Language：Others   Publishing type：Research paper (scientific journal)  

DOI： 10.1093/mr/roac100

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1177/1759720X221096367

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1093/mr/roab010

Language：English   Publishing type：Research paper (scientific journal)  

DOI： doi: 10.1186/s13075-021-02618-4.

Language：English   Publishing type：Research paper (scientific journal)  

DOI： doi: 10.1038/s41598-021-95711-2.

Language：English   Publishing type：Research paper (scientific journal)  

DOI： doi: 10.3389/fimmu.2021.713225. eCollection 2021.

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1007/s00296-020-04512-9

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1186/s13075-019-1823-0

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.4049/jimmunol.1403046

Language：Others   Publishing type：Research paper (scientific journal)  

Objectives

Understanding interpatient variation in CD4+T-cell responses is the bases for understanding the pathogenesis and management of rheumatoid arthritis (RA). We examined immune responses to SARS-CoV-2 vaccine in a cohort of patients with RA and determined factors associated with the responses.

Methods

Four hundred and thirty-one patients with RA having received two doses of BNT162b2, a messenger RNA-based vaccine for SARS-CoV-2, were included. Vaccine antigen-specific IgG was detected by ELISA, and antigen-specific CD4+T cells were detected by CD154 expression in response to antigenic stimulation. Expression of cytokines was concomitantly detected by intracellular staining. Associations among background variables, antigen-specific antibody production and the CD4+T-cell responses were analysed. Unsupervised hierarchical clustering was performed based on the profiles of antigen-specific cytokine production by CD4+T cells to stratify patients with RA.

Results

Multivariate analysis indicated that ageing negatively affects CD4+T-cell response as well as antibody production. No association was detected between the presence or the levels of rheumatoid factor/anti-cyclic citrullinated peptide antibody and anti-vaccine immune responses. Methotrexate and prednisolone reduced B cell but not T-cell responses. Conventional immunophenotyping by the expression of chemokine receptors was not associated with the actual CD4+T-cell response, except for T helper cells (Th1). Functional immunophenotyping based on the profiles of antigen-specific cytokine production of CD4+T cells stratified patients with RA into three clusters, among which Th1-dominant type less frequently underwent joint surgery.

Conclusions

Clinical and immunological variables that are associated with antigen-specific CD4 T-cell responses in patients with RA were determined by analysing immune responses against SARS-CoV-2 vaccine.

DOI： 10.1136/rmdopen-2023-003693

Language：Others   Publishing type：Research paper (scientific journal)  

Abstract

Objective

To evaluate trends in results of care and management for antineutrophil cytoplasmic antibodies (ANCA)‐associated vasculitis (AAV).

Methods

We employed multicenter cohort data collected during 2011–2021, recruiting 43 patients with granulomatosis with polyangiitis (GPA) and 91 with microscopic polyangiitis (MPA). According to the median registration date of September 2015, patients have split into two groups: an early group and a late group (both of them, n = 67). To prevent bias, a propensity score according to numerous baseline characteristics variables was calculated; 50 matching members of each group were statistically extracted. Their treatments and clinical outcomes were examined at 6, 12, and 24 months after initial remission therapy.

Results

Statistics demonstrated that the baseline characteristics were similar. The late group used rituximab (RTX) more often for both remission induction and maintenance therapy, compared with the early group. The mean daily PSL doses of the late group were significantly lower than those of early group at each time point. The late group discontinued PSL 14.0% at 12 months and 23.3% at 24 months. Despite their intensive glucocorticoids (GC) tapering, the remission rates and the relapse rates were significantly fairer in the late group. The Vasculitis Damage Index (VDI) and VDI due to GC at each time point were lower in the late group, and those differences had become wider over time.

Conclusion

Recent developments in AAV treatment have allowed efficient remission and prevention of relapses, which in turn enabled extensive GC tapering causing fewer sequelae.

DOI： 10.1111/1756-185x.15009

Language：Others   Publishing type：Research paper (scientific journal)  

Abstract

Objectives

To evaluate the long-term impact of immunosuppressive therapeutic agents on antibody response to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) mRNA vaccination in patients with autoimmune rheumatic diseases (AIRD) in order to propose a strategy for annual vaccination.

