Pulmonary fibrosis with predominant CD8 lymphocytic alveolitis and anti-Jo-1 antibodies

Sauty, Alain; Rochat, T.; Schoch, Otto D.; Hamacher, Jürg; Am, Kurt; Jm, Dayer; Nicod, Laurent P.

doi:10.1183/09031936.97.10122907

Cited by 103 publications

(81 citation statements)

References 22 publications

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“…Analyses of alveolitis using BAL fluid showed accumulation of neutrophils with or without increased percentages of T cells in the small airways of CTD-ILD (4,5), and neutrophils were reported as important effector cells and associated with poor outcome of CTD-ILD (5)(6)(7)(8). The CD4/CD8 ratios in BAL fluid of CTD-ILD patients vary with reports (30,(35)(36)(37)(38)(39); however, a previous report showed that correlation between CD4/CD8 ratios in lung tissue and CD4/CD8 ratios in BAL fluid was weak and that CD4/CD8 ratio in BAL fluid would rather reflect the extent of fibrosis (40). SKG arthritis is known to be mediated by Th17 cells (13), but the mechanisms underlying the progression of ILD are yet to be clarified.…”

Section: Discussionmentioning

confidence: 76%

GM-CSF but Not IL-17 Is Critical for the Development of Severe Interstitial Lung Disease in SKG Mice

Shiomi

Usui

Ishikawa

et al. 2014

The Journal of Immunology

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Interstitial lung disease (ILD) is a common complication and sometimes a prognostic factor of connective tissue diseases (CTDs) in humans. However, suitable animal model of severe CTD-associated ILD (CTD-ILD) has been limited. In this study, we showed that zymosan-treated SKG mice developed not only arthritis but also chronic–progressive ILD with high mortality over several months. The pathological and clinical features of ILD in zymosan-treated SKG mice were similar to that of human severe CTD-ILD. ILD in this mouse was characterized by massive infiltration of Th17 cells, GM-CSF–producing CD4+ T cells, and CD11b+ Gr1+ neutrophils with fibrosis. Naive SKG T cells were skewed to differentiate into GM-CSF–producing cells, and GM-CSF secreted by T cells enhanced IL-6 and IL-1β production by macrophages, which in turn enhanced differentiation of IL-17A– and/or GM-CSF–producing T cells and infiltration of neutrophils into lung. Neutralization of GM-CSF completely blocked the development of this ILD, and the blocking of IL-6 signaling resulted in partial prevention of it, whereas neutralization of IL-17A did not. In contrast, the progression of arthritis was inhibited by the neutralization of GM-CSF and slightly by the neutralization of IL-17A, but not by the blocking of IL-6 signaling. These data suggested zymosan-treated SKG mice could be a useful mouse model of severe CTD-ILD, and GM-CSF, rather than IL-17A or IL-6, contributed to the development of ILD in zymosan-treated SKG mice, indicating that neutralization of GM-CSF would be a useful therapeutic strategy for severe CTD-ILD.

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Section: Discussionmentioning

confidence: 76%

GM-CSF but Not IL-17 Is Critical for the Development of Severe Interstitial Lung Disease in SKG Mice

Shiomi

Usui

Ishikawa

et al. 2014

The Journal of Immunology

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“…38 In the presence of ILD, bronchoalveolar lavages consistently revealed lymphocytosis with a marked predominance of CD8 þ T cells, which was associated with anti-Jo-1 autoantibodies. 39 Recently, CX3CL1 and its receptor CX3CR1 might contribute to the inflammatory cell infiltration into the affected muscle and lung with ILD in PM/DM patients, among which CX3CR1 was expressed on a majority of CD8 þ T cells, most macrophages, and some CD4 þ T cells in the lung. 40 In our study, CD8 þ T cell, CD68 þ cell infiltrations were significantly increased in lung tissues in both PM and DM, further confirms that PM and DM have similar mechanisms in the lung.…”

Section: Discussionmentioning

confidence: 99%

Treatment with CA-074Me, a Cathepsin B inhibitor, reduces lung interstitial inflammation and fibrosis in a rat model of polymyositis

