Yoshinori Tanino

Anti-NXP2 autoantibodies in adult patients with idiopathic inflammatory myopathies: possible association with malignancy

Objectives Myositis-specific autoantibodies (MSAs) are useful tools for identifying clinically homogeneous subsets and predicting prognosis of patients with idiopathic inflammatory myopathies (IIM) including polymyositis (PM) and dermatomyositis (DM). Recent studies have shown that anti-NXP2 antibody (Ab) is a major MSA in juvenile dermatomyositis (JDM). In this study the frequencies and clinical associations of anti-NXP2 Ab were evaluated in adult patients with IIM. Methods Clinical data and serum samples were collected from 507 adult Japanese patients with IIM (445 with DM and 62 with PM). Eleven patients with JDM, 108 with systemic lupus erythematosus, 433 with systemic sclerosis and 124 with idiopathic pulmonary fibrosis were assessed as disease controls. Serum was examined for anti-NXP2 Ab by immunoprecipitation and western blotting using polyclonal anti-NXP2 Ab. Results Seven patients (1.6%) with adult DM and one (1.6%) with adult PM were positive for anti-NXP2 Ab. Except for two patients with JDM, none of the disease controls were positive for this autoantibody. Among eight adult patients with IIM, three had internal malignancies within 3 years of diagnosis of IIM. Another patient with DM also had a metastatic cancer at the diagnosis. All of the carcinomas were at an advanced stage (stage IIIb–IV). Conclusions While less common than in juvenile IIM, anti-NXP2 Ab was found in adult IIM. Anti-NXP2 Ab may be associated with adult IIM with malignancy.

Clinical usefulness of fractional exhaled nitric oxide for diagnosing prolonged cough

BACKGROUND Prolonged cough is one of the troublesome symptoms commonly seen in daily practice. Especially, detection of allergic cough such as bronchial asthma (BA), cough variant asthma (CVA) and eosinophilic bronchitis without asthma (EB) is important because the prevalence of these disorders are high. We previously reported fractional exhaled nitric oxide (FeNO) can be a non-invasive marker of allergic airway inflammation. We examined whether FeNO could be applicable for the proper diagnosis of prolonged cough. METHOD About 71 consecutive subjects complaining prolonged cough who gave informed consent for the study were enrolled. FeNO, pulmonary function tests, bronchial hyperresponsiveness (BHR), IgE, and eosinophils in induced sputum and peripheral blood were measured. Final diagnosis of the subjects was 30 with BA, 18 with CVA, 8 with EB, and 15 with other respiratory disorders (Others). RESULT FeNO had significant correlations with non-specific IgE, mite-specific IgE, FEV/FVC, BHR, and eosinophils. The level of cedar-specific IgE was significantly higher in subjects with EB than CVA. FeNO levels in BA and CVA were significantly higher than those in EB and Others. The optimal cutoff level of FeNO was 38.8 ppb with sensitivity of 79.2% and specificity of 91.3% for distinguishing BA and CVA from EB and Others. CONCLUSION FeNO could be used as a diagnostic marker of prolonged cough, especially for the differential diagnosis BA and CVA from EB and others.

A rapid increase in macrophage-derived versican and hyaluronan in infectious lung disease

The goals of this study were to characterize the changes in chondroitin sulfate proteoglycans and hyaluronan in lungs in acute response to gram-negative bacterial infection and to identify cellular components responsible for these changes. Mice were treated with intratracheal (IT) live Escherichia coli, E. coli lipopolysaccharide (LPS), or PBS. Both E. coli and LPS caused rapid selective increases in mRNA expression of versican and hyaluronan synthase (Has) isoforms 1 and 2 associated with increased immunohistochemical and histochemical staining for versican and hyaluronan in the lungs. Versican was associated with a subset of alveolar macrophages. To examine whether macrophages contribute to versican and hyaluronan accumulation, in vitro studies with primary cultures of bone marrow-derived and alveolar macrophages were performed. Unstimulated macrophages expressed very low levels of versican and hyaluronan synthase mRNA, with no detectible versican protein or hyaluronan product. Stimulation with LPS caused rapid increases in versican mRNA and protein, a rapid increase in Has1 mRNA, and concomitant inhibition of hyaluronidases 1 and 2, the major hyaluronan degrading enzymes. Hyaluronan could be detected following chloroquine pre-treatment, indicating rapid turnover and degradation of hyaluronan by macrophages. In addition, the effects of LPS, the M1 macrophage classical activation agonist, were compared to those of IL-4/IL-13 or IL-10, the M2a and M2c alternative activation agonists, respectively. Versican and Has1 increased only in response to M1 activation. Finally, the up-regulation of versican and Has1 in the whole lungs of wild-type mice following IT LPS was completely abrogated in TLR-4(-/-) mice. These findings suggest that versican and hyaluronan synthesis may play an important role in the innate immune response to gram-negative lung infection.

