Short-term and long-term outcomes of patients with anti-melanoma differentiation-associated gene 5 antibody-positive dermatomyositis.

OBJECTIVES: Anti-melanoma differentiation-associated gene 5 (MDA5) antibody-positive dermatomyositis (MDA5-DM) is a subtype of dermatomyositis characterized by frequent interstitial lung disease and reduced muscle involvement. This study aimed to determine the short-term and long-term outcomes of patients with MDA5-DM. METHODS: Information on baseline characteristics, treatments, and short-term and long-term outcomes of patients with MDA5-DM including survival, relapse, and the titer of anti-MDA5 antibody, was retrospectively collected. Descriptive statistics regarding clinical outcomes were calculated, and a comparison of clinical parameters between patients with and without relapse was performed. The short-term survival according to the use of Janus kinase inhibitors (JAKi) was also assessed. RESULTS: A total of 154 patients with MDA5-DM were included in the study. Forty patients (25.9%) died during the remission induction phase, with respiratory failure being the most common cause of mortality. Among the 114 patients who survived the remission induction phase, the 5-year cumulative survival and relapse-free survival rates were 96.8% and 77.4%, respectively, and 7.9% of patients achieved complete drug-free remission. Fifty-four patients achieved normalization of anti-MDA5 antibody titers and only two of them relapsed after normalization. In the severe patients, the 6-month survival rate became significantly higher after the emergence of the JAKi treatment compared with before its existence (p= 0.03). CONCLUSIONS: Although relapse often occurs, the long-term survival of MDA5-DM patients who survived the remission induction phase is generally favorable. The status of the anti-MDA5 antibody is associated with relapse. JAKi may improve the survival of refractory patients with severe MDA5-DM.

A20 (Tnfaip3) expressed in CD4+ T cells suppresses Th2 cell-mediated allergic airway inflammation in mice.

A20 (Tnfaip3), a ubiquitin-editing enzyme, inhibits NF-κB signaling pathways in response to pro-inflammatory cytokines. Previous studies have proved the anti-inflammatory roles of A20 in various cell types, including T cells, B cells, dendritic cells, and intestinal epithelial cells. Moreover, recent studies have shown that A20 expressed in lung epithelial cells is required for LPS-induced protection from asthma. In humans, a single-nucleotide polymorphism in TNFAIP3 is associated with asthma risk. However, the role of A20 expressed in T cells in asthmatic responses has not been elucidated. We addressed this point by generating mice lacking A20 expression in T cells (CD4-CreA20 fl/fl mice). We found that house dust mite (HDM)-induced allergic airway inflammation, mucus production, airway hyperresponsiveness, and Th2 cytokine production were significantly exacerbated in CD4-CreA20 fl/fl mice compared with those in control A20 fl/fl mice. In vitro differentiation of Th2 cells but not of Th1 cells or Th17 cells was enhanced in CD4+ T cells by the absence of A20. Consistently, enforced expression of A20 inhibited the differentiation of Th2 cells but not of Th1 cells or Th17 cells. Notably, the expression of GATA3 was significantly enhanced in A20-deficient CD4+ T cells, and the enhanced GATA3 expression was partly canceled by IL-2 neutralization. These results suggest that A20 functions as a stabilizing factor maintaining GATA3 levels during the induction of Th2 cells to prevent excessive Th2 cell differentiation.

Airway epithelial STAT3 inhibits allergic inflammation via upregulation of stearoyl-CoA desaturase 1.

BACKGROUND: Airway epithelial cells (AECs) play a crucial role in the induction and development of allergic inflammation through the development and activation of immune cells, including Th2 cells and ILC2s. Recent studies have revealed that STAT3 expressed in epithelial cells protects against pathogens and maintains homeostasis in the intestine. However, the roles of STAT3 in airway epithelium are poorly understood. Therefore, we sought to elucidate the roles of airway epithelial STAT3 in allergic airway inflammation. METHODS: Allergic airway inflammation was induced by intratracheal administration of house dust mite (HDM) extract in doxycycline-induced AEC-specific STAT3-deficient (STAT3-cKO) mice and their genetic control (STAT3-WT) mice. Airway inflammation was evaluated by flow cytometric analysis of bronchoalveolar lavage fluid cells and histological analysis of the lung. Purified airway epithelial cells were analyzed by quantitative PCR and RNA-sequencing (RNA-seq). RESULTS: HDM-induced airway inflammation was exacerbated in STAT3-cKO mice compared with STAT3-WT mice. RNA-seq analyses revealed that Scd1, coding stearoyl-CoA desaturase 1, was most significantly upregulated in HDM-treated STAT3-WT mice compared to HDM-treated STAT3-cKO mice. Notably, the administration of an SCD1 inhibitor exacerbated HDM-induced airway inflammation. AECs of HDM-treated STAT3-cKO mice and those of HDM-treated SCD1 inhibitor-injected mice shared 45 differentially expressed genes (DEGs). Gene enrichment analysis of the DEGs revealed that the enriched ontology clusters included fatty acid biosynthetic process and regulation of lipid biosynthetic process, suggesting the involvement of the STAT3-SCD1-lipid metabolism axis in suppressing allergic inflammation. CONCLUSIONS: STAT3 is crucial for suppressing HDM-induced allergic airway inflammation, possibly inducing SCD1 expression in AECs.

