Patients with Idiopathic Pulmonary Fibrosis with Antibodies to Heat Shock Protein 70 Have Poor Prognoses

Kahloon, Rehan; Xue, Jun; Bhargava, Arpit; Csizmadia, Eva; Otterbein, Leo E.; Kass, Daniel J.; Bon, Jessica; Soejima, Makoto; Levesque, Marc C.; Lindell, Kathleen O.; Gibson, Kevin F.; Kaminski, Naftali; Banga, Gunjan; Oddis, Chester V.; Pilewski, Joseph M.; Sciurba, Frank C.; Donahoe, Michael P.; Zhang, Yingze; Duncan, Steven R.

doi:10.1164/rccm.201203-0506oc

Cited by 170 publications

(196 citation statements)

References 45 publications

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“…Heparinized peripheral blood was obtained from consecutive patients with IPF (5,14,16,37), healthy volunteers, and subjects with cigarette smoking-attributable chronic obstructive pulmonary disease (COPD) and/or emphysema (henceforth collectively denoted as COPD) (38,39).…”

Section: Subjects and Specimensmentioning

confidence: 99%

“…All subjects with IPF fulfilled American Thoracic Society and European Respiratory Society diagnostic criteria, and had negative conventional autoimmune serologic tests (5,14,16,37). IPF acute exacerbations were defined by worsening hypoxemia and/or dyspnea during the preceding 30 days or less, with characteristic acute radiographic abnormalities, and no other attributable cause after thorough clinical evaluations (40).…”

Section: Subjects and Specimensmentioning

confidence: 99%

“…Optical densities at 405 nm of replicate specimens were determined in a plate reader, blanked against untreated wells (5,14).…”

Section: Circulating Cxcl13mentioning

confidence: 99%

“…B-cell aggregates in disease tissues are characteristic lesions of ongoing immune responses, and these lymphocytes have also been shown to directly exert numerous pathogenic effects (6)(7)(8)(9)(10). Complexes of antigens with the antibodies produced by B cells trigger cytotoxic and proinflammatory cascades (11), and these complexes are present in the circulation (12), bronchoalveolar lavage (13), and lung parenchyma of patients with IPF (5,14). Circulating B-lymphocyte stimulating factor (BLyS), a trophic factor necessary for B-cell survival, maturation, and antibody production, is increased and correlated with the clinical features of patients who have recognized autoantibody-mediated disorders, such as systemic lupus erythematosus and rheumatoid arthritis.…”

mentioning

confidence: 99%

“…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%

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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

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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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Section: Subjects and Specimensmentioning

confidence: 99%

Section: Subjects and Specimensmentioning

confidence: 99%

“…Optical densities at 405 nm of replicate specimens were determined in a plate reader, blanked against untreated wells (5,14).…”

Section: Circulating Cxcl13mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

See 3 more Smart Citations

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

Self Cite

166

115

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Review: Interstitial Lung Disease Associated With Systemic Sclerosis and Idiopathic Pulmonary Fibrosis: How Similar and Distinct?

Herzog

Mathur

Tager

et al. 2014

Arthritis & Rheumatology

166

132

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The contribution of animal models to understanding the role of the immune system in human idiopathic pulmonary fibrosis

et al. 2020

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Pulmonary fibrosis occurs in a heterogeneous group of lung disorders and is characterised by an excessive deposition of extracellular matrix proteins within the pulmonary interstitium, leading to impaired gas transfer and a loss of lung function. In the past 10 years, there has been a dramatic increase in our understanding of the immune system and how it contributes to fibrogenic processes within the lung. This review will compare some of the models used to investigate the pathogenesis and treatment of pulmonary fibrosis, in particular those used to study immune cell pathogenicity in idiopathic pulmonary fibrosis, highlighting their advantages and disadvantages in dissecting human disease.

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Patients with Idiopathic Pulmonary Fibrosis with Antibodies to Heat Shock Protein 70 Have Poor Prognoses

Cited by 170 publications

References 45 publications

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

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

Review: Interstitial Lung Disease Associated With Systemic Sclerosis and Idiopathic Pulmonary Fibrosis: How Similar and Distinct?

The contribution of animal models to understanding the role of the immune system in human idiopathic pulmonary fibrosis

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