Regulatory T cells (Tregs) have important functions in peripheral immune tolerance. Dysfunction of Tregs is considered to be a pivotal cause of autoimmune diseases, including rheumatoid arthritis ...(RA). However, previous reports describing the proportion of Tregs among CD4+ T cells in RA patients were controversial because a range of markers are used to identify Tregs with little consensus. To clarify the status of Tregs in RA, we investigated the proportion of Tregs with focusing on the definitions of them.
We identified the studies reporting the proportion of Tregs in RA patients using PubMed and Google Scholar. We performed a systematic review of them and a meta-analysis to evaluate the proportion of Tregs (FOXP3-positive and/or CD25-positive) among CD4+ T cells in peripheral blood (PB) and synovial fluid (SF) of RA patients and control subjects.
A total 31 studies were selected. The proportion of Tregs defined by all definitions among CD4+ T cells in PB was not significantly different between RA patients and control subjects (-0.65, -1.30, 0.01). Then we performed sub-analyses based on individual definitions. The proportion of Tregs defined by either CD25 or FOXP3 alone did not differ between RA patients and control subjects. The proportion of Tregs defined by both FOXP3 and CD25 was lower in RA patients than that in control subjects (-2.42 -3.49, -1.34). The proportion of Tregs defined by both FOXP3 and CD25 was higher in SF than that in PB among RA patients (3.27 0.40, 6.14).
The status of Tregs varied according to the definition system. The proportion of Tregs defined by stricter and functionally validated methods decreased in PB and increased in SF among RA patients. If the proportion of Tregs differs in RA, accurate and functionally relevant definitions of Tregs are necessary to elucidate their status in RA.
The global prevalence of metabolic diseases, such as obesity, diabetes, and atherosclerosis, is rapidly increasing and has now reached epidemic proportions. Chronic tissue inflammation is a ...characteristic of these metabolic diseases, indicating that immune responses are closely involved in the pathogenesis of metabolic disorders. However, the regulatory mechanisms underlying immunometabolic crosstalk in these diseases are not completely understood. Recent studies have revealed the multifaceted functions of semaphorins, originally identified as axon guidance molecules, in regulating tissue inflammation and metabolic disorders, thereby highlighting the functional coupling between semaphorin signaling and immunometabolism. In this review, we explore how semaphorin signaling transcends beyond merely guiding axons to controlling immune responses and metabolic diseases.
Inappropriate IL-17 responses are implicated in chronic tissue inflammation. IL-23 contributes to
-specific IL-17 production, but the molecular mechanisms underlying regulation of the IL-23-IL-17 ...axis during
infection are poorly understood. Here, we demonstrate a novel function of BATF2 as a negative regulator of
in innate immune cells. IL-17, but not IFN-γ, was more highly produced by CD4
T cells from spleens and livers of
-infected
mice than by those of wild-type mice. In this context,
mice showed severe multiorgan pathology despite reduced parasite burden.
-induced IL-23 production was increased in
innate immune cells. The
-induced enhanced Th17 response was abrogated in
mice. The interaction of BATF2 with c-JUN prevented c-JUN-ATF-2 complex formation, inhibiting
expression. These results demonstrate that IFN-γ-inducible BATF2 in innate immune cells controls Th17-mediated immunopathology by suppressing IL-23 production during
infection.
An anti-ficolin-1 mAb is effective as therapy for autoimmunity
Abstract
Previously, we reported that mRNA expression of ficolin-1 (FCN1), a component of the complement lectin pathway, is elevated in ...peripheral blood mononuclear cells of patients with vasculitis syndrome, and that FCN1-positive cells infiltrate into inflamed regions in patient specimens. In addition, we reported that the serum FCN1 concentration is elevated in patients with Kawasaki disease (KD), a pediatric vasculitis, but dramatically decreases after intravenous immunoglobulin (IVIG) treatment. Furthermore, we showed that FCN1 binds to IgG1 in a pull-down assay. These results suggested that removal of FCN1 may be a therapeutic mechanism of IVIG. In this study, we prepared anti-FCN1 monoclonal antibody (mAb) and examined its therapeutic potential in mice treated with Candida albicans water-soluble fraction (CAWS), which induces KD-like vasculitis in the coronary artery. Indeed, treatment with anti-FCN1 mAb decreased the histological score of vasculitis (P = 0.03). To investigate the role of FCN1, we assessed blood samples of patients with various autoimmune diseases and demonstrated that serum levels of FCN1 were elevated not only in patients with vasculitis, but also in those with rheumatoid arthritis. Additionally, FCN1-targeted treatment of a mouse model of arthritis collagen antibody-induced arthritis (CAIA) revealed that administration of anti-FCN1 mAb ameliorated symptoms of arthritis (P < 0.01). These results suggest that FCN1 is involved in the pathogenesis of autoimmune diseases, and that targeting FCN1 represents a promising strategy for treating these diseases.
Abstract
Antibodies produced by plasma cells are critical for protection from infection. It has been demonstrated that global epigenetic modification, such as changes in DNA methylation, occurs ...during differentiation of plasma cells from B cells. However, the precise mechanisms by which DNA methylation controls plasma cell differentiation are not fully understood. We examined the effect of deficiency of DNA demethylases, Tet2 and Tet3, on B-cell activation and plasma cell differentiation, by generating conditional Tet2/3 double-KO (Tet dKO) B cells. We found that Tet dKO B cells failed to differentiate into plasma cells upon immunization with antigens. Tet dKO B cells proliferated normally and were capable of generating cells with IRF4int, but not with IRF4hi, the majority of which were CD138+ plasma cells. IRF4 overexpression rescued the defect of Tet dKO B cells in plasma cell differentiation, suggesting that Tet2/3-dependent high IRF4 expression is required for plasma cell differentiation. We identified CpG sites in the Irf4 locus that were demethylated specifically in plasma cells and in a Tet2/3-dependent manner. Our results suggest that Tet2/3-dependent demethylation of these CpG sites is dispensable for initial IRF4 expression but is essential for high IRF4 expression which is prerequisite for plasma cell differentiation.