Allergic airway inflammation: key players beyond the Th2 cell pathway.

Allergic asthma is characterized by eosinophilic airway inflammation, mucus hyperproduction, and airway hyperreactivity, causing reversible airway obstruction. Accumulating evidence indicates that antigen-specific Th2 cells and their cytokines such as IL-4, IL-5, and IL-13 orchestrate these pathognomonic features of asthma. However, over the past decade, the understanding of asthma pathogenesis has made a significant shift from a Th2 cell-dependent, IgE-mediated disease to a more complicated heterogeneous disease. Recent studies clearly show that not only Th2 cytokines but also other T cell-related cytokines such as IL-17A and IL-22 as well as epithelial cell cytokines such as IL-25, IL-33, and thymic stromal lymphopoietin (TSLP) are involved in the pathogenesis of asthma. In this review, we focus on the roles of these players beyond Th2 pathways in the pathogenesis of asthma.

[Medication Support and Adverse Events Monitoring System Using Medical Social Networking Service(SNS)].

PURPOSE: We introduced the medication support and adverse events monitoring system using medical social networking service (SNS). METHODS: Thirty-two gastric cancer patients who were treated with oral anticancer drugs were included in this study. Patients or their families input the status of medication and adverse events using the ICT terminal every day, and the pharmacist confirmed the input contents on the PC. If there was a serious adverse events, the nurse confirmed the status of patient by telephone. RESULTS: Of the 32 registered cases, 3 cases (9.3%) discontinued input within less than 2 months during treatment. We experienced a case whose adverse events could be dealt with during long vacations and a case whose treatment could be continued by sharing information with home-visit nursing stations. In the questionnaire survey, there were many opinions that it would lead to anxiety reduction. CONCLUSION: Medication support system using medical SNS can be a safe and useful tool.

Fucosyltransferase 2 induces lung epithelial fucosylation and exacerbates house dust mite-induced airway inflammation.

BACKGROUND: One of the pathognomonic features of asthma is epithelial hyperproduction of mucus, which is composed of a series of glycoproteins; however, it remains unclear how glycosylation is induced in lung epithelial cells from asthmatic patients and how glycan residues play a role in the pathogenesis of asthma. OBJECTIVE: The objective of this study was to explore comprehensive epithelial glycosylation status induced by allergic inflammation and reveal its possible role in the pathogenesis of asthma. METHODS: We evaluated the glycosylation status of lung epithelium using a lectin microarray. We next searched for molecular mechanisms underlying epithelial glycosylation. We also examined whether epithelial glycosylation is involved in induction of allergic inflammation. RESULTS: On allergen inhalation, lung epithelial cells were heavily α(1,2)fucosylated by fucosyltransferase 2 (Fut2), which was induced by the IL-13-signal transducer and activator of transcription 6 pathway. Importantly, Fut2-deficient (Fut2-/-) mice, which lacked lung epithelial fucosylation, showed significantly attenuated eosinophilic inflammation and airway hyperresponsiveness in house dust mite (HDM)-induced asthma models. Proteome analyses and immunostaining of the HDM-challenged lung identified that complement C3 was accumulated in fucosylated areas. Indeed, Fut2-/- mice showed significantly reduced levels of C3a and impaired accumulation of C3a receptor-expressing monocyte-derived dendritic cells in the lung on HDM challenge. CONCLUSION: Fut2 induces epithelial fucosylation and exacerbates airway inflammation in asthmatic patients in part through C3a production and monocyte-derived dendritic cell accumulation in the lung.

Roles of IL-22 in allergic airway inflammation in mice and humans.