Reprint of: A rapid increase in macrophage-derived versican and hyaluronan in infectious lung disease.

The goals of this study were to characterize the changes in chondroitin sulfate proteoglycans and hyaluronan in lungs in acute response to gram-negative bacterial infection and to identify cellular components responsible for these changes. Mice were treated with intratracheal (IT) live Escherichia coli, E. coli lipopolysaccharide (LPS), or PBS. Both E. coli and LPS caused rapid selective increases in mRNA expression of versican and hyaluronan synthase (Has) isoforms 1 and 2 associated with increased immunohistochemical and histochemical staining for versican and hyaluronan in the lungs. Versican was associated with a subset of alveolar macrophages. To examine whether macrophages contribute to versican and hyaluronan accumulation, in vitro studies with primary cultures of bone marrow-derived and alveolar macrophages were performed. Unstimulated macrophages expressed very low levels of versican and hyaluronan synthase mRNA, with no detectible versican protein or hyaluronan product. Stimulation with LPS caused rapid increases in versican mRNA and protein, a rapid increase in Has1 mRNA, and concomitant inhibition of hyaluronidases 1 and 2, the major hyaluronan degrading enzymes. Hyaluronan could be detected following chloroquine pre-treatment, indicating rapid turnover and degradation of hyaluronan by macrophages. In addition, the effects of LPS, the M1 macrophage classical activation agonist, were compared to those of IL-4/IL-13 or IL-10, the M2a and M2c alternative activation agonists, respectively. Versican and Has1 increased only in response to M1 activation. Finally, the up-regulation of versican and Has1 in the whole lungs of wild-type mice following IT LPS was completely abrogated in TLR-4(-/-) mice. These findings suggest that versican and hyaluronan synthesis may play an important role in the innate immune response to gram-negative lung infection.

Pulmonary fibrosis in dyskeratosis congenita with TINF2 gene mutation

To the Editor: Dyskeratosis congenita is a rare inherited disorder of ectodermal dysplasia characterised by the classical mucocutaneous triad of abnormal skin pigmentation, nail dystrophy and leukoplakia [1–3], at least one of which is present in around 80–90% of dyskeratosis congenita cases. Bone marrow failure is another common feature, and a variety of other abnormalities ( e.g. dental, gastrointestinal, neurological, ophthalmic, pulmonary and skeletal) have been also described [1–3]. The main causes of mortality in dyskeratosis congenita are bone marrow failure, pulmonary disease and malignancy [1]. Three modes of inheritance have been recognised: X-linked recessive, autosomal dominant and autosomal recessive [1, 3]. Eight dyskeratosis congenita genes ( DKC1 (dyskeratosis congenita 1), TERC (telomerase RNA component), TERT (telomerase reverse transcriptase), NOP10 (nucleolar protein 10), NHP2 , TINF2 (TERF1-interacting nuclear factor 2), TCAB1 and RTEL1 (regulation of telomere elongation helicase 1)) have already been identified, and their mutations account for ∼60% of all dyskeratosis congenita cases [1]. Among the dyskeratosis congenita genes, mutations in TERC , TERT and DKC1 have recently been reported to be associated with familial pulmonary fibrosis and idiopathic pulmonary fibrosis, and pulmonary fibrosis is recognised as one of the features of dyskeratosis congenita. However, the relationship between mutations in the other dyskeratosis congenita genes and pulmonary fibrosis has not yet been clarified. To the best of our knowledge, this is the first case report describing a dyskeratosis congenita patient with pulmonary fibrosis who had a TINF2 mutation. A 43-year-old female visited our hospital with cough and progressive dyspnoea. She had never smoked, and had a …

The relationship between 25-hydroxyvitamin D levels and treatment course of pulmonary tuberculosis

