中島 裕史

Objective. FoxP3 induces Treg cells and prevents autoimmune diseases. However, the precise mechanisms of FoxP3 in the prevention of autoimmune diseases remain unknown. We undertook this study to determine the regulatory roles of FoxP3 in autoimmune inflammation by using FoxP3-mutant sf mice. Methods. We characterized interleukin-21 (IL-21)-producing cells in sf mice. We examined the underlying mechanisms of enhanced IL-21 production in sf mouse CD4+ T cells. We examined the roles of IL-21 and CD8+ T cells in autoimmune inflammation in sf mice using IL-21 receptor (IL-21R)-deficient sf mice. Results. IL-21-producing c-Maf+CD4+ T cells, which were distinct from Th17 cells, were increased in sf mice. Increased c-Maf expression was involved in enhanced IL-21 production in sf mouse CD4+ T cells. Experiments using bone marrow chimeric mice showed that lack of cell-extrinsic suppression by FoxP3+ Treg cells, but not cell-intrinsic defects in FoxP3 in sf mouse CD4+ T cells, was mainly involved in the development of IL-21-producing c-Maf+CD4+ T cells in sf mice. IL-21R deficiency prolonged survival and reduced multiorgan autoimmune inflammation in sf mice. Moreover, IL-21R deficiency decreased short-lived effector CD8+ T cells in the lung in sf mice. Furthermore, depletion of CD8+ T cells inhibited lung inflammation in sf mice, suggesting that CD8+ T cells are critical for inducing lung inflammation in sf mice. Conclusion. Unique IL-21-producing c-Maf+CD4+ T cells develop in the absence of FoxP3+ Treg cells, induce short-lived effector CD8+ T cells, and enhance multiorgan autoimmune inflammation in sf mice.

Loss-of-function mutations of EZH2, a catalytic component of polycomb repressive complex 2 (PRC2), are observed in similar to 10% of patients with myelodysplastic syndrome (MDS), but are rare in acute myeloid leukaemia (AML). Recent studies have shown that EZH2 mutations are often associated with RUNX1 mutations in MDS patients, although its pathological function remains to be addressed. Here we establish an MDS mouse model by transducing a RUNX1S291fs mutant into hematopoietic stem cells and subsequently deleting Ezh2. Ezh2 loss significantly promotes RUNX1S291fs-induced MDS. Despite their compromised proliferative capacity of RUNX1S291fs/Ezh2-null MDS cells, MDS bone marrow impairs normal hematopoietic cells via selectively activating inflammatory cytokine responses, thereby allowing propagation of MDS clones. In contrast, loss of Ezh2 prevents the transformation of AML via PRC1-mediated repression of Hoxa9. These findings provide a comprehensive picture of how Ezh2 loss collaborates with RUNX1 mutants in the pathogenesis of MDS in both cell autonomous and non-autonomous manners.

Objective. The aim of this prospective multicenter study was to identify biomarkers that can be used to predict therapeutic responses to tocilizumab in patients with rheumatoid arthritis (RA). Methods. We recruited patients with RA who were treated with tocilizumab for the first time, and determined therapeutic responses at 6 months. In the training cohort (n = 40), gene expression in peripheral blood mononuclear cells (PBMCs) at baseline was analyzed using genome-wide DNA microarray, with 41,000 probes derived from 19,416 genes. In the validation cohort (n = 20), expression levels of the candidate genes in PBMCs at baseline were determined using real-time quantitative polymerase chain reaction (qPCR) analysis. Results. We identified 68 DNA microarray probes that showed significant differences in signal intensity between nonresponders and responders in the training cohort. Nineteen putative genes were selected, and a significant correlation between the DNA microarray signal intensity and the qPCR relative expression was confirmed in 15 genes. In the validation cohort, a significant difference in relative expression between nonresponders and responders was reproduced for 3 type I interferon response genes (IFI6, MX2, and OASL) and MT1G. Receiver operating characteristic curve analysis of models incorporating these genes showed that the maximum area under the curve was 0.947 in predicting a moderate or good response to tocilizumab in the validation cohort. Conclusion. Using genome-wide DNA microarray analyses, we identified candidate biomarkers that can be used to predict therapeutic responses to tocilizumab in patients with RA. These findings suggest that type I interferon signaling and metallothioneins are involved in the pathophysiology of RA.