Methods

This prospective multicentre cohort study evaluated the humoral response to second and third BNT162b2 and/or mRNA-1273 vaccines in 382 Japanese AIRD patients classified into 12 different medication groups and in 326 healthy controls (HCs). The third vaccination was administered six months after the second vaccination. Antibody titres were measured using the Elecsys Anti-SARS-CoV-2 S assay.

Results

The seroconversion rate and antibody titres were lower in AIRD patients than in HCs 3–6 weeks after the second vaccination and 3–6 weeks after the third vaccination. Seroconversion rates were <90% after the third vaccination in patients receiving mycophenolate mofetil and rituximab. Antibody levels after the third vaccination were significantly lower in the groups prescribed TNF inhibitor with or without methotrexate, abatacept and rituximab or cyclophosphamide than those of HCs in a multivariate analysis adjusting for age, sex, and glucocorticoid dosage. The third vaccination induced an adequate humoral response in patients treated with sulfasalazine, bucillamine, methotrexate monotherapy, iguratimod, interleukin-6 inhibitors or calcineurin inhibitors including tacrolimus.

Conclusions

Repeated vaccinations in many immunosuppressed patients produced antibody responses similar to those observed in HCs. In contrast, annual vaccination in patients receiving TNF inhibitors, abatacept, mycophenolate mofetil and rituximab may require caution.

DOI： 10.1093/rheumatology/kead275

Language：Others   Publishing type：Research paper (scientific journal)  

Abstract

Objects

Recently, the involvement of basophils and IgE-type autoantibodies in the pathogenesis of SLE has been elucidated using mouse models; however, few studies have been conducted in humans. In this study, the role of basophils and anti-double-stranded DNA (dsDNA) IgE in SLE was examined using human samples.

Methods

The correlation between disease activity and serum levels of anti-dsDNA IgE in SLE was evaluated using enzyme-linked immunosorbent assay. Cytokines produced by IgE-stimulated basophils from healthy subjects were assessed using RNA sequences. The interaction of basophils and B cells to promote B cell differentiation was investigated using a co-culture system. The ability of basophils from patients with SLE with anti-dsDNA IgE to create cytokines that may be involved in B cell differentiation in response to dsDNA was examined using real-time PCR.

Results

Anti-dsDNA IgE levels in the serum of patients with SLE correlated with disease activity. Healthy donor basophils produced IL-3, IL-4 and TGF-β1 after anti-IgE stimulation. Co-culture of B cells with anti-IgE-stimulated basophils increased plasmablasts which were cancelled by neutralizing IL-4. After encountering the antigen, basophils released IL-4 more quickly than follicular helper T cells. Basophils isolated from patients with anti-dsDNA IgE promoted IL-4 expression by adding dsDNA.

Conclusions

These results suggest that basophils contribute to the pathogenesis of SLE by promoting B cell differentiation via dsDNA-specific IgE in patients similar to the process described in mouse models.

DOI： 10.1093/rheumatology/kead082

Language：Others  

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.4049/jimmunol.2100323

Language：English  

DOI： 10.1093/mr/roac030

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1186/s13075-022-02746-5

Language：English   Publishing type：Research paper (scientific journal)  

DOI： doi: 10.1177/09612033211031989.

Language：English   Publishing type：Research paper (scientific journal)  

DOI： doi: 10.1111/bjh.17456. Online ahead of print.

Language：English   Publishing type：Research paper (scientific journal)  

DOI： doi: 10.1097/MD.0000000000025406.

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.3389/fimmu.2021.654623

Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1016/j.cellimm.2020.104263

Language：English   Publishing type：Research paper (scientific journal)  

