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Aging is a significant risk factor for autoimmunity, and many autoimmune diseases tend to onset during adulthood. We conducted an extensive analysis of CD4+ T cell subsets from 354 patients with autoimmune disease and healthy controls via flow cytometry and bulk RNA sequencing. As a result, we identified a distinct CXCR3midCD4+ effector memory T cell subset that expands with age, which we designated "age-associated T helper (THA) cells." THA cells exhibited both a cytotoxic phenotype and B cell helper functions, and these features were regulated by the transcription factor ZEB2. Consistent with the highly skewed T cell receptor usage of THA cells, gene expression in THA cells from patients with systemic lupus erythematosus reflected disease activity and was affected by treatment with a calcineurin inhibitor. Moreover, analysis of single-cell RNA sequencing data revealed that THA cells infiltrate damaged organs in patients with autoimmune diseases. Together, our characterization of THA cells may facilitate improved understanding of the relationship between aging and autoimmune diseases. Editor's summary: Pathological CD4+ T cell responses contribute to the development of autoimmunity, but whether their age-related changes affect autoimmune disease susceptibility remains unclear. By analyzing a cohort of 354 patients with autoimmune disease, Goto et al. identified a population of peripheral blood CXCR3midCD4+ T cells that is expanded during aging and conditions such as systemic lupus erythematosus (SLE) and rheumatoid arthritis. These age-associated helper T (THA) cells promoted antibody production by B cells and were regulated by the transcription factor ZEB2. THA cell gene signatures correlated with SLE disease activity and were observed in target organs, indicating that THA cells may represent a therapeutic target for autoimmune diseases. —Claire Olingy [ABSTRACT FROM AUTHOR]

Aim: To elucidate the clinical features, long‐term survival, and prognostic factors for mortality among patients with microscopic polyangiitis (MPA), including those with anti‐neutrophil cytoplasmic antibody‐positive interstitial lung disease (ILD) (ANCA‐ILD), which could be a subset of its variant phenotype. Methods: We retrospectively included 76 consecutive patients between 2006 and 2014, diagnosed with MPA according to the European Medicines Agency algorithm using the Chapel Hill Consensus Conference definitions or ANCA‐ILD. ILD was classified as usual interstitial pneumonia (UIP) or nonspecific interstitial pneumonia pattern using chest computed tomography. Results: The mean (standard deviation) age of the patients (female, 68%) was 69 (12) years. The median (interquartile range) follow‐up period was 68 (33‐95) months. Comorbid ILD and glomerulonephritis were observed in 44 (58%) (68% UIP) and 54 (71%) patients, respectively. Comorbid ILD was associated with low survival (P =.0563). There were 17 (39%) and 5 (16%) deaths in the ILD and non‐ILD groups, respectively (P =.0404). In the ILD group, 6 and 5 of the deaths were attributed to infection and ILD progression, respectively. In the non‐ILD group, 1 and 2 patients expired from subsequently developed ILD and aspiration pneumonia, respectively. Age ≥ 70 years (hazard ratio = 2.78; 95% confidential interval 1.15‐6.70) and UIP (3.95; 1.60‐9.77) were independent risk factors for mortality. Conclusion: Age ≥ 70 years and ILD with a UIP pattern were associated with high mortality, owing to susceptibility to infection and ILD progression. A more effective and less toxic treatment is required for progressive ILD. [ABSTRACT FROM AUTHOR]

Objective Targeting synovial fibroblasts (SF) using a cyclin-dependent kinase (CDK) 4/6 inhibitor (CDKI) could be a potent therapy for RA via inhibition of proliferation and MMP-3 production. This study was designed to elucidate the mechanism of chondroprotective effects on SFs by CDK 4/6 inhibition. Methods CDK4/6 activity was inhibited using CDKI treatment or enhanced by adenoviral gene transduction. Chondroprotective effects were evaluated using a collagen-induced arthritis model (CIA). Gene and protein expression were evaluated with quantitative PCR, ELISA and Western blotting. The binding of nuclear extracts to DNA was assessed with an electrophoresis mobility shift assay. RNA-Seq was performed to identify gene sets affected by CDKI treatment. Results CDKI attenuated cartilage destruction and MMP-3 production in CIA. In RASFs, CDKI impaired the binding of AP-1 components to DNA and inhibited the production of MMP-1 and MMP-3, which contain the AP-1 binding sequence in their promoter. CDK4/6 protected JUN from proteasome-dependent degradation by inhibiting ubiquitination. The RNA-Seq analysis identified CDKI-sensitive inflammatory genes, which were associated with the pathway of RA-associated genes, cytokine-cytokine receptor interaction and IL-17 signalling. Notably, the AP-1 motif was enriched in these genes. Conclusion The mechanism of chondroprotective effects by CDK4/6 inhibition was achieved by the attenuation of AP-1 transcriptional activity via the impaired stability of JUN. Because the pharmacologic inhibition of CDK4/6 has been established as tolerable in cancer treatment, it could also be beneficial in patients with RA due to its chondroprotective and anti-inflammatory effects. [ABSTRACT FROM AUTHOR]

Objective: One of the histologic characteristics of systemic sclerosis (SSc) is an increased number of dermal myofibroblasts, and transforming growth factor β (TGFβ) plays a crucial role in the promotion of myofibroblast differentiation from fibroblasts, leading to dermal fibrosis. This study was undertaken to 1) examine whether inhibition of the cell cycle with a cyclin‐dependent kinase 4/6 (CDK4/6) inhibitor suppresses the proliferation of fibroblasts and their differentiation into myofibroblasts, and 2) assess the therapeutic effects of a CDK4/6 inhibitor, administered as monotherapy or in combination with a TGFβ receptor (TGFβR) inhibitor, on dermal fibrosis in murine models of SSc. Methods: Fibroblasts obtained from the skin of patients with SSc were cultured in the presence or absence of TGFβ. The effects of palbociclib, a CDK4/6 inhibitor, on fibroblast proliferation and TGFβ‐induced differentiation into myofibroblasts were examined using bromodeoxyuridine uptake assays as well as immunofluorescence and immunoblotting analyses. Murine models of HOCl‐ and bleomycin‐induced dermal fibrosis were used to study the effect of a CDK4/6 inhibitor on dermal fibrosis, with the CDK4/6 inhibitor treatment administered as monotherapy or in combination with galunisertib, a TGFβR inhibitor. Results: Addition of a CDK4/6 inhibitor to the cell cultures suppressed the proliferation of human dermal SSc fibroblasts and their TGFβ‐induced differentiation into myofibroblasts, without inhibiting canonical and noncanonical TGFβ signals. In murine models of dermal fibrosis, treatment of mice with a CDK4/6 inhibitor decreased dermal thickness and collagen content, as well as dermal fibroblast proliferation and the numbers of myofibroblasts. Combination therapy with the CDK4/6 inhibitor and TGFβR inhibitor resulted in additive antifibrotic effects. Mechanistically, the CDK4/6 inhibitor suppressed the expression of cellular communication network 2 and cadherin‐11, which are proteins that have important roles in the development and progression of fibrosis. Conclusion: Results of this study demonstrate the therapeutic effect of a CDK4/6 inhibitor on dermal fibrosis when administered as monotherapy or in combination with a TGFβR inhibitor. CDK4/6 inhibitors, including palbociclib used in the present study, may represent novel agents for the treatment of SSc, which, if used in combination with a TGFβR inhibitor, might result in increased efficacy. [ABSTRACT FROM AUTHOR]