Michiaki Tokuda

Non-specific interstitial pneumonia as pulmonary involvement of systemic sclerosis

The pathological features of lung disease in nine patients with systemic sclerosis (SSc) were evaluated. The patients comprised one man and eight women, with a median age of 58 years. SSc was diagnosed according to the criteria of the American Rheumatism Association. In all patients, high resolution computed radiographic scanning of the lungs (HRCT) was performed, and apparent honeycomb formation was seen in four patients. Pathologically, four patients were diagnosed with usual interstitial pneumonia (UIP), three with non-specific interstitial pneumonia (NSIP) group II, one NSIP group II–III, and one NSIP group II with diffuse alveolar damage. HRCT showed no apparent honeycomb formations in patients diagnosed with NSIP. This is the first report describing NSIP as a pulmonary complication of SSc.

Lung cancer associated with several connective tissue diseases: with a review of literature

Abstract. The association between connective tissue disease (CTD) and malignancy has been an area of debate. Whether this relation is casual or causal, it would seem that the importance of their possible relationship is twofold. The purpose of this study is to describe the clinical features of lung cancer associated with several CTDs. Patients with CTD associated with lung cancer were retrospectively evaluated. A review of the clinical features of 153 reported cases from 1944 to the present was conducted. There were 82 females and 71 males, with a median age of 58. Histological types of lung cancer were as follows, bronchioloalveolar cell carcinoma (39 cases), adenocarcinoma (36), squamous cell carcinoma (28), small cell lung cancer (27), large cell carcinoma (6), others (8), and unknown (10). There was a relationship between smoking and development of lung cancer in patients with rheumatoid arthritis (RA) and polymyositis/dermatomyositis (PM/DM). The majority of patients with progressive systemic sclerosis (PSS) who developed lung cancer were female, with underlying interstitial fibrosis, and most tumors were of bronchioloalveolar cell or adenocarcinoma cell type. Patient characteristics were significantly different among the various groups of CTD associated with lung cancer.

Sequential changes of KL-6 in sera of patients with interstitial pneumonia associated with polymyositis/dermatomyositis

OBJECTIVE KL-6 is a mucin-like high molecular weight glycoprotein, which is strongly expressed on type II alveolar pneumocytes and bronchiolar epithelial cells. It has been demonstrated that the KL-6 antigen is a useful marker for estimating the activity of interstitial pneumonia. In this study, it is hypothesised that serum KL-6 is a useful marker to evaluate the activity of interstitial pneumonia associated with polymyositis/dermatomyositis (PM/DM). METHODS KL-6 was measured in sera in 16 patients diagnosed with PM/DM. Five had non-specific interstitial pneumonia (NSIP), three had diffuse alveolar damage (DAD), and eight had no pulmonary involvement, and 10 were normal non-smokers as a control group. The correlation was also evaluated between the KL-6 level and each clinical course in patients with pulmonary involvement associated with PM/DM. Immunohistochemical analysis using monoclonal anti-KL-6 antibody was also performed. RESULTS KL-6 concentrations in sera of patients with interstitial pneumonia associated with PM/DM were significantly high compared with those of PM/DM without interstitial pneumonia, and normal non-smokers. KL-6 concentrations in sera in patients with DAD significantly increased compared with those of other groups. KL-6 values in sera changed according to the progression or improvement of interstitial pneumonia. Immunohistochemical study using pulmonary tissues obtained from patients with DAD demonstrated that the hyaline membrane, proliferating type II pneumocytes, bronchial epithelial cells and some endothelial cells in pulmonary veins were stained by antihuman KL-6 antibody. CONCLUSION These data demonstrate that measurement of serum KL-6 was a useful marker to evaluate the activity of acute interstitial pneumonia associated with PM/DM.

Nonspecific interstitial pneumonia as pulmonary involvement of primary Sjögren's syndrome.

