Genetic control of CCL24, POR, and IL23R contributes to the pathogenesis of sarcoidosis.

Sarcoidosis is a genetically complex systemic inflammatory disease that affects multiple organs. We present a GWAS of a Japanese cohort (700 sarcoidosis cases and 886 controls) with replication in independent samples from Japan (931 cases and 1,042 controls) and the Czech Republic (265 cases and 264 controls). We identified three loci outside the HLA complex, CCL24, STYXL1-SRRM3, and C1orf141-IL23R, which showed genome-wide significant associations (P < 5.0 × 10-8) with sarcoidosis; CCL24 and STYXL1-SRRM3 were novel. The disease-risk alleles in CCL24 and IL23R were associated with reduced CCL24 and IL23R expression, respectively. The disease-risk allele in STYXL1-SRRM3 was associated with elevated POR expression. These results suggest that genetic control of CCL24, POR, and IL23R expression contribute to the pathogenesis of sarcoidosis. We speculate that the CCL24 risk allele might be involved in a polarized Th1 response in sarcoidosis, and that POR and IL23R risk alleles may lead to diminished host defense against sarcoidosis pathogens.

[Clinical features of foreign-born tuberculosis patients treated at our hospital].

INTRODUCTION: There has been an increase in the number of foreign-born tuberculosis (TB) patients residing in Japan. The purpose of this study is to clarify the clinical features of the foreign-born TB patients treated at our hospital. MATERIALS AND METHODS: This study included foreign-born TB patients treated at our hospital between 2000 and 2009. A comparison was performed with Japanese TB patients in the same age group who were treated in the same period. RESULTS: There were 44 patients (17 males and 27 females; mean age: 23.6 +/- 5.1). These patients originated from 13 different countries, 12 of which were Asian countries such as China and the Philippines, and 8 of which were WHO-designated high-burden TB countries. The period between the patient's entry into Japan and the onset of TB was less than a year for half of the cases. As compared with the Japanese patients group, the foreign patients group included a significantly higher proportion of students and a significantly large number of cases found by periodic health examination. In terms of clinical findings, no significant difference was observed in the proportion of cavitary cases (37.5%) and of smear positive cases (37.5%); however, the frequency of drug-resistant cases (30.4%) was significantly higher among the foreign patients than the Japanese patients. The cure rate was 75% among foreign-born patients, and there were no defaulters. CONCLUSION: Compared with Japanese patients with the same ages, the foreign-born TB patients treated at our hospital included a high proportion of students from high-burden TB countries who were detected by periodic health examination and a higher proportion of drug-resistant cases. The treatment outcome was satisfactory without any defaulters. Periodic mass health examinations and drug susceptibility tests are important, and careful health examination is necessary for all individuals from high-burden TB countries when they enter Japan.

Circulating levels of both Th1 and Th2 chemokines are elevated in patients with sarcoidosis.

BACKGROUND: In sarcoidosis, the T helper type 1 (Th1) response tends to predominate at affected disease sites; however, whether Th1/Th2 polarization occurs in the peripheral circulation is unknown. METHODS: Fifty-two patients with sarcoidosis and 21 healthy volunteers were investigated. The concentrations of interferon-inducible protein 10 (IP-10)/CXCL10 and thymus- and activation-regulated chemokine (TARC)/CCL17 in the serum, bronchoalveolar lavage fluid (BALF) and culture supernatant were measured by an enzyme-linked immunosorbent assay. The circulating CXCR3+ CD4+ T cells and CCR4+ CD4+ T cells were assessed by flow cytometry. RESULTS: The CXCR3- or CCR4-positive ratios among CD4+ T cells were both higher in sarcoidosis than in healthy volunteers. The serum levels of both IP-10 and TARC of the patients with sarcoidosis were significantly higher than those of the healthy volunteers. In patients with sarcoidosis, a larger amount of IP-10 was generated by the BALF cells, whereas IP-10 production by peripheral blood mononuclear cells did not increase in comparison to the control subjects. The TARC levels produced by peripheral blood mononuclear cells of sarcoidosis patients were significantly higher than those of the controls, while no difference existed between the 2 groups regarding TARC production by BALF cells. CONCLUSION: IP-10 is mainly produced at the lung and TARC in the peripheral circulation in sarcoidosis patients. Both IP-10 and TARC cooperatively play a role in the pathogenesis of sarcoidosis.

Circulating IL-12 p40 is increased in the patients with sarcoidosis, correlation with clinical markers.

OBJECTIVE: Sarcoidosis is considered to be provocated by highly activated Th1 lymphocytes. Because interleukin 12 (IL-12) is one of the most important cytokines for promoting Th1 reaction, we tried to detect IL-12 and its ligand IL-12 receptor in sarcoidosis patients. PATIENTS AND METHODS: We measured the serum concentration of IL -12 p40 and IL-12 p70 by ELISA method with serum obtained from 60 sarcoidosis patients, and compared the serum concentration of IL-12 p40 with other clinical markers of disease activity. Next, we examined mRNA production of IL-12 p35, IL-12 p40, IL-12Rbeta1, and IL-12beta2 of sarcoid lymph nodes with semi-quantitative RT-PCR method. RESULTS: First, we showed that circulating IL-12 p40 was highly increased in sarcoidosis patients and was related to various other clinical markers. In particular, it was correlated with the number of involved organs which means systemic disease expansion. Second, we showed that the mRNA expression of IL-12 p40 and IL-12 receptor beta2 subunit was increased in sarcoid lymph nodes. CONCLUSION: Our data suggest that increased circulating IL-12 p40 is an important systemic marker for disease activity, and it reflects the increased interaction between Il-12 and its ligand IL-12R in sarcoid lesions of involved organs.

Virus associated hemophagocytic syndrome accompanied by acute respiratory failure caused by influenza A (H3N2).