Zhang

et al. 2015

Laboratory Investigation

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Cathepsin B (CB) is involved in the turnover of proteins and has various roles in maintaining the normal metabolism of cells. In our recent study, CB is increased in the muscles of polymyositis/dermatomyositis (PM/DM). However, the role of CB in interstitial lung disease (ILD) has not been reported. ILD is a frequent complication of PM/DM, which is the leading cause of death in PM/DM. It carries high morbidity and mortality in connective tissue diseases, characterized by an overproduction of inflammatory cytokines and induced fibrosis, resulting in respiratory failure. The etiology and pathogenesis of ILD remain incompletely understood. This study investigated whether treatment with CA-074Me, a specific inhibitor of CB, attenuates ILD in PM. CB expression, inflammation, and fibrosis were analyzed in the lung tissues from patients with PM/DM. The animal model of PM was induced in guinea pigs with Coxsackie virus B1 (CVB1). CA-074Me was given 24 h after CVB1 injection for 7 consecutive days. At the end of the experiment, the animals were killed and lung tissues were collected for the following analysis. Inflammation, fibrosis and apoptosis cells, and cytokines were assessed by histological examinations and immunohistochemical analyses, western blot analysis and transferasemediated dUTP nick-end labeling assay. In patients with PM/DM, the protein levels of CB were significantly elevated in lung tissues compared with healthy controls, which correlated with increases in inflammation and fibrosis. Similarly, the expression of CB, inflammation and fibrosis, CD8 þ T cell, CD68 þ cell, tumor necrosis factor-alpha, transforming growth factor-beta1 infiltrations, and apoptotic cell death were significantly increased in lung tissues of the guinea-pig model of CVB1-induced PM. These changes were attenuated by the administration of CA-074Me. In conclusion, this study demonstrates that PM/DM increases CB expression in lung tissues and inhibition of CB reduces ILD in a guinea-pig model of CVB1-induced PM. This finding suggests that CB may be a potential therapeutic target for ILD.

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“…These antibodies are directed against synthetases, the cytoplasmic enzymes facilitating attachment of amino acids to their correspondent transfer RNAs (tRNAs). Clinical characteristics of the syndrome include myositis, Raynaud's phenomenon, fever, mechanic's hands and arthralgias [51][52][53].…”

Section: Antisynthetase Syndromementioning

confidence: 99%

Occult connective tissue diseases mimicking idiopathic interstitial pneumonias

Toya²,

2007

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In patients with interstitial lung disease (ILD), the diagnosis of idiopathic interstitial pneumonia is usually made after excluding, among other conditions, connective tissue diseases (CTDs). Although in most patients with a CTD and respiratory symptoms, the systemic nature of the disease is obvious, the ILD-related manifestations in CTDs may often dominate the clinical picture or precede systemic findings and thus mimic idiopathic interstitial pneumonia.With the exception of systemic lupus erythematosus, all CTDs may imitate chronic idiopathic interstitial pneumonias. In this setting, clues to an underlying CTD may be entirely absent or include subtle findings from various systems, including skin, vascular and musculoskeletal system or internal organs. Since nonspecific interstitial pneumonia is a relatively frequent histological pattern in CTDs, biopsy reports of nonspecific interstitial pneumonia should also prompt a search for an underlying CTD.Ultimately, diagnosis of a CTD requires confirmation with immunological testing; interpretation of the various laboratory tests should always be carried out in conjunction with clinical findings.The present article reviews specific clinical aspects of connective tissue disease-related interstitial lung disease that may help differentiate it from idiopathic interstitial pneumonia, especially when interstitial lung disease is the predominant or sole manifestation of an occult connective tissue disease.

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Pulmonary fibrosis with predominant CD8 lymphocytic alveolitis and anti-Jo-1 antibodies

Cited by 103 publications

References 22 publications

GM-CSF but Not IL-17 Is Critical for the Development of Severe Interstitial Lung Disease in SKG Mice

GM-CSF but Not IL-17 Is Critical for the Development of Severe Interstitial Lung Disease in SKG Mice

Treatment with CA-074Me, a Cathepsin B inhibitor, reduces lung interstitial inflammation and fibrosis in a rat model of polymyositis

Occult connective tissue diseases mimicking idiopathic interstitial pneumonias

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