Objective. The proinflammatory cytokines tumor necrosis factor alpha and interleukin-6 (IL-6) and the Th17 cell cytokine IL-17A are implicated in the pathogenesis of rheumatoid arthritis (RA), and the blockade of these cytokines by biologic agents provides clinical benefits for RA patients. We undertook this study to clarify the mechanisms underlying the efficacy of IL-6 blockade in RA and to find a novel target for treatment of RA. Methods. We examined gene expression profiles of CD4+ T cells by DNA microarray analysis before and after treatment with an anti-IL-6 receptor antibody, tocilizumab (TCZ), in RA patients who exhibited good clinical responses to the treatment. Using murine CD4+ T cells, we then examined the roles of a newly identified molecule whose expression was significantly reduced in CD4+ T cells by TCZ therapy. We also examined the effect of the forced expression of the molecule on retinoic acid receptor-related orphan nuclear receptor gamma t (ROR gamma t)-induced IL-17A production in CD4+ T cells and on ROR gamma t-induced IL-17A promoter activation. Results. We identified AT-rich-interactive domain-containing protein 5A (ARID-5A) as a new molecule down-regulated by IL-6 blockade in the form of TCZ therapy. IL-6 induced the expression of ARID-5A in CD4+ T cells during Th17 cell differentiation by a STAT-3-dependent mechanism, whereas IL-6-induced ARID-5A expression was not affected by the absence of ROR gamma t, a lineage-specifying transcription factor of Th17 cells. Furthermore, ARID-5A physically associated with ROR gamma t through its N-terminal region and inhibited ROR gamma t-induced Th17 cell differentiation. Conclusion. ARID-5A is a lineage-specific attenuator of Th17 cell differentiation and may be involved in the pathogenesis of RA.

Objectives. This pilot multicenter exercise aimed to evaluate the inter-observer reproducibility of synovial power Doppler (PD) signals in rheumatoid arthritis (RA) patients and to determine the factors influencing the measurements. Methods. Two representative RA patients were assessed by four independent experienced sonographers. The influence of machine difference, deterioration of the transducer and pulse repetition frequency (PRF) on the assessment of synovial PD signals was investigated. Results. Intra-class correlation coefficient (ICC) for the scanner-reader reproducibility of semi-quantitative PD score was high (0.867). ICC for the inter-scanner reproducibility of synovial PD pixel count was higher than that of semi-quantitative PD score. The assessment of PD signals significantly differed between two machines with quantitative measurements but did not with semi-quantitative score. The assessment of PD signals with a deteriorated transducer was much less sensitive than that with an intact one. The semi-quantitative scores for PD signals were comparable between three different PRFs (500/800/1,300 Hz), whereas the pixel count was significantly lower with the highest one in the knee joint. Conclusions. Measurement of PD signal can be substantially affected by deteriorated quality of the transducer, whereas the differences are relatively modest between machines with similar specifications and also between PRF settings within a low range.

INTRODUCTION: In addition to the pivotal roles of mast cells in allergic diseases, recent data suggest that mast cells play crucial roles in a variety of autoimmune responses. However, their roles in the pathogenesis of autoimmune skeletal muscle diseases have not been clarified despite their distribution in skeletal muscle. Therefore, the objective of this study is to determine the roles of mast cells in the development of autoimmune skeletal muscle diseases. METHODS: The number of mast cells in the affected muscle was examined in patients with dermatomyositis (DM) or polymyositis (PM). The susceptibility of mast cell-deficient WBB6F1-Kit(W)/Kit(Wv) mice (W/W(v) mice) to a murine model of polymyositis, C protein-induced myositis (CIM), was compared with that of wild-type (WT) mice. The effect of mast cell reconstitution with bone marrow-derived mast cells (BMMCs) on the susceptibility of W/W(v) mice to CIM was also evaluated. RESULTS: The number of mast cells in the affected muscle increased in patients with PM as compared with patients with DM. W/W(v) mice exhibited significantly reduced disease incidence and histological scores of CIM as compared with WT mice. The number of CD8⁺ T cells and macrophages in the skeletal muscles of CIM decreased in W/W(v) mice compared with WT mice. Engraftment of BMMCs restored the incidence and histological scores of CIM in W/W(v) mice. Vascular permeability in the skeletal muscle was elevated in WT mice but not in W/W(v) mice upon CIM induction. CONCLUSION: Mast cells are involved in the pathogenesis of inflammatory myopathy.

The fact that sensitization against fungi is closely related to the severity of asthma suggests that immune systems recognizing fungi are involved in the pathogenesis of severe asthma. Recently, Dectin-2 (gene symbol, Clec4n), a C-type lectin receptor, has been shown to function as not only a major pattern-recognition receptor for fungi, but also a receptor for some components of house dust mite (HDM) extract, a major allergen for asthma. However, the roles of Dectin-2 in the induction of HDM-induced allergic airway inflammation remain largely unknown. Our objective was to determine the roles of Dectin-2 in HDM-induced allergic airway inflammation. We examined the roles of Dectin-2 in the induction of HDM-induced T helper (Th) 2 and Th17 cell differentiation and subsequent allergic airway inflammation by using Clec4n-deficient (Clec4n(-/-)) mice. We also investigated Dectin-2-expressing cells in the lung and their roles in HDM-induced allergic airway inflammation. Clec4n(-/-) mice showed significantly attenuated HDM-induced allergic airway inflammation and decreased Th2 and Th17 cell differentiation. Dectin-2 mRNA, together with Dectin-3 and Fc receptor-gamma mRNAs, was expressed in CD11b(+) dendritic cells (DCs), but not in CD4(+) T cells or epithelial cells in the lung. CD11b(+) DCs isolated from Clec4n(-/-) mice expressed lower amounts of proinflammatory cytokines and costimulatory molecules, which could lead to Th2 and Th17 cell differentiation than those from wildtype mice. HDM-pulsed Clec4n(-/-) DCs were less efficient for the induction of allergic airway inflammation than HDM-pulsed wildtype DCs. In conclusion, Dectin-2 expressed on CD11b(+) DCs promotes HDM-induced Th2 and Th17 cell differentiation and allergic airway inflammation.

