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Takayuki Sumida - One of the best experts on this subject based on the ideXlab platform.

  • revisit of autoimmunity to glucose 6 phosphate Isomerase in experimental and rheumatoid arthritis
    Modern Rheumatology, 2020
    Co-Authors: Isao Matsumoto, Hiroto Tsuboi, Yuya Kondo, Izumi Kurata, Ayako Ohyama, Hoshimi Kawaguchi, Hiroshi Ebe, Atsumu Osada, Takayuki Sumida
    Abstract:

    Rheumatoid arthritis (RA) is an inflammatory disorder characterized by synovial inflammation in multiple joints. Autoantibodies (Abs) are the hallmark of RA, and as disease-specific and diagnostic markers, rheumatoid factor and anti-citrullinated protein antibody (ACPA) are produced pre-clinically, but their pathogenic roles in RA remain elusive. In this review, we focus on one of the candidate autoantigens in RA; Glucose-6-Phosphate Isomerase (GPI). The arthritogenic role of GPI has been confirmed in two different mouse models: the K/BxN- and GPI-induced arthritis models. Both anti-GPI Abs and citrullinated-GPI peptide Abs have been detected in human RA. Studies conducted in these rodent models have confirmed that the pathogenesis of arthritis involves the localization of autoantigens not only in the joints but also in the circulation. In this review, we revisit and summarize the arthritogenic relevance of GPI in animal RA models and in human RA, and extend the discussion to joint-specific inflammation.

  • thu0077 increased follicular helper t cell regulates autoantibody hyposialylation in glucose 6 phosphate Isomerase induced arthritis
    Annals of the Rheumatic Diseases, 2018
    Co-Authors: Izumi Kurata, Isao Matsumoto, Hiroto Tsuboi, Yuya Kondo, Hoshimi Kawaguchi, Hiroshi Ebe, Atsumu Osada, Takayuki Sumida
    Abstract:

    Background Circulating follicular helper T (Tfh) cells were reported to be increased and promote B cell activation and antibody production in rheumatoid arthritis. Recently, IL-23-Th17 cells axis and hyposialylation of antibodies were proved to be linked to the inflammation of experimental and rheumatoid arthritis. However it remains uncertain how Tfh, including IL-17 producing Tfh (Tfh17), is associated to arthritis and whether its function includes promotion of antibody hyposialylation. Objectives The aim of this study is to explore the relation between Tfh and autoantibody hyposialylation in Glucose-6-Phosphate Isomerase (GPI) induced arthritis (GIA), which mouse model was dependent on T cells, B cells and IL-17. Methods Fluctuation of Tfh and its subsets in draining lymph nodes (dLNs) were analysed and expression of co–stimulatory molecules were assessed among these subsets. Their localization were examined by immunofluorescence (IF) staining. In order to explore the counterpart reaction, serial changes of plasmablast and plasma cell population in dLNs were also analysed. To elucidate Tfh function in ex–vivo, naive B cells were co–cultured with Tfh and the ratio of differentiated plasmablast was quantified. Anti–GPI antibody production from plasmablast was measured in the existence of Tfh. The titers of anti–GPI antibodies in GIA sera were measured by ELISA. DCs were stimulated with purified anti–GPI antibodies from day 7 (arthritis onset phase) and day 28 (resolving phase) GIA to examine the pathogenicity change of antibody. MRNA of ST6 beta–galactoside alpha–2,6–sialyltransferase 1 (st6gal1), the responsible protein for antibody sialylation, in plasmablast was quantified by PCR and detection of sialic acid in anti–GPI antibody was performed by lectin blotting. Naive B cells were co–cultured with Tfh and the st6gal1 expression in differentiated plasmablast was measured by flow cytometry. Results Tfh cells were increased in GIA. It peaked at day 7, the onset of arthritis, and Tfh17 was specifically increased at the same time. Moreover, OX40 expression in Tfh17 was higher than other subsets. IF showed that Tfh and Tfh17 were accumulated in germinal centre of dLNs. As counterparts, plasmablasts and plasma cells were most increased at day 7 as well. When co–cultured with Tfh, the frequency of differentiated plasmablast was much higher than other conditions, and anti–GPI antibody production was up–regulated in the existence of Tfh and GPI. Conflicting with the results above, anti–GPI antibody titers in the sera were gradually elevated even after day 7 and this elevation continued while GIA peaked out. DCs produced higher level of TNF–alpha when stimulated with the antibody from day 7 GIA than day 28. St6gal1 expression in plasmablast was significantly decreased at day 7 and recovered at day 28. In addition, the day 7 antibodies were tended to be contain less sialic acid. Decreased expression of st6gal1 was observed in differentiated plasmablast co–cultured with Tfh. Conclusions Tfh, especially Tfh17 were increased in the induction phase of arthritis. Also, Tfh could have a crucial role in the development of arthritis via plasmablast activation and regulation of autoantibody hyposialylation in GIA. Disclosure of Interest None declared

  • Peptidylarginine deiminase type 4 deficiency reduced arthritis severity in a Glucose-6-Phosphate Isomerase-induced arthritis model.
    Scientific Reports, 2015
    Co-Authors: Yu Seri, Hirofumi Shoda, Akari Suzuki, Keishi Fujio, Takayuki Sumida, Isao Matsumoto, Kazuhiko Yamamoto
    Abstract:

    Peptidyl arginine deiminase 4 (PAD4) is an enzyme that is involved in protein citrullination, and is a target for anti-citrullinated peptide antibodies (ACPAs) in rheumatoid arthritis (RA). Genetic polymorphisms in the PADI4 gene encoding PAD4 are associated with RA susceptibility. We herein analyzed the roles of PADI4 in inflammatory arthritis using a Glucose-6-Phosphate Isomerase (GPI)-induced arthritis (GIA) model in Padi4 knockout (KO) mice. Arthritis severity, serum anti-GPI antibody titers, and IL-6 concentrations were significantly reduced in Padi4 KO mice. The frequency of Th17 cells was decreased in GPI-immunized Padi4 KO mice, whereas WT and Padi4-deficient naive CD4+ T cells displayed the same efficiencies for Th17 cell differentiation in vitro. In addition, the numbers of myeloid lineage cells were reduced with the increased expression of pro-apoptotic genes in GPI-immunized Padi4 KO mice. Furthermore, the survival of Padi4-deficient neutrophils was impaired in vitro. Our results suggest that PADI4 exacerbates arthritis with diverse immunological modifications.

  • antigen specific over expression of human cartilage glycoprotein 39 on cd4 cd25 forkhead box protein 3 regulatory t cells in the generation of glucose 6 phosphate Isomerase induced arthritis
    Clinical and Experimental Immunology, 2014
    Co-Authors: Yasuhito Tanaka, Isao Matsumoto, Asuka Inoue, Naoto Umeda, Chinatsu Takai, Takayuki Sumida
    Abstract:

    Human cartilage gp-39 (HC gp-39) is a well-known autoantigen in rheumatoid arthritis (RA). However, the exact localization, fluctuation and function of HC gp-39 in RA are unknown. Therefore, using a Glucose-6-Phosphate Isomerase (GPI)-induced model of arthritis, we investigated these aspects of HC gp-39 in arthritis. The rise in serum HC gp-39 levels was detected on the early phase of GPI-induced arthritis (day 7) and the HC gp-39 mRNA was increased significantly on splenic CD4(+) T cells on day7, but not on CD11b(+) cells. Moreover, to identify the characterization of HC gp-39(+) CD4(+) T cells, we assessed the analysis of T helper (Th) subsets. As a result, HC gp-39 was expressed dominantly in CD4(+) CD25(+) forkhead box protein 3 (FoxP3)(+) refulatory T cells (T(reg)), but not in Th1, Th2 or Th17 cells. Furthermore, to investigate the effect of HC gp-39 to CD4(+) T cells, T cell proliferation assay and cytokine production from CD4(+) T cells using recombinant HC gp-39 was assessed. We found that GPI-specific T cell proliferation and interferon (IFN)-γ or interleukin (IL)-17 production were clearly suppressed by addition of recombinant HC gp-39. Antigen-specific over-expression of HC gp-39 in splenic CD4(+) CD25(+) FoxP3(+) T(reg) cells occurs in the induction phase of GPI-induced arthritis, and addition of recombinant HC gp-39 suppresses antigen-specific T-cell proliferation and cytokine production, suggesting that HC gp-39 in CD4(+) T cells might play a regulatory role in arthritis.

  • activation of invariant nkt cells with glycolipid ligand α galactosylceramide ameliorates glucose 6 phosphate Isomerase peptide induced arthritis
    PLOS ONE, 2012
    Co-Authors: Masanobu Horikoshi, Isao Matsumoto, Keiichi Iwanami, Asuka Inoue, Daisuke Goto, Yuki Tanaka, Seiji Segawa, Yohei Yoshiga, Takayuki Sumida
    Abstract:

    Objective Invariant natural killer T (iNKT) cells regulate collagen-induced arthritis (CIA) when activated by their potent glycolipid ligand, alpha-galactosylceramide (α-GalCer). Glucose-6-Phosphate Isomerase (GPI)-induced arthritis is a closer model of human rheumatoid arthritis based on its association with CD4+ T cells and cytokines such as TNF-α and IL-6 than CIA. Dominant T cell epitope peptide of GPI (GPI325-339) can induce arthritis similar to GPI-induced arthritis. In this study, we investigated the roles of activation of iNKT cells by α-GalCer in GPI peptide-induced arthritis. Methods Arthritis was induced in susceptible DBA1 mice with GPI peptide and its severity was assessed clinically. The arthritic mice were treated with either the vehicle (DMSO) or α-GalCer. iNKT cells were detected in draining lymph nodes (dLNs) by flow cytometry, while serum anti-GPI antibody levels were measured by enzyme-linked immunosorbent assay. To evaluate GPI peptide-specific cytokine production from CD4+ T cells, immunized mice were euthanized and dLN CD4+ cells were re-stimulated by GPI-peptide in the presence of antigen-presenting cells. Results α-GalCer induced iNKT cell expansion in dLNs and significantly decreased the severity of GPI peptide-induced arthritis. In α-GalCer-treated mice, anti-GPI antibody production (total IgG, IgG1, IgG2b) and IL-17, IFN-γ, IL-2, and TNF-α produced by GPI peptide-specific T cells were significantly suppressed at day 10. Moreover, GPI-reactive T cells from mice immunized with GPI and α-GalCer did not generate any cytokines even when these cells were co-cultured with APC from mice immunized with GPI alone. In vitro depletion of iNKT cells did not alter the suppressive effect of α-GalCer on CD4+ T cells. Conclusion α-GalCer significantly suppressed GPI peptide-induced arthritis through the suppression of GPI-specific CD4+ T cells.