Asthma is a chronic inflammatory disease of the airways that is characterized by eosinophilic inflammation, mucus hypersecretion and airway remodeling that leads to airway obstruction. Although these pathognomonic features of asthma are primarily mediated by allergen-specific T helper type 2 cells (Th2 cells) and their cytokines, recent studies have revealed critical roles of lung epithelial cells in the pathogenesis of asthma. Lung epithelial cells not only form physical barriers by covering the surfaces of the airways but also sense inhaled allergens and initiate communication between the environment and the immune system. The causative involvement of lung epithelium in the pathogenesis of asthma suggests that some molecules that modulate epithelial function have a regulatory role in asthma. IL-22, an IL-10-family cytokine produced by IL-17A-producing T helper cells (Th17 cells), γδ T cells and group 3 innate lymphoid cells (ILC3s), primarily targets epithelial cells and promotes their proliferation. In addition, IL-22 has been shown to induce epithelial production of various molecules that regulate local immune responses. These findings indicate that IL-22 plays crucial roles in the pathogenesis of asthma by regulating epithelial function. Here, we review the current understanding of the molecular and cellular mechanisms underlying IL-22-mediated regulation of airway inflammation in asthma.

Dectin-1 Plays an Important Role in House Dust Mite-Induced Allergic Airway Inflammation through the Activation of CD11b+ Dendritic Cells.

It is well known that sensitization against fungi is closely associated with severity of asthma. Dectin-1 (gene symbol Clec7a), a C-type lectin receptor, recognizes the fungal cell wall component ß-glucan, as well as some component(s) in house dust mite (HDM) extract. However, the roles of Dectin-1 in HDM-induced allergic airway inflammation remain unclear. In this study, we used Dectin-1-deficient (Clec7a-/-) mice to examine whether Dectin-1 is involved in HDM-induced allergic airway inflammation. We found that HDM-induced eosinophil and neutrophil recruitment into the airways was significantly attenuated in Clec7a-/- mice compared with that in wild-type mice. In addition, HDM-induced IL-5, IL-13, and IL-17 production from mediastinum lymph node cells was reduced in HDM-sensitized Clec7a-/- mice. Dectin-1 was expressed on CD11b+ dendritic cells (DCs), an essential DC subset for the development of allergic inflammation, but not on CD103+ DCs, plasmacytoid DCs, or lung epithelial cells. Transcriptome analysis revealed that the expression of chemokine/chemokine receptors, including CCR7, which is indispensable for DC migration to draining lymph nodes, was decreased in Clec7a-/- DCs. In accordance with these results, the number of HDM-labeled CD11b+ DCs in mediastinum lymph nodes was significantly reduced in Clec7a-/- mice compared with wild-type mice. Taken together, these results suggest that Dectin-1 expressed on CD11b+ DCs senses some molecule(s) in HDM extract and plays a critical role in the induction of HDM-induced allergic airway inflammation by inducing the expression of chemokine/chemokine receptors in DCs.

Bidirectional roles of IL-22 in the pathogenesis of allergic airway inflammation.

Asthma is the most prevalent allergic disease of the airway, which is characterized by eosinophilic inflammation, mucus hyperproduction, and airway hyper-responsiveness. Although these pathognomonic features are mainly mediated by antigen-specific Th2 cells and their cytokines, such as IL-4, IL-5, and IL-13, recent studies have revealed that other inflammatory cells, including Th17 cells and innate lymphoid cells (ILCs), also play a critical role in the pathogenesis of asthma. IL-22, one of the cytokines produced by Th17 cells and type 3 ILCs, has distinct functional properties, as IL-22 exclusively acts on non-hematopoietic cells including epithelial cells of mucosal surface and exhibits a broad range of action in regeneration and host protection. In accordance with the fact that lung epithelial cells play a critical role in the pathogenesis of asthma, we and other groups have shown that IL-22 is involved in the regulation of allergic airway inflammation. In this review, we discuss recent advances in the biology of IL-22 and its involvement in the pathogenesis of allergic airway inflammation.

Roles of Dectin-1 in Allergic Airway Inflammation.

Asthma is a chronic allergic inflammatory disease of the airways. The symptoms can be controlled by inhaled corticosteroids together with long-acting ß2 agonists in the majority of patients; however, in some patients, their symptoms remain uncontrolled even under intensive treatment. Although underlying mechanisms of the heterogeneous responses to the treatment are largely unknown, a series of recent epidemiological studies have suggested a link between the severity of asthma and the sensitization to fungi. Dectin-1, a C-type lectin receptor expressed on myeloid cells and plays protective roles against fungi by recognizing a cell-wall component of fungi, has recently been suggested to be involved in the development of severe asthma. In this review, we summarize the roles of Dectin-1 in the pathogenesis of severe asthma and discuss the possibility of its therapeutic application.