BACKGROUND Low serum vitamin D level is associated with a high risk of developing active tuberculosis (TB). We investigated the relationships between serum vitamin D levels and clinical course of TB after standard chemotherapy in hospitalized non-HIV patients with TB. METHODS Hospitalized patients with TB were recruited between February 2008 and July 2010. Confirmatory tests were performed using sputum smear and culture positivity tests for Mycobacterium tuberculosis. Drug sensitivity testing was performed for all the subjects and those not showing drug resistances for the first-line anti-TB drugs were included in the study. These patients were treated with the standard first-line anti-TB drugs. Serum 25-hydroxyvitamin D [25(OH)D] levels were measured on admission, and the relationships between 25(OH)D and clinical characteristics (laboratory data on admission and treatment outcomes) were examined. We defined vitamin D deficiency as a condition where serum level of 25(OH)D was lower than 20 ng/ml. RESULTS A total of 38 patients were included in the study. Mean (± SD) 25(OH)D levels were 13.7 ± 5.9 ng/ml. The prevalence of vitamin D deficiency was 87%. In 23 patients treated with the standard first-line 4-drug regimen (Age < 80 years) serum 25(OH)D levels showed significant negative correlation with time taken to obtain 3 consecutive negative sputum smears or TB bacteria cultures. This relationship suggests that low serum vitamin D level may not only increase the risk of developing active TB but may also be related to the poor treatment outcomes in these patients. CONCLUSIONS Low serum vitamin D level is a good predictor of prolonged clinical course in patients with active pulmonary TB.

Mannose binding lectin gene polymorphisms and asthma

Background Bronchial asthma is a chronic inflammatory disorder of the airways. Recently, it has been suggested that complement plays significant roles in asthma. Mannose‐binding lectin (MBL) is one of the key molecules in complement activation pathways that are associated with several infectious and immune disorders.

Validation study of asthma screening criteria based on subjective symptoms and fractional exhaled nitric oxide

BACKGROUND In the latest Global Initiative for Asthma guideline, neither sputum eosinophilia nor fractional exhaled nitric oxide (FeNO) have been evaluated prospectively as an aid in asthma diagnosis, but these measurements are being evaluated for potential use in determining optimal treatment. OBJECTIVE To report criteria for screening asthma using subjective symptoms and FeNO levels and results of a prospective validation study using these criteria. METHODS Sixty-one outpatients with recurrent cough, wheezing, or dyspnea underwent measurements of FeNO levels, pulmonary function, methacholine airway responsiveness, and inflammatory cells in induced sputum. The sensitivity, specificity, and concordance achieved using the FeNO-based criteria (at least 1 of the following subjective symptoms: recurrent cough, wheezing, or dyspnea and/or FeNO level ≥ 40 ppb) were analyzed and compared with the values obtained using conventional asthma diagnostic criteria, which includes subjective symptoms with any 2 of the following conditions: airway hyperresponsiveness, reversible airflow limitation, and eosinophilia in induced sputum. RESULTS Of the 61 patients, 41 were diagnosed as having asthma by the conventional criteria, and 33 were diagnosed as having asthma by the FeNO-based criteria, which showed a sensitivity of 78.6%, a specificity of 89.5%, and a concordance rate of 0.62. Nine of 42 patients were misdiagnosed as not having asthma by FeNO-based criteria (mean [SD] FeNO level, 23.9 [8.0] ppb). Seven of 9 patients were diagnosed as having nonatopic asthma according to IgE levels. CONCLUSIONS Asthma may be accurately diagnosed in daily practice on the basis of subjective symptoms and FeNO levels, particularly in atopic patients.

Serum Syndecan-4 as a Possible Biomarker in Patients With Acute Pneumonia

BACKGROUND Syndecan-4 is a transmembrane heparan sulfate proteoglycan expressed in a variety of cells, and glycosaminoglycan side chains of syndecan-4 bind to several proteins, suggesting several biological functions. However, the role of syndecan-4 in acute bacterial pneumonia has not yet been elucidated. METHODS Serum syndecan-4 levels were measured in patients with acute pneumonia, and the relationships between serum syndecan-4 levels and clinical parameters were analyzed. Next, we treated wild-type and syndecan-4-deficient mice with Streptococcus pneumoniae intranasally and analyzed the phenotype of syndecan-4-deficient mice. RESULTS In the patients with acute pneumonia, serum syndecan-4 levels were significantly higher than in the healthy volunteers and correlated negatively with the pneumonia severity score. In addition, in patients who improved with short-term antibiotic therapy, serum syndecan-4 levels were higher on admission and gradually increased during antibiotic therapy. Furthermore, in syndecan-4-deficient mice, the survival rate was significantly worse, and total neutrophil counts in bronchoalveolar lavage fluid, bacterial counts in blood, and plasma levels of inflammatory cytokines were significantly higher than in wild-type mice. CONCLUSIONS These results suggest that syndecan-4 has an anti-inflammatory function in acute pneumonia and could serve as a useful biomarker in these patients.

Clinical significance of serum hyaluronan in chronic fibrotic interstitial pneumonia.

Hyaluronan is an important constituent of the extracellular matrix in lungs, and growing evidence demonstrates its important biological properties in the lung. However, its role in interstitial pneumonia remains to be fully clarified. The goal of this study was to clarify the role of hyaluronan in interstitial pneumonia.