Isao Matsumoto - One of the best experts on this subject based on the ideXlab platform.

  • revisit of autoimmunity to glucose 6 phosphate Isomerase in experimental and rheumatoid arthritis
    Modern Rheumatology, 2020
    Co-Authors: Isao Matsumoto, Hiroto Tsuboi, Yuya Kondo, Izumi Kurata, Ayako Ohyama, Hoshimi Kawaguchi, Hiroshi Ebe, Atsumu Osada, Takayuki Sumida
    Abstract:

    Rheumatoid arthritis (RA) is an inflammatory disorder characterized by synovial inflammation in multiple joints. Autoantibodies (Abs) are the hallmark of RA, and as disease-specific and diagnostic markers, rheumatoid factor and anti-citrullinated protein antibody (ACPA) are produced pre-clinically, but their pathogenic roles in RA remain elusive. In this review, we focus on one of the candidate autoantigens in RA; Glucose-6-Phosphate Isomerase (GPI). The arthritogenic role of GPI has been confirmed in two different mouse models: the K/BxN- and GPI-induced arthritis models. Both anti-GPI Abs and citrullinated-GPI peptide Abs have been detected in human RA. Studies conducted in these rodent models have confirmed that the pathogenesis of arthritis involves the localization of autoantigens not only in the joints but also in the circulation. In this review, we revisit and summarize the arthritogenic relevance of GPI in animal RA models and in human RA, and extend the discussion to joint-specific inflammation.

  • thu0077 increased follicular helper t cell regulates autoantibody hyposialylation in glucose 6 phosphate Isomerase induced arthritis
    Annals of the Rheumatic Diseases, 2018
    Co-Authors: Izumi Kurata, Isao Matsumoto, Hiroto Tsuboi, Yuya Kondo, Hoshimi Kawaguchi, Hiroshi Ebe, Atsumu Osada, Takayuki Sumida
    Abstract:

    Background Circulating follicular helper T (Tfh) cells were reported to be increased and promote B cell activation and antibody production in rheumatoid arthritis. Recently, IL-23-Th17 cells axis and hyposialylation of antibodies were proved to be linked to the inflammation of experimental and rheumatoid arthritis. However it remains uncertain how Tfh, including IL-17 producing Tfh (Tfh17), is associated to arthritis and whether its function includes promotion of antibody hyposialylation. Objectives The aim of this study is to explore the relation between Tfh and autoantibody hyposialylation in Glucose-6-Phosphate Isomerase (GPI) induced arthritis (GIA), which mouse model was dependent on T cells, B cells and IL-17. Methods Fluctuation of Tfh and its subsets in draining lymph nodes (dLNs) were analysed and expression of co–stimulatory molecules were assessed among these subsets. Their localization were examined by immunofluorescence (IF) staining. In order to explore the counterpart reaction, serial changes of plasmablast and plasma cell population in dLNs were also analysed. To elucidate Tfh function in ex–vivo, naive B cells were co–cultured with Tfh and the ratio of differentiated plasmablast was quantified. Anti–GPI antibody production from plasmablast was measured in the existence of Tfh. The titers of anti–GPI antibodies in GIA sera were measured by ELISA. DCs were stimulated with purified anti–GPI antibodies from day 7 (arthritis onset phase) and day 28 (resolving phase) GIA to examine the pathogenicity change of antibody. MRNA of ST6 beta–galactoside alpha–2,6–sialyltransferase 1 (st6gal1), the responsible protein for antibody sialylation, in plasmablast was quantified by PCR and detection of sialic acid in anti–GPI antibody was performed by lectin blotting. Naive B cells were co–cultured with Tfh and the st6gal1 expression in differentiated plasmablast was measured by flow cytometry. Results Tfh cells were increased in GIA. It peaked at day 7, the onset of arthritis, and Tfh17 was specifically increased at the same time. Moreover, OX40 expression in Tfh17 was higher than other subsets. IF showed that Tfh and Tfh17 were accumulated in germinal centre of dLNs. As counterparts, plasmablasts and plasma cells were most increased at day 7 as well. When co–cultured with Tfh, the frequency of differentiated plasmablast was much higher than other conditions, and anti–GPI antibody production was up–regulated in the existence of Tfh and GPI. Conflicting with the results above, anti–GPI antibody titers in the sera were gradually elevated even after day 7 and this elevation continued while GIA peaked out. DCs produced higher level of TNF–alpha when stimulated with the antibody from day 7 GIA than day 28. St6gal1 expression in plasmablast was significantly decreased at day 7 and recovered at day 28. In addition, the day 7 antibodies were tended to be contain less sialic acid. Decreased expression of st6gal1 was observed in differentiated plasmablast co–cultured with Tfh. Conclusions Tfh, especially Tfh17 were increased in the induction phase of arthritis. Also, Tfh could have a crucial role in the development of arthritis via plasmablast activation and regulation of autoantibody hyposialylation in GIA. Disclosure of Interest None declared

  • suppression of glucose 6 phosphate Isomerase induced arthritis by oral administration of transgenic rice seeds expressing altered peptide ligands of glucose 6 phosphate Isomerase
    Modern Rheumatology, 2017
    Co-Authors: Tomoya Hirota, Hiroto Tsuboi, Mana Iizukakoga, Hiroyuki Takahashi, Hiromitsu Asashima, Masahiro Yokosawa, Yuya Kondo, Masaru Ohta, Yuhya Wakasa, Isao Matsumoto
    Abstract:

    AbstractObjective: To investigate the effects of transgenic rice seeds expressing the altered peptide ligand (APL) of human Glucose-6-Phosphate-Isomerase (hGPI325–339) in mice model of GPI-induced arthritis (GIA).Methods: We generated transgenic rice expressing T-cell epitope of hGPI325–339 and APL12 contained in the seed endosperm. The transgenic rice seeds were orally administered prophylactically before the induction of GIA. The severity of arthritis and titers of serum anti-GPI antibodies were evaluated. We examined for IL-17 production in splenocytes and inguinal lymph node (iLN) cells, and analyzed the expression levels of functional molecules in splenocytes.Results: Prophylactic treatment of GIA mice with APL12 transgenic (APL12-TG) rice seeds significantly reduced the severity of arthritis and titers of serum anti-GPI antibodies compared with non-transgenic (Non-TG) rice-treated mice. APL12-TG and hGPI325–339 transgenic (hGPI325–339-TG) rice seeds improved the histopathological arthritis scores an...

  • Peptidylarginine deiminase type 4 deficiency reduced arthritis severity in a Glucose-6-Phosphate Isomerase-induced arthritis model.
    Scientific Reports, 2015
    Co-Authors: Yu Seri, Hirofumi Shoda, Akari Suzuki, Keishi Fujio, Takayuki Sumida, Isao Matsumoto, Kazuhiko Yamamoto
    Abstract:

    Peptidyl arginine deiminase 4 (PAD4) is an enzyme that is involved in protein citrullination, and is a target for anti-citrullinated peptide antibodies (ACPAs) in rheumatoid arthritis (RA). Genetic polymorphisms in the PADI4 gene encoding PAD4 are associated with RA susceptibility. We herein analyzed the roles of PADI4 in inflammatory arthritis using a Glucose-6-Phosphate Isomerase (GPI)-induced arthritis (GIA) model in Padi4 knockout (KO) mice. Arthritis severity, serum anti-GPI antibody titers, and IL-6 concentrations were significantly reduced in Padi4 KO mice. The frequency of Th17 cells was decreased in GPI-immunized Padi4 KO mice, whereas WT and Padi4-deficient naive CD4+ T cells displayed the same efficiencies for Th17 cell differentiation in vitro. In addition, the numbers of myeloid lineage cells were reduced with the increased expression of pro-apoptotic genes in GPI-immunized Padi4 KO mice. Furthermore, the survival of Padi4-deficient neutrophils was impaired in vitro. Our results suggest that PADI4 exacerbates arthritis with diverse immunological modifications.

  • antigen specific over expression of human cartilage glycoprotein 39 on cd4 cd25 forkhead box protein 3 regulatory t cells in the generation of glucose 6 phosphate Isomerase induced arthritis
    Clinical and Experimental Immunology, 2014
    Co-Authors: Yasuhito Tanaka, Isao Matsumoto, Asuka Inoue, Naoto Umeda, Chinatsu Takai, Takayuki Sumida
    Abstract:

    Human cartilage gp-39 (HC gp-39) is a well-known autoantigen in rheumatoid arthritis (RA). However, the exact localization, fluctuation and function of HC gp-39 in RA are unknown. Therefore, using a Glucose-6-Phosphate Isomerase (GPI)-induced model of arthritis, we investigated these aspects of HC gp-39 in arthritis. The rise in serum HC gp-39 levels was detected on the early phase of GPI-induced arthritis (day 7) and the HC gp-39 mRNA was increased significantly on splenic CD4(+) T cells on day7, but not on CD11b(+) cells. Moreover, to identify the characterization of HC gp-39(+) CD4(+) T cells, we assessed the analysis of T helper (Th) subsets. As a result, HC gp-39 was expressed dominantly in CD4(+) CD25(+) forkhead box protein 3 (FoxP3)(+) refulatory T cells (T(reg)), but not in Th1, Th2 or Th17 cells. Furthermore, to investigate the effect of HC gp-39 to CD4(+) T cells, T cell proliferation assay and cytokine production from CD4(+) T cells using recombinant HC gp-39 was assessed. We found that GPI-specific T cell proliferation and interferon (IFN)-γ or interleukin (IL)-17 production were clearly suppressed by addition of recombinant HC gp-39. Antigen-specific over-expression of HC gp-39 in splenic CD4(+) CD25(+) FoxP3(+) T(reg) cells occurs in the induction phase of GPI-induced arthritis, and addition of recombinant HC gp-39 suppresses antigen-specific T-cell proliferation and cytokine production, suggesting that HC gp-39 in CD4(+) T cells might play a regulatory role in arthritis.

Thomas Kamradt - One of the best experts on this subject based on the ideXlab platform.

