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Background: Previous studies have shown that mice lacking T-bet, a critical transcription factor for TH1 cell differentiation, spontaneously develop airway inflammation with intense eosinophil infiltrates. However, the mechanism underlying T-bet–mediated inhibition of allergic airway inflammation is still unknown. Objective: To determine the regulatory role of T-bet in antigen-induced allergic airway inflammation. Methods: We examined the role of T-bet in antigen-induced allergic airway inflammation using T-bet−/− mice on a BALB/c background that did not develop spontaneous airway inflammation. We also examined the role of T-bet expression of CD4+ T cells in airway inflammation by adoptive transfer experiments. Results: We found that antigen-induced eosinophil recruitment, goblet cell hyperplasia, and TH2 cytokine production in the airways were enhanced in T-bet−/− mice. However, in the absence of signal transducer and activator of transcription 6 (STAT6), T-bet deficiency could not induce the antigen-induced eosinophilic airway inflammation. Adoptive transfer of T-bet−/− or T-bet+/+ CD4+ T cells to T-bet−/−Rag-2−/− mice revealed that the expression of T-bet in CD4+ T cells was vital for the inhibition of antigen-induced eosinophilic airway inflammation. Interestingly, antigen-induced neutrophil recruitment in the airways was also enhanced in T-bet−/− mice. Moreover, T-bet−/− CD4+ T cells preferentially differentiated into IL-17–producing cells that mediated neutrophilic airway inflammation. Conclusion: T-bet inhibits both TH2 cell–mediated eosinophilic inflammation and TH17 cell–mediated neutrophilic inflammation in the airways. Clinical implications: The dysfunction of T-bet may be involved in the pathogenesis of severe asthma, in which accumulation of neutrophils as well as eosinophils in the airways is a hallmark of disease. [Copyright &y& Elsevier]

AbstractBackground and Methods: We have previously reported that CD4+ T cells induced primary biliary cirrhosis (PBC)-like hepatic lesions in mice with graft-versus-host reaction due to major histocompatibility complex class II disparity. To clarify the relationship between the cytokine profile produced by CD4+ T cells and the formation of hepatic lesions, we sorted CD4+ T cells from the liver by using flow cytometry and examined their cytokine mRNA expression at various times after GVHR induction. We also examined the associated changes in the serum levels of antimitochondrial antibodies (AMA). Results: Histologically, the infiltration of CD4+ T cells around the bile ducts was observed from day 5, and the lesions deteriorated gradually until day 14. On day 14, CD8+, B220+ and Mac-1+ cells, as well as CD4+ T cells were seen around the bile ducts. In the liver-infiltrating CD4+ T cells, the expression level of interferon-γ (IFN-γ) mRNA was observed to increase at an early phase (day 3), whereas that of interleukin (IL)-10 mRNA was elevated at a later phase (day 14). The elevation of IFN-γ mRNA expression at an early phase before the appearance of non-suppurative destructive cholangitis suggests that IFN-γ may be related to the pathogenesis of PBC in this model. Serum levels of AMA on day 14 were significantly higher than those on day 5. Interleukin-10 was considered to stimulate antibody production, to show an inhibitory effect upon the function of T helper 1 cells, and to inhibit fibrosis. Conclusions: Interferon-γ may play an important role in the pathogenesis of this model. Moreover, delayed expression of IL-10 mRNA may control PBC-like hepatic lesions. [ABSTRACT FROM AUTHOR]

Recombinant inbred (RI) lines were established from (MRL/lpr × AKR) crosses in order to analyze the role of the lpr gene and the particiption of background genes in the lymphoproliferation and the development of lupus glomerulonephritis (LGN). In this study, six lines were used to compare with MRL/lpr and AKR mice. Lymphadenopathy was pressent in four lines (A-22, A-31 b, A-31 e and C-12) but absent in the other two (A-21 and C-21). The degree of lymphoproliferation varied between individuals of the RI lines showing lymphadenopathy. On gross examinations, the most marked lymph node enlargement was seen in the A-31 b line, which resembled MRL/ lpr mice in this respect; lymphadenopathy was least prominent in the C-12 line and intermediate degrees occurred in the A-22 and A-31 e lines. Like MRL/lpr mice, deaths in the RI lines were due to LGN; however, in the lines with lymphadenopathy, 50% mortalities occurred a few weeks later than in MRL/lpr mice. The kidneys were examined histologically for proliferative, exudative, extracapillary and membranous changes in the glomeruli. The glomerular lesions in the A-22, A-31 b and A-31 e lines closely resembled those in MRL/lpr mice, but in the C12 line in which lymph node enlargement was least apparent, the histological abnormalities were significantly more severe. Of the lines without lymphadenopathy, histopathological examination showed obvious renal abnormalities in the A-21 line but none in the C-21 line or in AKR mice. From these findings it appears that there are autosomal genes which affect the expression of the lpr gene and thus modify the development of LGN and lymphoproliferation. [ABSTRACT FROM AUTHOR]