Abstract. The pathologic patterns of lung involvement in nine patients with Sjögrens syndrome (SjS) are evaluated. The patients consisted of three males and six females, with a median age of 59 years. The SjS was diagnosed according to the criteria of the First International Seminar on SjS. In all patients, high-resolution computed radiographic scanning (HRCT) of the lungs was performed, and apparent honeycomb or microhoneycomb formation was observed in six patients. Pathologically, six patients were diagnosed with usual interstitial pneumonia (UIP), and three were diagnosed with nonspecific interstitial pneumonia/fibrosis (NSIP) (group II). There were no apparent honeycomb formations on HRCT in patients diagnosed with NSIP. In conclusion, NSIP is also a possible histologic classification of interstitial pneumonia associated with SjS.

Primary lung cancer associated with polymyositis/dermatomyositis, with a review of the literature.

Abstract It has been suggested that lung cancer is frequently associated with polymyositis/dermatomyositis (PM/DM). The purpose of this study was to describe the clinical features of primary lung cancer associated with PM/DM. We first describe the clinical features of two cases treated in our hospital, and then provide a review of the literature. Finally, 24 patients (five females and 19 males) with primary lung cancer associated with PM/DM are retrospectively evaluated. Histological types of lung cancer were as follows: small cell lung cancer (n=7), squamous cell carcinoma (n=5), adenocarcinoma (n=2), others (n=5), and unknown (4). The onset of PM/DM is frequently observed before the detection of lung cancer. This is the first report to describe the clinical features of lung cancer associated with PM/DM.

Lymphocyte subsets in lung tissues of interstitial pneumonia associated with untreated polymyositis/dermatomyositis

Abstract. This study was designed to evaluate the distribution of lymphocyte subsets in lung specimens obtained by surgical lung biopsy from 12 patients with interstitial pneumonia associated with untreated polymyositis/dermatomyositis (PM/DM). Differences of histological findings and distributions of lymphocyte subsets between PM and DM were also evaluated. Distributions of B lymphocytes, CD4-positive T lymphocytes, and CD8-positive T lymphocytes were evaluated immunohistochemically. Interstitial pneumonia was pathologically classified as basically nonspecific interstitial pneumonia (NSIP) in all patients. Immunohistochemically, the distribution of B lymphocytes was mostly restricted to inside and/or around lymphoid follicles. The CD4-positive T lymphocytes were distributed diffusely in fibrotic areas and unrelated to lymphoid follicles. Most CD8-positive T lymphocytes were diffusely distributed, especially in relatively normal alveoli. There were no significant differences in the distribution of lymphocyte subsets between PM and DM. Although the distribution of B lymphocytes and CD4- and CD8-positive T lymphocytes in the lung were different, there were no significant differences in distributions of lymphocyte subsets between PM and DM.

Growth Hormone Prevents Fas-Induced Apoptosis in Lymphocytes through Modulation of Bcl-2 and Caspase-3

Objective: Growth hormone (GH) has been reported to have a potent effect on the immune system. However, the detailed mechanism of the effect of GH on the immune system has not yet been clarified. This study was designed to investigate the nature of this mechanism. Methods: In the present study, we investigated the effects of GH on the susceptibility of both human CEM/C7 lymphocytes and human IM-9 lymphocytes to Fas-induced apoptosis. Results: Both cell lines expressed GH receptor mRNA. GH rescued Fas-induced suppression of [3H]-thymidine incorporation into each cell line. GH prevented Fas-induced apoptosis in each cell line without changing Fas antigen expression. We next investigated the mechanisms of the prevention of Fas-induced apoptosis, by focusing on intracellular molecules related to the apoptotic signal. Bcl-2 expression was increased by GH treatment in both CEM/C7 and IM-9 lymphocytes. GH also downregulated caspase-3 expression and inhibited activation of caspase-3 in both cell lines. Conclusion: These findings suggest that GH regulates the human immune system through inhibition of Fas-induced apoptosis in activated T and B lymphocytes.