  • contribution of inflammation and bone destruction to pain in arthritis a study in murine glucose 6 phosphate Isomerase induced arthritis
    Arthritis & Rheumatism, 2019
    Co-Authors: Matthias Ebbinghaus, Thomas Kamradt, Andreas Hess, Sylvia Muller, Gisela Segond Von Banchet, Annett Eitner, Isabel Wank, Ingrid Hilger, Hansgeorg Schaible
    Abstract:

    OBJECTIVE Arthritis is often characterized by inflammation and bone destruction. This study was undertaken to investigate the contribution of inflammation and bone destruction to pain. METHODS Inflammation, bone resorption, pain-related behaviors, and molecular markers (activating transcription factor 3 [ATF-3], p-CREB, and transient receptor potential vanilloid channel 1) in sensory neurons were measured in murine Glucose-6-Phosphate Isomerase (G6PI)-induced arthritis, a model of rheumatoid arthritis. Depletion of Treg cells before immunization changed self-limiting arthritis into nonremitting arthritis with pronounced bone destruction. Zoledronic acid (ZA) was administered to reduce bone resorption. RESULTS Compared to nondepleted mice, Treg cell-depleted mice exhibited arthritis with more severe bone destruction and higher guarding scores (P < 0.05; n = 10 mice per group) as well as more persistent thermal hyperalgesia (P < 0.05), but displayed similar mechanical hyperalgesia at the hindpaws (n = 18-26 mice per group). These pain-related behaviors, as well as an up-regulation of the neuronal injury marker ATF-3 in sensory neurons (studied in 39 mice), appeared before the clinical score (inflammation) became positive and persisted in Treg cell-depleted and nondepleted mice. In the late stage of arthritis, Treg cell-depleted mice treated with ZA showed less bone resorption (<50%; P < 0.01) and less thermal hyperalgesia (P < 0.01) than Treg cell-depleted mice without ZA treatment (n = 15 mice per group), but ZA treatment did not reduce the clinical score and local mechanical hyperalgesia. CONCLUSION Pain-related behaviors precede and outlast self-limiting arthritis. In nonremitting arthritis with enhanced bone destruction, mainly local thermal, but not local mechanical, hyperalgesia was aggravated. The up-regulation of ATF-3 indicates an early and persisting affection of sensory neurons by G6PI-induced arthritis.

  • in vivo activation of treg cells with a cd28 superagonist prevents and ameliorates chronic destructive arthritis in mice
    European Journal of Immunology, 2016
    Co-Authors: Stephanie J Win, Anja A Kuhl, Tim Sparwasser, Thomas Hunig, Thomas Kamradt
    Abstract:

    Although regulatory T (Treg) cells are necessary to prevent autoimmune diseases, including arthritis, whether Treg cells can ameliorate established inflammatory disease is controversial. Using the Glucose-6-Phosphate Isomerase (G6PI)-induced arthritis model in mice, we aimed to determine the therapeutic efficacy of increasing Treg cell number and function during chronic destructive arthritis. Chronic destructive arthritis was induced by transient depletion of Treg cells prior to immunization with G6PI. At different time points after disease induction, mice were treated with a CD28 superagonistic antibody (CD28SA). CD28SA treatment during the induction phase of arthritis ameliorated the acute signs of arthritis and completely prevented the development of chronic destructive arthritis. CD28SA treatment of mice with fully developed arthritis induced a significant reduction in clinical and histological signs of arthritis. When given during the chronic destructive phase of arthritis, 56 days after disease induction, CD28SA treatment resulted in a modest reduction of clinical signs of arthritis and a reduction in histopathological signs of joint inflammation. Our data show that increasing the number and activation of Treg cells by a CD28SA is therapeutically effective in experimental arthritis.

  • b cell depletion reduces the number of autoreactive t helper cells and prevents glucose 6 phosphate Isomerase induced arthritis
    PLOS ONE, 2011
    Co-Authors: Oliver Frey, Lisa Bruns, Lars Morawietz, Kyri Dunussijoannopoulos, Thomas Kamradt
    Abstract:

    The therapeutic benefit of B cell depletion in patients with rheumatoid arthritis has provided proof of concept that B cells are relevant for the pathogenesis of arthritis. It remains unknown which B cell effector functions contribute to the induction or chronification of arthritis. We studied the clinical and immunological effects of B cell depletion in Glucose-6-Phosphate Isomerase-induced arthritis. We targeted CD22 to deplete B cells. Mice were depleted of B cells before or after immunization with Glucose-6-Phosphate Isomerase (G6PI). The clinical and histological effects were studied. G6PI-specific antibody responses were measured by ELISA. G6PI-specific T helper (Th) cell responses were assayed by polychromatic flow cytometry. B cell depletion prior to G6PI-immunization prevented arthritis. B cell depletion after immunization ameliorated arthritis, whereas B cell depletion in arthritic mice was ineffective. Transfer of antibodies from arthritic mice into B cell depleted recipients did not reconstitute arthritis. B cell depleted mice harbored much fewer G6PI-specific Th cells than control animals. B cell depletion prevents but does not cure G6PI-induced arthritis. Arthritis prevention upon B cell depletion is associated with a drastic reduction in the number of G6PI-specific effector Th cells.