Background: Anaphylaxis after the ingestion of foods contaminated with mites has recently been recognized. Case series and case reports thus far have shown that mite-contaminated wheat flour is the major cause of oral mite anaphylaxis. However, we have found 8 cases of oral mite anaphylaxis which were caused by mite-contaminated okonomiyaki-mix, a savory Japanese style pancake mix, in our hospital. Methods: In addition to our 8 cases, the databases of MEDLINE and ICHUSHI were systematically searched for patients with oral mite anaphylaxis in Japan. Results: Thirty-six patients including our 8 cases with oral mite anaphylaxis were identified. Thirty-four out of 36 cases (94%) ingested okonomiyaki or takoyaki, prepared at home using okonomiyaki-mix or takoyaki-mix which was previously opened and stored for months at ambient temperature. Microscopic examination of culprit mixes of 16 cases including our 1 case revealed contamination of mites such as Dermatophagoides farina (Der f) (5 cases), Tyrophagus putrescentiae (Tyr p) (4 cases), and Dermatophagoides pteronyssinus (Der p) (3 cases). The specific IgE to each mite is generally upregulated in these patients. Especially, the titers of specific IgE to Der p and Der f were more than class 2 in all cases. Conclusions: Mite-contaminated flavored flour is the major cause of oral mite anaphylaxis in Japan.

Inflammatory DCs are crucial for the development of airway hyper-reactivity.Dendritic cells (DCs) play critical roles in determining the fate of CD4 T cells. Among DC sub-populations, monocyte-derived inflammatory DCs (iDCs) have been shown to play an important role in the induction of adaptive immune responses under inflammatory conditions. Although previous studies have shown that DCs have an indispensable role in the induction of allergic airway inflammation and airway hyperreactivity (AHR) in murine asthma models, the precise roles of iDCs in the asthmatic responses remain largely unknown. We show here that T(h)2 cell-mediated inflammation in murine asthma models induces the expression of some markers of alternatively activated macrophage such as arginase 1 and resistin-like molecule- in iDCs by a mechanism depending on the intrinsic expression of STAT6. In contrast, T(h)1 cell-mediated inflammation induces iDCs to express TNF- and inducible nitric oxide synthase (iNOS), markers of TNF-- and iNOS-producing DCs. Moreover, we show that iDCs under a T(h)2 environment play an important role in the induction of AHR, independently of allergic airway inflammation. Our results thus indicate the importance of iDCs in the induction of AHR as downstream effector cells in T(h)2 cell-mediated asthmatic responses.

Introduction: Arthritis is the most frequent manifestation of Blau syndrome, an autoinflammatory disorder caused by the genetic mutation of NOD2. However, detailed information on arthritis in Blau syndrome on which the therapeutic strategy should be based on is lacking. This multi-center study aimed to accurately characterize the articular manifestation of Blau syndrome and also to demonstrate the utility of musculoskeletal ultrasound in Blau syndrome.Methods: Patients who had been diagnosed with Blau syndrome by genetic analysis of NOD2 were recruited. A total of 102 synovial sites in 40 joints were assessed semiquantitatively by ultrasound for gray-scale synovitis and synovial power Doppler (PD) signal.Results: In total, 10 patients whose age ranged from 10 months to 37 years enrolled in this study. Although only 4 joints (0.8%) were tender on physical examination, 81 joints (16.9%) were clinically swollen. Moreover, 240 (50.0%), and 124 (25.8%) joints showed gray-scale (GS) synovitis and synovial PD signal on ultrasound, respectively. Importantly, GS synovitis was present in 168 out of 399 non-swollen joints, in which 61 also exhibited synovial PD signal. Among 40 joint regions, the ankle, the wrist, and the proximal interphalangeal joints were the most frequently and severely affected joints. Comparisons between different synovial tissues demonstrated a significantly higher proportion of the joints with tenosynovitis as compared with that with intra-articular synovitis (41.5% versus 27.9%, P < 0.0001). In respect of age and treatment, synovial PD signals were minimal in the youngest patient and in the oldest two patients, and were relatively mild in patients receiving treatment with methotrexate plus TNF antagonists. In two patients who underwent the second ultrasound examination, total PD scores markedly decreased after initiating the treatment with a tumor necrosis factor (TNF) antagonist.Conclusions: The detailed information on synovial inflammation obtained by ultrasound confirms the dissociation between pain and inflammation and the frequently involved joint regions and synovial tissue in the arthritis of Blau syndrome. Our data also demonstrate that ultrasonography can be a potent tool in monitoring the activity of synovial inflammation and in investigating the pathophysiology of arthritis in this rare but archetypical autoinflammatory condition.