Tet2 and Tet3 regulate IRF4 levels during B cell activation
Since the discovery of group 2 innate lymphoid cells (ILC2s) in 2010, subsequent studies have revealed their developmental pathways, mechanisms of activation and regulation, and immunological roles ...in tissue homeostasis and tissue-specific diseases in various organs. Although ILC2s are known to express tissue-specific features depending on where they reside, how the surrounding environment affects the functions of ILC2s remains to be fully elucidated. Recent histologic analyses revealed that ILC2s resides in specific perivascular regions in peripheral tissues with their function being controlled by the surrounding cells via cytokines, lipid mediators, neurotransmitters, and cell-cell interactions through surface molecules. This review summarizes the interactions between ILC2s and surrounding cells, including epithelial cells, neurons, immune cells, and mesenchymal cells, with the objective of promoting the development of novel diagnostic and therapeutic methods for ILC2-related diseases.
Alteration of the gut microbiome has been linked to the pathogenesis of systemic lupus erythematosus (SLE). However, a comprehensive view of the gut microbiome in SLE and its interaction with the ...host remains to be revealed. This study aimed to reveal SLE-associated changes in the gut microbiome and its interaction with the host by a comprehensive metagenome-wide association study (MWAS) followed by integrative analysis.
We performed a MWAS of SLE based on shotgun sequencing of the gut microbial DNA from Japanese individuals (
=47,
=203). We integrated the result of the MWAS with the genome-wide association study (GWAS) data and plasma metabolite data.
Via species level phylogenetic analysis, we identified and validated increases of
and
in the patients with SLE. Microbial gene analysis revealed increases of
-derived genes including one involved in redox reaction. Additionally, microbial pathways related to sulfur metabolism and flagella assembly were altered in the patients with SLE. We identified an overlap in the enriched biological pathways between the metagenome and the germline genome by comparing the result of the MWAS and the GWAS of SLE (ie, MWAS-GWAS interaction). α-diversity and β-diversity analyses provided evidence of dysbiosis in the metagenome of the patients with SLE. Microbiome-metabolome association analysis identified positive dosage correlation of acylcarnitine with
, an SLE-associated taxon.
Our MWAS followed by integrative analysis revealed SLE-associated changes in the gut microbiome and its interaction with the host, which contribute to our understanding of the relationship between the microbiome and SLE.
Background:Pulmonary arterial hypertension (PAH), particularly connective tissue disease-associated PAH (CTD-PAH), is a progressive disease and novel therapeutic agents based on the specific ...molecular pathogenesis are desired. In the pathogenesis of CTD-PAH, inflammation, immune cell abnormality, and fibrosis play important roles. However, the existing mouse pulmonary hypertension (PH) models do not reflect these features enough. The relationship between inflammation and hypoxia is still unclear.Methods and Results:Intraperitoneal administration of pristane, a kind of mineral oil, and exposure to chronic hypoxia were combined, and this model is referred to as pristane/hypoxia (PriHx) mice. Hemodynamic and histological analyses showed that the PriHx mice showed a more severe phenotype of PH than pristane or hypoxia alone. Immunohistological and flow cytometric analyses revealed infiltration of immune cells, including hemosiderin-laden macrophages and activated CD4+helper T lymphocytes in the lungs of PriHx mice. Pristane administration exacerbated lung fibrosis and elevated the expression of fibrosis-related genes. Inflammation-related genes such asIl6andCxcl2were also upregulated in the lungs of PriHx mice, and interleukin (IL)-6 blockade by monoclonal anti-IL-6 receptor antibody MR16-1 ameliorated PH of PriHx mice.Conclusions:A PriHx model, a novel mouse model of PH reflecting the pathological features of CTD-PAH, was developed through a combination of pristane administration and exposure to chronic hypoxia.
This multi-center, retrospective study aimed to clarify the factors affecting drug retention of the Janus kinase inhibitors (JAKi) including baricitinib (BAR) and tofacitinib (TOF) in patients with ...RA. Patients were as follows; females, 80.6%; age, 60.5 years; DAS28-ESR, 4.3; treated with either BAR (n = 166) or TOF (n = 185); bDMARDs- or JAKi-switched cases (76.6%). The reasons for drug discontinuation were classified into four major categories. The drug retention was evaluated at 24 months using the Kaplan-Meier method and multivariate Cox proportional hazards modelling adjusted by confounders. Discontinuation rates for the corresponding reasons were as follows; ineffectiveness (22.3%), toxic adverse events (13.3%), non-toxic reasons (7.2%) and remission (0.0%). Prior history of anti-interleukin-6 receptor antibody (aIL-6R) ineffectiveness significantly increased the risk of treatment discontinuation due to ineffectiveness (p = 0.020). Aging (≥ 75 years) (p = 0.028), usage of PSL ≥ 5 mg/day (p = 0.017) and female sex (p = 0.041) significantly increased the risk of treatment discontinuation due to toxic adverse events. Factors not associated with treatment discontinuation were: number of prior bDMARDs or JAKi, concomitant MTX usage, difference of JAKi, and prior use of TNF inhibitor, CTLA4-Ig or other JAKi.
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