  • ameliorated course of glucose 6 phosphate Isomerase g6pi induced arthritis in ifn γ receptor knockout mice exposes an arthritis promoting role of ifn γ
    Journal of Autoimmunity, 2011
    Co-Authors: Oliver Frey, Thomas Kamradt, Tania Mitera, Hilde Kelchtermans, Evelien Schurgers, Patrick Matthys
    Abstract:

    The absence of IFN-γ signaling leads to an increased inflammatory response in many murine models of autoimmune diseases induced by a CFA-assisted immunization schedule. We investigated the role of endogenous IFN-γ in arthritis induced by immunization with Glucose-6-Phosphate Isomerase (G6PI) in CFA in DBA/1 mice. Surprisingly, and in contrast to our previous findings in collagen-induced arthritis (CIA), G6PI-induced arthritis was found to be reduced in IFN-γ receptor-deficient (IFN-γR KO) mice, demonstrating a proinflammatory role for IFN-γ in this model. Milder disease in IFN-γR KO mice was associated with less vigorous innate and adaptive immune responses early (day 9) after immunization: less proliferation of myeloid cells in the spleen, less osteoclast formation, less G6PI-reactive Th cells (as measured by ex vivo stimulation and flow cytometry and by in vivo skin reactivity to G6PI) and lower G6PI-specific immunoglobulin serum levels. Surprisingly, on day 21, despite continued milder disease in IFN-γR KO mice, their Th cell responses were no longer diminished but augmented as compared to wild-type mice, and their numbers of immature myeloid splenocytes were also more increased. These data reveal that IFN-γ signaling is critical for the induction of the early immune responses which trigger G6PI-induced arthritis. The strikingly different clinical consequences of absent IFN-γ signaling in G6PI-induced arthritis compared with the very similarly induced CIA emphasize that the role of a single cytokine in experimentally induced arthritis depends critically on the very nature of the inciting (auto)antigen and in particular on the kinetics of the disease manifestation elicited by the antigen.

  • regulatory t cells control the transition from acute into chronic inflammation in glucose 6 phosphate Isomerase induced arthritis
    Annals of the Rheumatic Diseases, 2010
    Co-Authors: Oliver Frey, Lars Morawietz, Andreas Reichel, Kerstin Bonhagen, Una Rauchhaus, Thomas Kamradt
    Abstract:

    Objectives Glucose-6-Phosphate Isomerase (G6PI)-induced arthritis is a spontaneously remitting experimental arthritis model. It was hypothesised that regulatory T cells (Tregs) are involved in remission and their role in G6PI-induced arthritis was investigated. Methods Tregs were depleted by injection of anti-CD25 before immunisation of DBA/1 mice with G6PI. The severity of arthritis was assessed clinically and histologically and the number and function of G6PI-specific T helper (Th) cells were determined by flow cytometry. Th cells and monocytes/macrophages were depleted using anti-CD4 or clodronate-containing liposomes. Results Injection of anti-CD25 depleted Tregs transiently. Normal numbers of Tregs were restored 5 weeks after G6PI immunisation. Whereas arthritis started to resolve in control mice 3 weeks after immunisation with G6PI, severe arthritis was still present in the anti-CD25-treated mice 12 weeks after immunisation. The most striking ex vivo correlate of non-remitting arthritis was a strong increase in G6PI-specific Th cells 3 days after G6PI immunisation. This difference between treated and control mice declined at later time points. Depletion of CD4 cells ameliorated arthritis in controls but not in anti-CD25-treated mice. In contrast, clodronate-containing liposomes were an effective treatment in both groups. Conclusions Tregs control the transition from acute self-limiting to non-remitting destructive G6PI-induced arthritis already in the preclinical disease stage. Once established, non-remitting destructive arthritis is not controlled by restoration of normal Treg numbers. These findings question the rationale of therapeutic approaches augmenting Treg number or function in established arthritis.

Asuka Inoue - One of the best experts on this subject based on the ideXlab platform.

  • Activation of Invariant NKT Cells with Glycolipid Ligand a-Galactosylceramide Ameliorates Glucose-6-Phosphate Isomerase Peptide-Induced Arthritis
    2016
    Co-Authors: Masanobu Horikoshi, Keiichi Iwanami, Asuka Inoue, Daisuke Goto, Seiji Segawa, Yohei Yoshiga, Yuki Tanaka
    Abstract:

    Objective: Invariant natural killer T (iNKT) cells regulate collagen-induced arthritis (CIA) when activated by their potent glycolipid ligand, alpha-galactosylceramide (a-GalCer). Glucose-6-Phosphate Isomerase (GPI)-induced arthritis is a closer model of human rheumatoid arthritis based on its association with CD4+ T cells and cytokines such as TNF-a and IL-6 than CIA. Dominant T cell epitope peptide of GPI (GPI325-339) can induce arthritis similar to GPI-induced arthritis. In this study, we investigated the roles of activation of iNKT cells by a-GalCer in GPI peptide-induced arthritis. Methods: Arthritis was induced in susceptible DBA1 mice with GPI peptide and its severity was assessed clinically. The arthritic mice were treated with either the vehicle (DMSO) or a-GalCer. iNKT cells were detected in draining lymph nodes (dLNs) by flow cytometry, while serum anti-GPI antibody levels were measured by enzyme-linked immunosorbent assay. To evaluate GPI peptide-specific cytokine production from CD4+ T cells, immunized mice were euthanized and dLN CD4+ cells were re-stimulated by GPI-peptide in the presence of antigen-presenting cells. Results: a-GalCer induced iNKT cell expansion in dLNs and significantly decreased the severity of GPI peptide-induced arthritis. In a-GalCer-treated mice, anti-GPI antibody production (total IgG, IgG1, IgG2b) and IL-17, IFN-c, IL-2, and TNF-a produced by GPI peptide-specific T cells were significantly suppressed at day 10. Moreover, GPI-reactive T cells from mice immunized with GPI and a-GalCer did not generate any cytokines even when these cells were co-cultured with APC fro