Objective: Late-onset systemic lupus erythematosus (LoSLE) is known to possess characteristics different from those of early-onset SLE (EoSLE), thereby making their diagnosis difficult. This study aimed to assess the characteristic features of LoSLE in Japan, a model country with a super-aged society., Methods: Data were obtained from the Lupus Registry of Nationwide Institutions, which includes a multicenter cohort of patients with SLE in Japan who satisfied the 1997 American College of Rheumatology revised classification criteria for SLE. Data were compared between patients with LoSLE (≥50 years old at onset) and EoSLE (<50 years old at onset). To identify factors associated with LoSLE, binary logistic regression was used for the multivariate analysis, and missing values were complemented by multiple imputations. We also conducted a sub-analysis for patients diagnosed within 5 years of onset., Results: Out of 929 enrolled patients, 34 were excluded owing to a lack of data regarding onset age. Among the 895 remaining patients, 100 had LoSLE, whereas 795 had EoSLE. The male-to-female ratio was significantly higher in the LoSLE group than in the EoSLE group (0.32 vs 0.11, p < 0.001). With respect to SLEDAI components at onset, patients with LoSLE exhibited a higher frequency of myositis (11.9% vs 3.75%, p = 0.031), lower frequency of skin rash (33.3% vs 67.7%, p < 0.001), and lower frequency of alopecia (7.32% vs 24.7%, p = 0.012). No significant differences in overall disease activity at onset were observed between the two groups. Regarding medical history, immunosuppressants were more commonly used in EoSLE. A multivariate analysis revealed that a higher male proportion and a lower proportion of new rash at onset were independent characteristic features of LoSLE. We also identified late onset as an independent risk factor for a high SDI score at enrollment and replicated the result in a sub-analysis for the population with a shorter time since onset., Conclusions: We clarified that LoSLE was characterized by a higher male proportion, a lower frequency of skin rash and a tendency to organ damage. Now that the world is faced with aging, our results may be helpful at diagnosis of LoSLE., Competing Interests: Declaration of conflicting interestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Ken-ei Sada received a speaker’s fee from GlaxoSmithKline PLC and research grants from Pfizer Inc. Yohei Kirino received a speaker’s fee from Amgen and Novartis and research funding from Nippon Shinyaku. Ryusuke Yoshimi received a speaker’s fee from GlaxoSmithKline PLC, AstraZeneca PLC, and Sanofi S.A.

Objectives: The predictive validity of disease-specific quality of life (QOL) remains unknown in patients with systemic lupus erythematosus (SLE), although disease-specific measures are equally or more responsive to changes than generic QOL. We aimed to examine the predictive validity of the Lupus patient-reported outcome (PRO) for damage accrual., Methods: Patients with SLE and ≥2 measurements over time were included in Japanese nationwide multicentre registry (LUNA). The Lupus PRO questionnaire contains both health-related (HR) and non-HR-QOL measures. Damage accrual was evaluated using the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SDI). We examined the association between the Lupus-PRO score at baseline and longitudinal SDI scores using mixed-effects models adjusted for prognostic factors., Results: Among 1295 patients, those with higher HR-QOL of Lupus PRO at baseline demonstrated a significantly lower increase in SDI (-0.005/year, 95% confidence interval [CI]: -0.007 to - 0.004, p < 0.001). According to the categorisation of HR-QOL based on tertile, a similar dose-dependent effect of HR-QOL on longitudinal SDI was identified (second vs first tertile category: -0.101/year, 95% CI: -0.172 to - 0.030; third tertile category: -0.211/year, 95% CI: -0.281 to - 0.142). Non-HR-QOL was not significantly associated with the SDI scores. Among the HR-QOL domains, cognition, procreation, and physical health were significantly associated with the total SDI scores over time. HR-QOL was associated with corticosteroid-dependent and -independent SDI scores., Conclusion: A higher HR-QOL of Lupus PRO was associated with a lower increase in SDI scores. Our findings imply the importance of disease-specific HR-QOL measurements in assessing prognosis., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

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., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Detecting the toxic effects of chemicals on reproduction and development without using mammalian animal models is crucial in the exploitation of pharmaceuticals for human use. Zebrafish are a promising animal model for investigating pharmacological effects and toxicity during vertebrate development. Several studies have suggested the use of zebrafish embryos for the assessment of malformations or embryo-fetal lethality (MEFL). However, a reproducible protocol as a standard for the zebrafish MEFL test method that fulfills global requests has not been established based on the International Council of Harmonisation (ICH) S5 (R3) guidelines. To establish such a toxicity test method, we developed a new and easy protocol to detect MEFL caused by chemicals, especially those with teratogenic potential, using fertilized zebrafish eggs (embryos) within 5 days of development. Our toxicity test trials using the same protocol in two to four different laboratories corroborated the high inter-laboratory reproducibility. Our test method enabled the detection of 18 out of 22 test compounds that induced rat MEFL. Thus, the prediction rate of our zebrafish test method for MEFL was almost 82% compared with that of rat MEFL. Collectively, our study proposes the establishment of an easy and reproducible protocol for the zebrafish MEFL test method for reproductive and developmental toxicity that meets ICH guideline S5 (R3), which can be further considered in combination with information from other sources for regulatory use.

Historical control data from prenatal developmental toxicity studies in rats have been used to evaluate whether toxicology outcomes were induced by exposure to a chemical or were within the range of spontaneous variation. These data are also important for monitoring animal characteristics. As a follow-up to historical control data from 1998 to 2010, this study analyzed control data from prenatal developmental studies performed in rats from 2011 to 2015. Data were collected from studies performed by 24 Japanese laboratories, including 15 pharmaceutical and chemical companies and nine contract research organizations, in Sprague-Dawley and two-sub-strains of Wistar Hannover rats. The data included maternal reproductive findings at terminal cesarean section and fetal findings, including incidences of spontaneous external, visceral, and skeletal anomalies. No noticeable differences in maternal reproductive data were observed among laboratories. The inter-laboratory variations in the incidences of fetal anomalies seemed to be due to differences in the selection of observation parameters, observation criteria, and classification of the findings, as well as to differences in terminology of fetal alterations. These historical control data may be helpful for adequate interpretation of experimental results and for evaluating the reproductive and developmental toxicities of various chemicals., (© 2018 Japanese Teratology Society.)