A 40-year-old Japanese woman was admitted to Oita University Hospital with progressive dyspnea, consciousness disturbance and severe cytopenias. Her chest roentgenogram showed diffuse bilateral infiltrates. She was therefore forced to receive mechanical ventilation. Bone marrow aspiration disclosed numerous hemophagocytic histiocytes, thus suggesting her condition to be hemophagocytic syndrome. In addition, she also developed myocarditis and renal failure. Pulsed methylprednisolone, gamma-globulin, granulocyte colony-stimulating factor and sivelestat sodium hydrate were administrated, and thereafter the patient recovered from cytopenia and organ failure. Afterwards, influenza A H3N2 was detected from bronchial extracts. We should recognize that an influenza A virus infection can induce hemophagocytic syndrome and acute respiratory failure as the initial manifestations of multiple organ failure.

Links between bronchial asthma and allergic rhinitis in the Oita Prefecture, Japan.

Recent studies have strengthened the concept that bronchial asthma and allergic rhinitis are manifestations of an inflammatory process within a continuous airway. This study was performed to compare clinical findings in asthma with or without rhinitis in Japan. Nasal symptoms were present in 99.6% of asthma patients. The prevalence of allergic rhinitis in patients with asthma was 52.4%. Bronchial asthma attacks in one third of patients with rhinitis were coincident with worsening of nasal symptoms. In adults (> 16 years of age), rhinitis frequently preceded asthma, whereas asthma preceded rhinitis in children (< 16 years of age). The frequency of rhinitis in asthma decreases with increasing age. This study demonstrated a clear link between upper and lower airway disorders in Japan.

National survey on status of steroid therapy for cardiac sarcoidosis in Japan.

AIM: This investigation was undertaken to clarify the current status of steroid therapy for cardiac sarcoidosis in Japan. METHODS: A questionnaire survey was conducted throughout Japan concerning cases in which steroid therapy had been administered. Replies describing 52 cases (15 men, 37 women; mean age +/- SD, 59.8 +/- 14.5 years) were analyzed. RESULTS: Of the 49 patients whose New York Heart Association (NYHA) functional classification was reported, 29 (55.8%) were in class I; 13 (25.0%) class II; 4 (7.7%) class III and 3 (5.8%) class IV. The most common initial steroid dose (used in 35 cases, or 67.3%) was 30 mg/day or 60 mg on alternate days. In most cases (85.4%), this dose was continued for 1 month followed by tapering by 5 mg every 2 to 4 weeks until reaching the maintenance dose of 5 to 10 mg/day. Steroid therapy was reported to result in improvement in 54%, no change in 40%, and deterioration in 6%. CONCLUSION: This nationwide questionnaire survey indicated fairly uniform patterns of steroid therapy for cardiac sarcoidosis in Japan, with clinical improvement in over one-half of cases and possible stabilization in most others.

Clinical characteristics of 195 Japanese sarcoidosis patients treated with oral corticosteroids.

Questionnaires were sent to 46 hospitals of all over Japan in order to obtain the clinical data on sarcoidosis patients who were treated with oral corticosteroids. The number of female patients was greater than that of male patients (1.5:1), and the average age was 44.9 +/- 16.5 with peaks at 20 and at 50 to 60. The markers of disease activity were high in serum or bronchoalveolar lavage fluids (BALF): specifically, the serum angiotensin-converting enzyme (sACE) was 27.9 +/- 31.9 IU/ml (n.v. < 21.4), and the CD4/CD8 lymphocyte ratio was 6.5 +/- 5.7. Eye involvement was the most common reason for systemic steroid therapy, followed in order by lung and heart involvement. The main reasons for steroid therapy were the exacerbation of ocular symptoms, visual disturbance, respiratory symptoms, such as cough or exertional dyspnea, progression of chest radiographic findings, heart failure and severe arrhythmia, such as AV block. The initial corticosteroid dose was usually 30 mg of predinisolone per day, but for some refractory cases, a 40-60 mg per day was used. Immunosuppressive drugs, such as methotrexate, were also used in the small number of patients who responded poorly to the steroid. Overall, a good clinical response to the drug was found in 70-80% of the steroid treated patients, but in those with cardiac disease, the response rate was only 48%.

Elevated levels of thymus- and activation-regulated chemokine in bronchoalveolar lavage fluid from patients with eosinophilic pneumonia.

Thymus- and activation-regulated chemokine (TARC/CCL17) is a lymphocyte-directed CC chemokine, which plays a role in the recruitment of CC chemokine receptor-4 positive T helper 2 (Th2) cells. In this study, we measured concentrations of TARC and Th2 cell-derived cytokines in bronchoalveolar lavage (BAL) fluid, as well as TARC concentrations in serum from patients with eosinophilic pneumonia and other interstitial lung diseases. TARC was significantly elevated in BAL fluids from patients with eosinophilic pneumonia (median, 240 pg/ml), whereas TARC was undetectable (< 7 pg/ml) in most cases of hypersensitivity pneumonitis, sarcoidosis, and idiopathic pulmonary fibrosis, as well as in healthy control subjects. Also, when present, quantities were less than 20 pg/ml. Elevated concentrations of interleukin (IL)-4, IL-5, and IL-13 were also detected in BAL fluid from patients with eosinophilic pneumonia. Interestingly, TARC concentrations in BAL fluids were closely correlated with the concentrations of IL-5 and IL-13. A serial examination showed that elevated TARC in BAL fluid rapidly fell to below detectable limits preceding decreases in IL-5 concentration and eosinophil percentage. Our results, in concordance with previous studies, demonstrate the potential activity of TARC for recruiting Th2 cells to the lungs and suggest a significant role for TARC in the pathogenesis of eosinophilic pneumonia.