95% confidence interval 1.3–5.5, p = 0.006). These data show that anti-vimentin autoreactivity is prevalent in IPF patients and is strongly associated with disease manifestations. These findings have implications with regard to the pathogenesis of this enigmatic disease and raise the possibility that therapies specifically directed at these autoimmune processes could have therapeutic efficacy.

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confidence: 99%

Autoimmunity to Vimentin Is Associated with Outcomes of Patients with Idiopathic Pulmonary Fibrosis

Surolia

et al. 2017

The Journal of Immunology

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“…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).…”

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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

161

112

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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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“…First, the relatively low number of patients did not allow us to show statistical power. Second, this study was performed exclusively in Japan, so more patients of different ethnicities and from countries with different genetic, epigenetic, and environmental risk factors are needed to confirm our results because the proteins of the plakin family are detected as autoantibodies in other lesions (Park et al, 2006;Taille et al, 2011). Third, periplakin is located not only in urothelium but also in other cells.…”

Section: Discussionmentioning

confidence: 84%

“…Although investigations of autoantibodies to periplakin were performed in several reports (such as those involving pulmonary and skin diseases) (Park et al, 2006;Taille et al, 2011), this is the first study to evaluate serum periplakin for cancer detection, particularly UCB. Serum periplakin was significantly lower in patients with UCB than in normal controls.…”

Section: Discussionmentioning

confidence: 99%

Serum Periplakin as a Potential Biomarker for Urothelial Carcinoma of the Urinary Bladder

Matsumoto¹,

Ikeda²,

Matsumoto³

et al. 2014

Asian Pacific Journal of Cancer Prevention

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The objectives of this study were to examine serum periplakin expression in patients with urothelial carcinoma of the urinary bladder and in normal controls, and to examine relationships with clinicopathological findings. Detection of serum periplakin was performed in 50 patients and 30 normal controls with anti-periplakin antibodies using the automatic dot blot system, and a micro-dot blot array with a 256 solid-pin system. Levels in patients with urothelial carcinoma of the urinary bladder were significantly lower than those in normal controls (0.31 and 5.68, respectively; p<0.0001). The area under the receiver-operator curve level for urothelial carcinoma of the urinary bladder was 0.845. The sensitivity and specificity, using a cut-off point of 4.045, were 83.7% and 73.3%, respectively. In addition, serum periplakin levels were significantly higher in patients with muscle-invasive cancer than in those with nonmuscle-invasive cancer (P = 0.03). In multivariate Cox proportional hazards regression analysis, none of the clinicopathological factors was associated with an increased risk for progression and cancer-specific survival. Examination of the serum periplakin level may play a role as a noninvasive diagnostic modality to aid urine cytology and cystoscopy.

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Identification of Periplakin as a New Target for Autoreactivity in Idiopathic Pulmonary Fibrosis

Cited by 103 publications

References 38 publications

Autoimmunity to Vimentin Is Associated with Outcomes of Patients with Idiopathic Pulmonary Fibrosis

Autoimmunity to Vimentin Is Associated with Outcomes of Patients with Idiopathic Pulmonary Fibrosis

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

Serum Periplakin as a Potential Biomarker for Urothelial Carcinoma of the Urinary Bladder

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