T-bet inhibits innate lymphoid cell-mediated eosinophilic airway inflammation by suppressing IL-9 production.

BACKGROUND: Innate lymphoid cells (ILCs) are emerging subsets of immune cells that produce large amounts of cytokines upon cytokine and/or alarmin stimulation. Recent studies have shown that T-bet plays pivotal roles in the development of ILC3s and type 1 ILCs; however, the roles of T-bet in lung type 2 innate lymphoid cells (ILC2s) remain unknown. OBJECTIVE: We sought to determine the role of T-bet in ILC2-mediated airway inflammation. METHODS: The expression of T-bet in lung ILCs (defined as Thy1.2+ Lin- cells) was examined. The roles of T-bet in the development of lung ILC2s and airway inflammation induced by IL-33 administration were examined by using T-bet-deficient (T-bet-/-) mice. Gene expression profiles of T-bet-/- lung ILCs were analyzed by RNA sequencing. RESULTS: T-bet was expressed in lung ILC2s (defined as Thy1.2+ Lin- cells expressing ST2 or CD25) and IFN-γ enhanced its expression. Although the development of lung ILC2s at steady-state conditions was normal in T-bet-/- mice, IL-33-induced accumulation of lung ILC2s and eosinophilic airway inflammation were exacerbated in T-bet-/- mice. The exacerbated accumulation of ILC2s and eosinophilic airway inflammation by the absence of T-bet were evident even in a RAG2-/- background, suggesting that T-bet expressed in non-T/non-B population is involved in the suppression of IL-33-induced eosinophilic airway inflammation. Transcriptome analysis revealed that IL-9 expression in IL-33-stimulated lung ILCs was upregulated in T-bet-/- mice compared with that in wild-type mice. Importantly, neutralization of IL-9 markedly attenuated IL-33-induced accumulation of lung ILC2s and eosinophilic inflammation in T-bet-/- mice. CONCLUSIONS: T-bet suppresses IL-9 production from lung ILC2s and thereby inhibits IL-33-induced eosinophilic airway inflammation.

Th2-type inflammation instructs inflammatory dendritic cells to induce airway hyperreactivity.

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-α 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-α and inducible nitric oxide synthase (iNOS), markers of TNF-α- 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.

Tumor suppressor p53 inhibits systemic autoimmune diseases by inducing regulatory T cells.

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.

Corticosteroid-sparing effect of tacrolimus in the initial treatment of dermatomyositis and polymyositis.

OBJECTIVE: In the treatment of polymyositis (PM) and dermatomyositis (DM), muscle inflammation and underlying autoimmunity need to be suppressed promptly; however, catabolic effects of corticosteroids such as myopathy can be detrimental in PM/DM. In this study, we aimed to assess the corticosteroid-sparing effect of tacrolimus in the initial treatment of PM/DM. METHODS: We retrospectively identified 19 PM/DM patients who received initial treatment with prednisolone at an initial dose of 1 mg/kg/day (Conventional Monotherapy, our standard therapy before 2008) and 23 patients with tacrolimus plus prednisolone at an initial dose 0.8 mg/kg/day (Tacrolimus Combination, our standard therapy after 2008). Data until 36 months after commencing treatment were collected. RESULTS: There were no statistically significant differences in baseline characteristics between two groups. Median daily dose of prednisolone in the Tacrolimus Combination Group was significantly lower than that in the Conventional Monotherapy Group during the study period, whereas the proportion of patients who required additional immunosuppressive medications for remission induction was comparable. Remission was achieved in all patients, except one who died of refractory interstitial lung disease after receiving Conventional Monotherapy. The time required for creatine kinase normalization and relapse rate was comparable between two groups. The period of hospitalization for initial treatment was significantly shorter and survival without serious infection or relapse tended to be longer in the Tacrolimus Combination than the Conventional Monotherapy. CONCLUSION: This study provides real-life data which demonstrate that tacrolimus has a corticosteroid-sparing effect and reduces the length of hospitalization period for the initial treatment of PM/DM.

Dectin-2 promotes house dust mite-induced T helper type 2 and type 17 cell differentiation and allergic airway inflammation in mice.

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-γ 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 wild-type mice. HDM-pulsed Clec4n(-/-) DCs were less efficient for the induction of allergic airway inflammation than HDM-pulsed wild-type DCs. In conclusion, Dectin-2 expressed on CD11b(+) DCs promotes HDM-induced Th2 and Th17 cell differentiation and allergic airway inflammation.