Growth hormone restores glucocorticoid-induced T cell suppression

Growth hormone (GH) is a potent anabolic hormone, and its clinical use has been extended to the improvement of metabolic imbalance in many disease,s including autoimmune disorders treated with glucocorticoids (GCs). GH has, however, a potential action on the immune system, and this might be a demerit in GH therapy for those diseases. We report here the anti‐GC effects of GH on T lymphocytes. Human peripheral T lymphocytes (HPTLs) expressed GH receptor mRNA. GH stimulated tyrosine phosphorylation of cellular proteins, including JAK2 and STAT5b in HPTLs. GH and IGF‐I alleviated dexamethasone (Dex)‐induced suppression of [3H]thymidine incorporation into HPTLs. GH alleviated Dex‐induced apoptosis in CD4+ (positive) HPTLs. GH increased Bcl‐2 expression in CD4+ HPTLs but not in CD8+ HPTLs. In vivo, GH raised the CD4/8 ratio of T lymphocytes in rats chronically administered with Dex. These findings indicate that GH may inhibit GC‐induced apoptosis predominantly in CD4+ T lymphocytes and present important implications of GH therapy, especially for autoimmune disorders treated with GCs.

Detection of anti-cytokeratin 8 antibody in the serum of patients with cryptogenic fibrosing alveolitis and pulmonary fibrosis associated with collagen vascular disorders

BACKGROUND It has been suggested that the humoral immune system plays a role in the pathogenesis of cryptogenic fibrosing alveolitis (CFA). Although circulating autoantibodies to lung protein(s) have been suggested, none of the lung proteins have been characterised. The purpose of this study was to determine the antigen to which the serum from patients with pulmonary fibrosis reacted. METHODS The anti-A549 cell antibody was characterised in a patient with CFA using Western immunoblotting and immunohistochemical staining of A549 cells. As we identified that one of the antibodies against A549 cells was anti-cytokeratin 8, the expression of mRNA of cytokeratin 8 in A549 cells was evaluated. In addition, we attempted to establish an enzyme linked immunosorbent assay to measure the levels of anti-cytokeratin 8 antibody in the serum of patients with CFA and pulmonary fibrosis associated with collagen vascular disorders (PF-CVD). RESULTS Initially two anti-A549 cell antibodies were detected in the serum of patients with pulmonary fibrosis, one of which was characterised as anti-cytokeratin 8 antibody by Western immunoblotting. We were able to establish an ELISA to measure anti-cytokeratin 8 antibody and found significantly higher levels in patients with CFA and PF-CVD than in normal volunteers, patients with sarcoidosis, pneumonia, and pulmonary emphysema. CONCLUSIONS One of the anti-A549 cell antibodies in the serum of patients with CFA was against cytokeratin 8. The serum levels of anti-cytokeratin 8 antibody were increased in patients with CFA and PF-CVD. These results suggest that anti-cytokeratin 8 antibody may be involved in the process of lung injury in pulmonary fibrosis.

Two cases of refractory thrombotic thrombocytopenic purpura associated with collagen vascular disease were significantly improved by rituximab treatment

Thrombotic thrombocytopenic purpura (TTP) is a rare disorder of small vessels. TTP is associated with deficiency of the von Willebrand factor-cleaving protease, ADAMTS13, and its inhibitor. Low ADAMTS13 activity is present in most of idiopathic TTP patients. The prognosis of TTP was improved by plasma exchange treatment, which replaces the ADAMTS13 and removes ADAMTS13 inhibitor. However, ADAMTS13 activity is normal in some TTP patients. These are found among the secondary TTP patients associated with collagen disease, hematopoietic stem cell transplantation, malignancy, or drugs. In addition, most of them do not respond to plasma exchange. On the other hand, several reports demonstrated that rituximab, which is an anti-CD20 monoclonal antibody, is effective for refractory TTP cases caused by ADAMTS13 deficiency. It is considered that the effect of rituximab is associated with disappearance of ADAMTS13 inhibitor. However, rituximab therapy was effective for the TTP patients with normal ADAMTS13 activity in our cases. We considered another mechanism of rituximab for TTP cases.