Introduction: In addition to the pivotal roles of mast cells in allergic diseases, recent data suggest that mast cells play crucial roles in a variety of autoimmune responses. However, their roles in the pathogenesis of autoimmune skeletal muscle diseases have not been clarified despite their distribution in skeletal muscle. Therefore, the objective of this study is to determine the roles of mast cells in the development of autoimmune skeletal muscle diseases. Methods: The number of mast cells in the affected muscle was examined in patients with dermatomyositis (DM) or polymyositis (PM). The susceptibility of mast cell-deficient WBB6F1-Kit(W)/Kit(Wv) mice (W/W-v mice) to a murine model of polymyositis, C protein-induced myositis (CIM), was compared with that of wild-type (WT) mice. The effect of mast cell reconstitution with bone marrow-derived mast cells (BMMCs) on the susceptibility of W/W-v mice to CIM was also evaluated. Results: The number of mast cells in the affected muscle increased in patients with PM as compared with patients with DM. W/W-v mice exhibited significantly reduced disease incidence and histological scores of CIM as compared with WT mice. The number of CD8(+) T cells and macrophages in the skeletal muscles of CIM decreased in W/W-v mice compared with WT mice. Engraftment of BMMCs restored the incidence and histological scores of CIM in W/W-v mice. Vascular permeability in the skeletal muscle was elevated in WT mice but not in W/W-v mice upon CIM induction. Conclusion: Mast cells are involved in the pathogenesis of inflammatory myopathy.

T helper 2 (Th2) cells induce allergic inflammation through the production of Th2 cytokines such as interleukin (IL)-4, IL-5, and IL-13. In addition, it has been demonstrated that IL-25 (IL-17E) is involved in the initiation and amplification of type 2 immune responses. Recent studies have shown that a number of cell types including activated Th2 cells, epithelial cells, mast cells, eosinophils, and macrophages produce IL-25 in response to a variety of stimuli. Regarding IL-25-responding cells, accumulating evidence has revealed that IL-25 induces type 2 immune responses through the activation of Th2 cells, natural killer T (NKT) cells, eosinophils, and innate immune cells including multipotent progenitor type 2 (MPP type2) cells, natural helper cells (NH cells), nuocytes, innate type 2 helper (Ih2) cells, and type 2 myeloid (T2M) cells. In vivo, we and others have shown that IL-25 is expressed in the airways in murine asthma models and is involved in the induction of antigen-induced airway inflammation and remodeling. In humans, IL-25 is suggested to be involved in the pathogenesis of allergic diseases such as asthma and Churg–Strauss syndrome. In this chapter, we summarize recent advances regarding the biology of IL-25.

The tumor suppressor p53 has been shown to play a central role in tumor suppression by inducing apoptosis, cell cycle arrest, senescence, and DNA repair. In addition, recent observations indicate that the dysfunction of p53 is associated with the development of autoimmune diseases. In this review, we discuss the importance of p53 in various human and murine autoimmune diseases. We also discuss the role of p53 in controlling the balance between Th17 cells and Tregs, the alteration of which is shown to be involved in the development of autoimmunity. It is postulated that the selective restoration of p53 function in T cells could be applicable to the treatment of systemic autoimmune diseases.

Objective. Our prospective study aimed to demonstrate that the cumulative synovial power Doppler (PD) ultrasound scores correlate with radiographic progression better than conventional measures in patients with rheumatoid arthritis (RA). We also investigated the difference between antirheumatic agents. Methods. Sixty-nine patients with RA who had recently received either methotrexate (MTX; n = 23), tumor necrosis factor (TNF) antagonists (n = 28), or tocilizumab (TCZ; n = 18) were enrolled. Patients underwent clinical, laboratory, and ultrasonographic assessment at baseline, 12 weeks, and 24 weeks. Radiographic damage was evaluated using van der Heijde modified total Sharp score (TSS) at baseline and 24 weeks. Results. Fifty-seven patients continued the same treatment regimen for 24 weeks and completed the study, and 21 patients (36.8%) showed radiographic progression during the study period. In all patients, Delta TSS significantly correlated both with cumulative 28-joint Disease Activity Score C-reactive protein (DAS28-CRP; rho = 0.342, p = 0.009) and cumulative total PD scores (rho = 0.357, p = 0.006). In MTX-treated patients, cumulative total PD scores significantly correlated with ATSS (rho = 0.679, p = 0.004), whereas cumulative DAS28-CRP did not (rho = 0.487, p = 0.056). However, cumulative total PD scores did not correlate with Delta TSS in TNF antagonist treated or TCZ-treated patients. Conclusion. Our data confirm the evidence that synovial PD activity more accurately reflects active synovial inflammation (which actually causes joint destruction) than do conventional measures in patients treated with MTX. Our data also indicate that TNF antagonists can inhibit short-term radiographic progression in the presence of active synovitis.