Systemic sclerosis (SSc) is a T helper type 2 (Th2)-associated autoimmune disease characterized by vasculopathy and fibrosis. Efficacy of B cell depletion therapy underscores antibody-independent functions of B cells in SSc. A recent study showed that the Th2 cytokine interleukin (IL)-4 induces granulocyte–macrophage colony-stimulating factor (GM-CSF)-producing effector B cells (GM-B_effs) in humans. In this study, we sought to elucidate the generation mechanism of GM-B_effs and also determine a role of this subset in SSc. Among Th-associated cytokines, IL-4 most significantly facilitated the generation of GM-B_effs within memory B cells in healthy controls (HCs). In addition, the profibrotic cytokine transforming growth factor (TGF)-β further potentiated IL-4- and IL-13-induced GM-B_effs. Of note, tofacitinib, a Janus kinase (JAK) inhibitor, inhibited the expression of GM-CSF mRNA and protein in memory B cells induced by IL-4, but not by TGF-β. GM-B_effs were enriched within CD20⁺CD30⁺CD38^−/low cells, a distinct population from plasmablasts, suggesting that GM-B_effs exert antibody-independent functions. GM-B_effs were also enriched in a CD30⁺ fraction of freshly isolated B cells. GM-B_effs generated under Th2 conditions facilitated the differentiation from CD14⁺ monocytes to DC-SIGN⁺CD1a⁺CD14⁻CD86⁺ cells, which significantly promoted the proliferation of naive T cells. CD30⁺ GM-B_effs were more pronounced in patients with SSc than in HCs. A subpopulation of SSc patients with the diffuse type and concomitant interstitial lung disease exhibited high numbers of GM-B_effs. Together, these findings suggest that human GM-B_effs are enriched in a CD30⁺ B cell subset and play a role in the pathogenesis of SSc.

DOI： 10.1111/cei.13477

Language：English   Publishing type：Research paper (scientific journal)  

Background: Concomitant use of methotrexate (MTX) improves the clinical efficacy of anti-TNF agents in the treatment of rheumatoid arthritis (RA). We aimed to clarify the cytotoxic effect of MTX on transmembrane TNF (tmTNF)-expressing cells treated with anti-TNF agents. Methods: Jurkat T cells stably expressing tmTNF were used for the following experiments. Cytotoxicity induced by an anti-TNF agent (infliximab, adalimumab, or certolizumab pegol) with concomitant MTX were compared with that by MTX alone or by an anti-TNF agent alone using flow cytometry. Apoptosis-induction mediated by reverse signal through tmTNF, complement-dependent cytotoxicity (CDC), antibody-dependent cell-mediated cytotoxicity (ADCC), and antibody-dependent cellular phagocytosis (ADCP) were evaluated. Folic acid and Y-27632, a Rho kinase inhibitor, were used as inhibitors to study intracellular signaling pathway in apoptosis induced by MTX and anti-TNF agents. Results: Apoptosis of tmTNF-expressing cells was significantly increased by the concomitant administration of MTX and an anti-TNF agent, compared with MTX alone or an anti-TNF agent alone. The apoptosis induction by concomitant MTX was most pronounced in infliximab-treatment. Reverse signal transduction, but not CDC or ADCC/ADCP, was responsible for the coordinate effect of MTX and an anti-TNF agent on tmTNF-expressing cells. Folic acid inhibited MTX-mediated apoptosis, while Y-27632 suppressed JNK activation and infliximab-induced apoptosis via revere signal through tmTNF. Conclusion: The apoptotic effect was enhanced by combination of MTX and an anti-TNF agent in tmTNF-expressing cells. The intracellular pathways induced by MTX and anti-TNF agents seem to be independent. These findings might explain at least in part improved the clinical response upon co-therapy of MTX and an anti-TNF agent in RA.

DOI： 10.3389/fimmu.2020.02042

Language：English   Publishing type：Research paper (scientific journal)  