Objectives: To investigate the clinical characteristics and risk factors of Pneumocystis jirovecii pneumonia (PCP) in rheumatoid arthritis (RA) patients treated with adalimumab. Methods: We conducted a multicenter, retrospective, case-control study to compare RA patients treated with adalimumab with and without PCP. Data from 17 RA patients who were diagnosed with PCP and from 89 RA patients who did not develop PCP during adalimumab treatment were collected. Results: For the PCP patients, the median age was 68 years old, with a median RA disease duration of eight years. The median length of time from the first adalimumab injection to the development of PCP was 12 weeks. At the onset of PCP, the median dosages of prednisolone and methotrexate were 5.0 mg/day and 8.0 mg/week, respectively. The patients with PCP were significantly older (p &lt 0.05) and had more structural changes (p &lt 0.05) than the patients without PCP. Computed tomography of the chest revealed ground-glass opacity without interlobular septal boundaries in the majority of the patients with PCP. Three PCP patients died. Conclusions: PCP may occur early in the course of adalimumab therapy in patients with RA. Careful monitoring, early diagnosis, and proper management are mandatory to secure a good prognosis for these patients. © Japan College of Rheumatology 2012.

Objective. Although several miRNAs have been shown to regulate autoimmune pathogenesis by affecting lymphocyte function, the roles of miRNAs in the pathogenesis of SSc remain unclear. Therefore the purpose of this study was to identify miRNAs that play a role in the pathogenesis of SSc by quantitative PCR screening of serum miRNAs. Methods. Ninety-five miRNAs that were predicted to target SSc-related genes [IL-4, TGF-β, CTGF, PDGFB, PDGF receptor (PDGFR) α/β and COL1A2] by in silico analyses were selected. The expression of these miRNAs in sera of SSc patients and healthy controls was measured by quantitative PCR. Involvement of miR-30b, which was most strongly down-regulated in SSc patients, in the regulation of PDGFR-β expression was examined by transfection experiments and 3'-untranslated region (3'-UTR) target luciferase assays. The expression of miR-30b in skin was evaluated in a bleomycin-induced dermal fibrosis model in mice and in SSc patients. Results. Nineteen of 95 miRNAs were significantly decreased in the sera of SSc patients. Among them, miR-30b was most strongly down-regulated in SSc patients (P = 0.00006) and the levels of miR-30b were inversely correlated with modified Rodnan skin scores. Transfection of a miR-30b mimic repressed PDGFR-β expression in dermal fibroblasts and the activity of a luciferase reporter containing 3'-UTR of PDGFR-β. Moreover, the expression of miR-30b was down-regulated in bleomycin-treated sclerotic skin and in affected skin in SSc patients. Conclusion. Down-regulation of miR-30b might be involved in the pathogenesis of SSc. © The Author 2013. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved.

OBJECTIVES: To investigate the clinical characteristics and risk factors of Pneumocystis jirovecii pneumonia (PCP) in rheumatoid arthritis (RA) patients treated with adalimumab. METHODS: We conducted a multicenter, retrospective, case-control study to compare RA patients treated with adalimumab with and without PCP. Data from 17 RA patients who were diagnosed with PCP and from 89 RA patients who did not develop PCP during adalimumab treatment were collected. RESULTS: For the PCP patients, the median age was 68 years old, with a median RA disease duration of eight years. The median length of time from the first adalimumab injection to the development of PCP was 12 weeks. At the onset of PCP, the median dosages of prednisolone and methotrexate were 5.0 mg/day and 8.0 mg/week, respectively. The patients with PCP were significantly older (p &lt; 0.05) and had more structural changes (p &lt; 0.05) than the patients without PCP. Computed tomography of the chest revealed ground-glass opacity without interlobular septal boundaries in the majority of the patients with PCP. Three PCP patients died. CONCLUSIONS: PCP may occur early in the course of adalimumab therapy in patients with RA. Careful

The tumor suppressor p53 plays a central role in tumor suppression by inducing apoptosis, cell cycle arrest, senescence, and DNA repair. In addition to the antitumor functions of p53, accumulating evidence using systemic p53-deficient mice suggests that p53 suppresses autoimmunity. However, it remains unknown how p53 suppresses autoimmunity. In this study, we generated T cell-specific p53-deficient mice (CD4-Cre p53(fl/fl) mice, or p53 conditional knockout [cKO] mice) and found that aged p53-cKO mice spontaneously developed inflammatory lesions in various organs, including lung, liver, stomach, thyroid gland, submandibular gland, and kidney. Additionally, anti-nuclear Abs and autoantibodies against gastric parietal cells were detected in p53-cKO mice but not in control p53(fl/fl) mice (p53 wild-type mice). Importantly, the number of Foxp3(+)CD4(+) regulatory T cells (Tregs) in the spleen and lung as well as in vitro differentiation of induced Tregs was significantly reduced in p53-cKO mice as compared with that in p53 wild-type mice. Regarding the mechanisms underlying p53-mediated Treg induction, p53 enhanced the transcription of Foxp3 by binding to the promoter and the conserved noncoding DNA sequence-2 of the Foxp3 gene. Taken together, these results suggest that p53 expressed in T cells functions as a suppressor for autoimmunity by inducing Treg differentiation.

Objective The 2010 American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) classification criteria for rheumatoid arthritis (RA) refer to a possible use of ultrasound for confirmation of the clinical findings. We undertook this study to determine the optimized definition of ultrasound-detected synovitis for the 2010 ACR/EULAR criteria and to assess the impact of its use on the accuracy of RA classification. Methods One hundred nine patients with musculoskeletal symptoms for 3 years were enrolled in the study. Patients underwent clinical, laboratory, radiographic, and comprehensive ultrasonographic assessments at baseline and received routine management from expert rheumatologists who were blinded to the ultrasound findings. Results Sensitivity and specificity of the 2010 ACR/EULAR criteria using different definitions of synovitis to identify patients who developed a disease requiring methotrexate (MTX) treatment within 1 year were 58.5% and 79.4%, respectively, for clinical synovitis (tenderness or swelling), 78.0% and 79.4%, respectively, for ultrasound-detected synovitis with a gray-scale (GS) imaging score 1 (GS 1 ultrasound synovitis), and 56.1% and 93.7%, respectively, for GS 2 ultrasound synovitis or a synovial power Doppler (PD) signal score 1 (GS 2/PD 1 ultrasound synovitis). Receiver operating characteristic curve analysis for the criteria scores revealed the largest area under the curve with GS 2/PD 1 ultrasound synovitis. Conclusion Ultrasound assessment improves the accuracy of the 2010 ACR/EULAR criteria for identifying patients with a disease requiring MTX treatment. Our data provide preliminary but vital information for the methodology to confirm the presence of synovitis using ultrasound in the 2010 ACR/EULAR criteria.

A significant proportion of patients with connective tissue disease (CTD) have gastric esophageal reflux disease (GERD) symptoms despite receiving proton pump inhibitors (PPIs). Although pre-meal administration of PPIs is recommended in Western countries, the benefit of this administration timing in Japanese CTD patients with refractory GERD symptoms has not been proven. To determine whether pre-dinner administration of PPIs is more efficacious for refractory GERD symptoms in Japanese CTD patients. CTD patients receiving oral PPIs were instructed to take PPIs 1 h before dinner. Gastrointestinal symptoms were evaluated with frequency scale for the symptoms of GERD (FSSG) and gastrointestinal symptom rating scale (GSRS) before and after the intervention. Pre-dinner administration of PPIs significantly improved FSSG total score, from a median of 8 to 6.5 (P = 0.005). Pre-dinner administration was more effective in patients with overt GERD symptoms (from median 18 to 10, P &lt; 0.001) than in those with mild GERD symptoms (from median 2 to 2, P = 0.201). In addition to reflux syndrome, pre-dinner administration of PPIs significantly decreased abdominal pain syndrome and constipation syndrome of GSRS. Pre-dinner administration of PPIs may increase their efficacy in Japanese CTD patients with GERD, especially those with overt symptoms.

Yellow nail syndrome is an idiopathic condition characterized by a triad consisting of yellow nail, lymphedema, and pulmonary manifestations. Thiol compounds such as D-penicillamine have been reported to be the major cause of drug-induced yellow nail syndrome in patients with rheumatoid arthritis (RA). We recently experienced two Japanese cases with RA who developed yellow nail under treatment with bucillamine, a thiol-containing anti-rheumatic drug developed and approved in Japan. We reviewed the literature for similar cases and identified 36 RA cases with bucillamine-induced yellow nail, mostly in Japanese medical journals. Most of these cases (90.3%) showed improvement of yellow nail after discontinuation of bucillamine, whereas lymphedema and pulmonary manifestations improved only in 30.8 and 35.0% of the patients, respectively. © 2011 Springer-Verlag.