Background: Follicular helper CD4⁺ T (Tfh) cells have a critical role in IgG4 production by B cells in IgG4-related disease (IgG4-RD). Recent studies including ours showed that SLAMF7⁺CD4⁺ T cells are an important pathological driver of IgG4-RD. In this study, we have sought to elucidate a relationship between helper CD4⁺ T (Th), particularly Tfh, cells and SLAMF7⁺ CD4⁺ T cells in IgG4-RD. Results: The patients with IgG4-RD enrolled in this study were aged 66 ± 12 years and their titers of serum IgG4 were 372 ± 336 mg/dl. Th1 cells, activated circulating Tfh1 (cTfh1), and activated cTfh2 cells increased in IgG4-RD. SLAMF7 was mainly expressed on Th1 and cTfh1, but not cTfh2, cells in the patients. SLAMF7⁺ cTfh1 cells were PD-1/CD28 double-positive, whereas SLAMF7⁺ Th1 cells were CD28 negative. Positive correlations were noted between serum IgG4 levels and the number of activated cTfh2 cells and SLAMF7⁺ cTfh1 cells, but not SLAMF7⁺ Th1 cells. Intriguingly, among cTfh1 cells, activated SLAMF7⁺ cTfh1 cells were high producers of IL-10 along with IL-21. Blimp-1, but not Bcl-6, mRNA was expressed at high levels in activated SLAMF7⁺ cTfh1 cells. In addition to CD4⁺ T cells, the frequency of SLAMF7⁺ fraction was higher in memory B cells than naïve B cells in patients with IgG4RD. Finally, upon stimulation via B-cell receptor and CD40, Tfh1-associated cytokines, IL-21 and IFN-γ, most significantly induced SLAMF7 expression in memory B cells. Conclusions: Together, these results suggest that circulating SLAMF7⁺ Tfh1 cells, along with Tfh2 cells, play a pathologic role in IgG4 production in IgG4-RD.

DOI： 10.1186/s12865-020-00361-0

Language：English   Publishing type：Research paper (scientific journal)  

DNase 1-like 3 (DNase1L3), which belongs to DNase1 family, was originally identified as one of apoptosis- and necrosis-related endonucleases that fragmentate intranucleosomal DNA. A loss-of-function mutation has been reported in murine models of systemic lupus erythematosus (SLE) and in familial SLE patients. These reports suggest DNase1L3 plays an important role in the prevention of developing SLE; however, expression and function of DNase1L3 in human immune systems have been largely unclarified. As previous reports showed DNase1L3 is expressed in hematopoietic organs, we first analyzed expression levels of DNase1L3 in each subset of human peripheral blood cells by quantitative real-time PCR. Plasmacytoid dendritic cells showed the highest expression levels of DNase1L3 mRNA among peripheral blood cells. IL-4 enhanced DNase1L3 expression in monocytes, monocyte-derived dendritic cells, and monocyte-derived macrophages (MDMs), but not in T cells, B cells, or plasmacytoid dendritic cells. Together with IL-4, all-trans retinoic acid and apoptotic cells efficiently upregulated expression of DNalse1L3 in MDMs. As a result of intracellular signaling analysis, Jak1-IRS2-ERK/PI3K pathway was essential for IL-4-induced DNase1L3 expression. IL-4-treated monocyte-derived dendritic cells and MDMs secreted active DNase1L3 protein that could degrade liposome-DNA complexes, which were resistant to DNase1. Our results indicate DNase1L3 is secreted by innate immune cells and may play a critical role in the tissue homeostasis and on prevention of developing autoimmunity by degrading self-DNA.

DOI： 10.4049/jimmunol.1901304

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1186/s13075-019-1984-x

Language：English   Publishing type：Research paper (scientific journal)  

DOI： https://doi.org/10.1080/24725625.2018.1523830

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1371/journal.pone.0196368

Language：English   Publishing type：Research paper (scientific journal)  

DOI： doi: 10.5152/eurjrheum.2017.17068.

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1186/s13075-015-0547-z

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1097/MIB.0b013e318280b169

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1186/ar4087

Language：English   Publishing type：Research paper (scientific journal)  

DOI： doi: 10.1001/archdermatol.2011.52.

Event date： 2018.9

Language：Japanese   Presentation type：Symposium, workshop panel (public)  

Venue：佐賀市   Country：Japan  

Event date： 2018.4

Language：Japanese   Presentation type：Symposium, workshop panel (public)  

Venue：東京   Country：Japan  

Event date： 2017.4

Language：Japanese   Presentation type：Symposium, workshop panel (public)  

Venue：福岡   Country：Japan  

Event date： 2017.3

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：別府   Country：Japan  

Event date： 2017.1

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：東京   Country：Japan  

Language：Others  

Country：Other  

Language：Japanese  

Country：Japan  

Language：Others  

Country：Other  

Language：Others  

Country：Other  

Language：Others  

Country：Other  

Language：Others  

Country：Other  

Language：Others  

Country：Other  

Language：Others  

Country：Other  

Event date： 2016.9

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：熊本   Country：Japan