In the past decade, mechanisms underlying allergic contact dermatitis have been intensively investigated by using contact hypersensitivity (CHS) models in mice. However, the regulatory mechanisms, which could be applicable for the treatment of allergic contact dermatitis, are still largely unknown. To determine the roles of B and T lymphocyte attenuator (BTLA), a CD28 family coinhibitory receptor, in hapten-induced CHS, BTLA-deficient (BTLA(-/-)) mice and littermate wild-type (WT) mice were subjected to DNFB-induced CHS, severe combined immunodeficient (SCID) mice were injected with CD4(+) T cells, and CD8(+) T cells from either WT mice or BTLA(-/-) mice were subjected to CHS. BTLA(-/-) mice showed enhanced DNFB-induced CHS and proliferation and IFN-gamma production of CD8(+) T cells as compared with WT mice. SOD mice injected with WT CD4(+) T cells and BTLA(-/-) CD8(+) T cells exhibited more severe CHS as compared with those injected with WT CD4(+) T cells and WT CD8(+) T cells. On the other hand, SCID mice injected with BTLA(-/-) CD4(+) T cells and WT CD8(+) T cells exhibited similar CHS to those injected with WT CD4(+) T cells and WT CD8(+) T cells. Finally, to evaluate the therapeutic potential of an agonistic agent for BTLA on CHS, the effects of an agonistic anti-BTLA antibody (6A6) on CHS were examined. In vivo injection of 6A6 suppressed DNFB-induced CHS and IFN-gamma production of CD8(+) T cells. Taken together, these results suggest that stimulation of BTLA with agonistic agents has therapeutic potential in CHS. Journal of Investigative Dermatology (2013) 133, 702-711; doi:10.1038/jid.2012.396; published online 29 November 2012

Introduction. This study aimed to investigate the efficacy of abatacept for arthritis in patients with rhupus, an overlap syndrome between rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). Methods. Patients who fulfilled both the 2010 ACR/EULAR criteria for RA classification and the 1997 ACR revised criteria for classification of SLE and received abatacept treatment for arthritis were retrospectively studied. Results. Six rhupus patients who fulfilled the inclusion criteria above were identified. All patients had active arthritis despite receiving antirheumatic drugs including methotrexate when abatacept was initiated. Clinical Disease Activity Index (CDAI) significantly decreased between baseline and 12 weeks (P=0.028) and remained low through 24 weeks. All patients achieved either a good or moderate response according to the EULAR response criteria at 24 weeks. Health Assessment Questionnaire-Disability Index (HAQ-DI) also significantly decreased between baseline and 24 weeks (P=0.043). In addition, the levels of immunoglobulin G and anti-DNA antibody significantly decreased between baseline and 24 weeks (P=0.028 and P=0.043, resp.). Conclusions. Treatment with abatacept is likely to be efficacious in patients with rhupus whose arthritis is refractory to methotrexate. In addition, abatacept may have a moderate effect on abnormal antibody production in rhupus patients. © 2013 Kei Ikeda et al.

Although Nocardiosis has considerable recurrence and mortality rates, characteristics and risk factors of Nocardia infection have not been assessed in patients with rheumatic diseases. Here, we examined the characteristics and risk factors of Nocardia infection in rheumatic disease patients in our hospital. Ten rheumatic disease patients who developed Nocardia infection were identified by retrospectively reviewing the medical records. Possible predisposing factors for Nocardia infection were high-dose glucocorticoid treatment, concomitant use of immunosuppressants, preexisting pulmonary diseases, and diabetes mellitus. All patients had pulmonary Nocardiosis, and six of them had disseminated Nocardiosis when their pulmonary lesions were identified.

Background: Recent studies have shown that prolonged Th2-type immune inflammation in the lung induces pulmonary arterial remodeling, in part through the induction of resistin-like molecule alpha (RELM alpha) expression. However, the role of interleukin-25 (IL-25; which promotes this inflammation) in the development of the pulmonary arterial remodeling remains unknown. Methods: Ovalbumin (OVA)-sensitized C57BL/6 mice were challenged with OVA inhalation 3 times a week for 3 weeks. The effects of neutralizing antiIL- 25 antibody on OVA-induced pulmonary arterial remodeling and RELMa expression in the lung were examined. The pulmonary arterial remodeling and RELMa expression in the lung were examined in lung-specific IL-25 transgenic mice (CC10 IL-25 mice) and CC10 IL-25 mice in a natural killer T (NKT) cell-deficient background (CC10 IL-25 NKT-/- mice). Results: Repeated OVA inhalation induced pulmonary arterial wall thickening and the expression of IL-25 and RELMa mRNA in the lung in OVA-sensitized mice. Injection of neutralizing anti-IL-25 antibody inhibited OVA-induced pulmonary arterial wall thickening and RELMa expression in the lung. CC10 IL-25 mice, but not CC10 IL-25 NKT-/- mice, spontaneously developed pulmonary arterial wall thickening and RELMa expression in the lung at 6 months of age. Conclusions: Prolonged expression of IL-25 in the lung induces pulmonary arterial wall thickening by NKT cell-dependent mechanisms. Copyright (C) 2013 S. Karger AG, Basel

Background: Mast cells are known to play a pivotal role in allergic diseases by releasing granules containing histamine and other preformed chemical mediators. Cross-linking of high-affinity receptors for IgE (Fc epsilon RI) on mast cells results in rapid increases in intracellular free calcium concentration [Ca2+](i) and consequent activation of many transcription factors, including NFAT, NF-kB, JNK and CREB. Ca2+ signaling is essential for many cellular activities such as proliferation, gene expression and degranulation in mast cells. In addition to Ca2+ signaling, previous reports have shown that IkappaB kinase 2 (IKK2 or IKK beta), a central component of the IKK complex mediating NF-kB activation, also plays a crucial role in Fc epsilon RI-mediated degranulation and cytokine production. Moreover, it has been demonstrated that activation of PKC beta, a calcium-dependent PKC isoform, leads to IKK2 activation in many cell types. However, the roles of Ca 2+ signaling and PKC beta in the activation of IKK2 in mast cells remain largely unknown. Methods: We investigated the effect of PKC inhibitor Go6976 on calcium ionophore A23187-induced activation of IKK2 in mast cells. We also examined the role of IKK2 in A23187-induced NF-kB-dependent gene induction, degranulation, proinflammatory cytokine production and extracellular signal-regulated kinases 1 and 2 (ERK1/2) activation by using IKK2-deficient (IKK2(-/-)) fetal liver-derived mast cells (FLMCs). Results: A23187 activated IKK2 and NF-kB even in the presence of Go6976 in mast cells. A23187-induced degranulation, cytokine production and activation of ERK1/2 were diminished in IKK2(-/-)FLMCs compared to those in wild-type FLMCs. Conclusions: Ca2+-IKK2 signaling is involved in the degranulation and cytokine production in activated mast cells by a mechanism independent of PKC beta. Copyright (C) 2013 S. Karger AG, Basel

A number of studies have suggested a correlation between a decreased incidence in infectious diseases and an increased incidence of allergic diseases, including asthma. Although several pathogen-derived products have been shown to possess therapeutic potential for allergic diseases, it remains largely unknown whether beta-glucan, a cell wall component of a variety of fungi, yeasts, and bacteria, has a regulatory potential for allergic diseases. In this study, we examined the effect of curdlan, a linear beta-(1-3)-glucan, on the development of allergic airway inflammation. We found that i.p. injection of curdlan significantly inhibited Ag-induced eosinophil recruitment and Th2 cytokine production in the airways. The activation of CD4(+) T cells in the presence of curdlan induced IL-10-producing CD4(+) T cells with high levels of c-Maf expression. Curdlan-induced development of IL-10-producing CD4(+) T cells required the presence of APCs and ICOS/ICOS ligand interaction. Curdlan-induced development of IL-10-producing CD4(+) T cells also required intrinsic expression of STAT6. Furthermore, the transfer of Ag-specific CD4(+) T cells that were stimulated in the presence of curdlan inhibited Ag-induced eosinophil recruitment into the airways. Taken together, these results suggest that curdlan is capable of inducing IL-10 producing CD4(+) T cells and inhibiting the development of eosinohilic airway inflammation, underscoring the therapeutic potential of curdlan for allergic diseases. The Journal of Immunology, 2012, 189: 5713-5721.

Coinhibitory molecules such as CTLA-4, PD-1 and BTLA negatively regulate immune responses. Multiple studies indicate that the deficiency ormutation of coinhibitorymolecules leads to the development of autoimmune diseases in mice and humans, indicating that the negative signals from coinhibitory molecules are crucial for the prevention of autoimmunity. In some conditions, the administration of decoy coinhibitory receptors (e. g., CTLA-4 Ig) or mAb against coinhibitory molecules suppresses the responses of self-reactive T cells in autoimmune diseases. Therefore, modulation of coinhibitory signals seems to be an attractive approach to induce tolerance in autoimmune diseases in humans where the disease-inducing self-antigens are not known. Particularly, administration of CTLA-4 Ig has shown great promise in animal models of autoimmune diseases and has been gaining increasing attention in clinical investigation in several autoimmune diseases in humans.

The I kappa B kinase (IKK) complex plays a crucial role in the activation of the transcription factor NF-kappa B by phosphorylating an inhibitory molecule I kappa B alpha. Recently, we showed that IKK2 (also called IKK beta), a catalytic subunit of the IKK complex, induces immunoglobulin E-mediated degranulation in mast cells by phosphorylating SNAP-23, the target-membrane soluble N-ethylmaleimide-sensitive fusion factor attachment protein receptor (SNARE). In addition to IKK2, a recent study has shown that ELKS, a regulatory subunit of the IKK complex, also induces the degranulation of rat basophilic leukemia cells. These findings indicate that the two subunits of the IKK complex, IKK2 and ELKS, function not only in NF-kappa B-dependent transcriptional activation but also in NF-kappa B-independent pathways. This review focuses on the functions of IKK2 and ELKS in mast cell degranulation. Copyright (C) 2012 S. Karger AG, Basel