  • antigen specific over expression of human cartilage glycoprotein 39 on cd4 cd25 forkhead box protein 3 regulatory t cells in the generation of glucose 6 phosphate Isomerase induced arthritis
    Clinical and Experimental Immunology, 2014
    Co-Authors: Yasuhito Tanaka, Isao Matsumoto, Asuka Inoue, Naoto Umeda, Chinatsu Takai, Takayuki Sumida
    Abstract:

    Human cartilage gp-39 (HC gp-39) is a well-known autoantigen in rheumatoid arthritis (RA). However, the exact localization, fluctuation and function of HC gp-39 in RA are unknown. Therefore, using a Glucose-6-Phosphate Isomerase (GPI)-induced model of arthritis, we investigated these aspects of HC gp-39 in arthritis. The rise in serum HC gp-39 levels was detected on the early phase of GPI-induced arthritis (day 7) and the HC gp-39 mRNA was increased significantly on splenic CD4(+) T cells on day7, but not on CD11b(+) cells. Moreover, to identify the characterization of HC gp-39(+) CD4(+) T cells, we assessed the analysis of T helper (Th) subsets. As a result, HC gp-39 was expressed dominantly in CD4(+) CD25(+) forkhead box protein 3 (FoxP3)(+) refulatory T cells (T(reg)), but not in Th1, Th2 or Th17 cells. Furthermore, to investigate the effect of HC gp-39 to CD4(+) T cells, T cell proliferation assay and cytokine production from CD4(+) T cells using recombinant HC gp-39 was assessed. We found that GPI-specific T cell proliferation and interferon (IFN)-γ or interleukin (IL)-17 production were clearly suppressed by addition of recombinant HC gp-39. Antigen-specific over-expression of HC gp-39 in splenic CD4(+) CD25(+) FoxP3(+) T(reg) cells occurs in the induction phase of GPI-induced arthritis, and addition of recombinant HC gp-39 suppresses antigen-specific T-cell proliferation and cytokine production, suggesting that HC gp-39 in CD4(+) T cells might play a regulatory role in arthritis.

  • anti citrullinated glucose 6 phosphate Isomerase peptide antibodies in patients with rheumatoid arthritis are associated with hla drb1 shared epitope alleles and disease activity
    Clinical and Experimental Immunology, 2013
    Co-Authors: Naoto Umeda, Isao Matsumoto, Asuka Inoue, Ikue Ito, Aya Kawasaki, Yuki Tanaka, Hiroto Tsuboi, Takeshi Suzuki, Taichi Hayashi, Satoshi Ito
    Abstract:

    To identify and characterize anti-citrullinated Glucose-6-Phosphate Isomerase (GPI) peptide antibodies in patients with rheumatoid arthritis (RA). Nine GPI arginine-bearing peptides in human GPI protein were selected and cyclic citrullinated GPI peptides (CCG-1–9) were constructed. Samples were obtained from RA (n = 208), systemic lupus erythematosus (SLE) (n = 101), Sjogren's syndrome (SS; n = 101) and healthy controls (n = 174). Antibodies against CCG-1–9 were measured, and anti-citrullinated α-enolase-1 (CEP-1), -cyclic citrullinated peptides (CCP) and -GPI proteins antibodies were also examined. Patients with RA were genotyped for HLA-DRB1. The numbers of shared epitope (SE) alleles were counted and compared with those of the autoantibodies. Rabbit GPI was citrullinated with rabbit peptidylarginine deiminase and immunoblot analysis of RA sera performed. The levels of autoantibodies were compared before and after treatment with TNF antagonists in 58 RA patients. Anti-CCG-2, -4 and -7 antibodies were detected in 25·5, 33·2 and 37·0% patients with RA, respectively, and these antibodies were very specific for RA (specificity, 98·1–99·7%). Altogether, 44·2, 86·1 and 13·9% of RA sera were positive for anti-CEP-1, -CCP and -GPI protein antibodies, respectively. Anti-CCG-2, -4 and -7 antibodies were correlated with anti-CCP and anti-CEP-1 antibodies and with the presence of HLA-DRB1 SE alleles. Citrullinated GPI protein was detected using RA sera. Treatment with tumour necrosis factor antagonists reduced significantly the levels of anti-CCG-2 and -7 but not of anti-CEP-1 antibodies. This is the first report documenting the presence of anti-CCG antibodies in RA. Anti-CCG-2 and -7 antibodies could be considered as markers for the diagnosis of RA and its disease activity.

  • activation of invariant nkt cells with glycolipid ligand α galactosylceramide ameliorates glucose 6 phosphate Isomerase peptide induced arthritis
    PLOS ONE, 2012
    Co-Authors: Masanobu Horikoshi, Isao Matsumoto, Keiichi Iwanami, Asuka Inoue, Daisuke Goto, Yuki Tanaka, Seiji Segawa, Yohei Yoshiga, Takayuki Sumida
    Abstract:

    Objective Invariant natural killer T (iNKT) cells regulate collagen-induced arthritis (CIA) when activated by their potent glycolipid ligand, alpha-galactosylceramide (α-GalCer). Glucose-6-Phosphate Isomerase (GPI)-induced arthritis is a closer model of human rheumatoid arthritis based on its association with CD4+ T cells and cytokines such as TNF-α and IL-6 than CIA. Dominant T cell epitope peptide of GPI (GPI325-339) can induce arthritis similar to GPI-induced arthritis. In this study, we investigated the roles of activation of iNKT cells by α-GalCer in GPI peptide-induced arthritis. Methods Arthritis was induced in susceptible DBA1 mice with GPI peptide and its severity was assessed clinically. The arthritic mice were treated with either the vehicle (DMSO) or α-GalCer. iNKT cells were detected in draining lymph nodes (dLNs) by flow cytometry, while serum anti-GPI antibody levels were measured by enzyme-linked immunosorbent assay. To evaluate GPI peptide-specific cytokine production from CD4+ T cells, immunized mice were euthanized and dLN CD4+ cells were re-stimulated by GPI-peptide in the presence of antigen-presenting cells. Results α-GalCer induced iNKT cell expansion in dLNs and significantly decreased the severity of GPI peptide-induced arthritis. In α-GalCer-treated mice, anti-GPI antibody production (total IgG, IgG1, IgG2b) and IL-17, IFN-γ, IL-2, and TNF-α produced by GPI peptide-specific T cells were significantly suppressed at day 10. Moreover, GPI-reactive T cells from mice immunized with GPI and α-GalCer did not generate any cytokines even when these cells were co-cultured with APC from mice immunized with GPI alone. In vitro depletion of iNKT cells did not alter the suppressive effect of α-GalCer on CD4+ T cells. Conclusion α-GalCer significantly suppressed GPI peptide-induced arthritis through the suppression of GPI-specific CD4+ T cells.

  • tumor necrosis factor α induced adipose related protein expression in experimental arthritis and in rheumatoid arthritis
    Arthritis Research & Therapy, 2009
    Co-Authors: Asuka Inoue, Isao Matsumoto, Keiichi Iwanami, Daisuke Goto, Satoshi Ito, Yoko Tanaka, Akihiro Kanamori, Naoyuki Ochiai, Takayuki Sumida
    Abstract:

    Introduction Tumor necrosis factor-alpha (TNFα) plays a pivotal role in rheumatoid arthritis (RA); however, the mechanism of action of TNFα antagonists in RA is poorly defined. Immunization of DBA/1 mice with Glucose-6-Phosphate Isomerase (GPI) induces severe acute arthritis. This arthritis can be controlled by TNFα antagonists, suggesting similar etiology to RA. In this study, we explored TNFα-related mechanisms of arthritis.

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  • Activation of Invariant NKT Cells with Glycolipid Ligand a-Galactosylceramide Ameliorates Glucose-6-Phosphate Isomerase Peptide-Induced Arthritis
    2016
    Co-Authors: Masanobu Horikoshi, Keiichi Iwanami, Asuka Inoue, Daisuke Goto, Seiji Segawa, Yohei Yoshiga, Yuki Tanaka
    Abstract:

    Objective: Invariant natural killer T (iNKT) cells regulate collagen-induced arthritis (CIA) when activated by their potent glycolipid ligand, alpha-galactosylceramide (a-GalCer). Glucose-6-Phosphate Isomerase (GPI)-induced arthritis is a closer model of human rheumatoid arthritis based on its association with CD4+ T cells and cytokines such as TNF-a and IL-6 than CIA. Dominant T cell epitope peptide of GPI (GPI325-339) can induce arthritis similar to GPI-induced arthritis. In this study, we investigated the roles of activation of iNKT cells by a-GalCer in GPI peptide-induced arthritis. Methods: Arthritis was induced in susceptible DBA1 mice with GPI peptide and its severity was assessed clinically. The arthritic mice were treated with either the vehicle (DMSO) or a-GalCer. iNKT cells were detected in draining lymph nodes (dLNs) by flow cytometry, while serum anti-GPI antibody levels were measured by enzyme-linked immunosorbent assay. To evaluate GPI peptide-specific cytokine production from CD4+ T cells, immunized mice were euthanized and dLN CD4+ cells were re-stimulated by GPI-peptide in the presence of antigen-presenting cells. Results: a-GalCer induced iNKT cell expansion in dLNs and significantly decreased the severity of GPI peptide-induced arthritis. In a-GalCer-treated mice, anti-GPI antibody production (total IgG, IgG1, IgG2b) and IL-17, IFN-c, IL-2, and TNF-a produced by GPI peptide-specific T cells were significantly suppressed at day 10. Moreover, GPI-reactive T cells from mice immunized with GPI and a-GalCer did not generate any cytokines even when these cells were co-cultured with APC fro

  • activation of invariant nkt cells with glycolipid ligand α galactosylceramide ameliorates glucose 6 phosphate Isomerase peptide induced arthritis
    PLOS ONE, 2012
    Co-Authors: Masanobu Horikoshi, Isao Matsumoto, Keiichi Iwanami, Asuka Inoue, Daisuke Goto, Yuki Tanaka, Seiji Segawa, Yohei Yoshiga, Takayuki Sumida
    Abstract:

    Objective Invariant natural killer T (iNKT) cells regulate collagen-induced arthritis (CIA) when activated by their potent glycolipid ligand, alpha-galactosylceramide (α-GalCer). Glucose-6-Phosphate Isomerase (GPI)-induced arthritis is a closer model of human rheumatoid arthritis based on its association with CD4+ T cells and cytokines such as TNF-α and IL-6 than CIA. Dominant T cell epitope peptide of GPI (GPI325-339) can induce arthritis similar to GPI-induced arthritis. In this study, we investigated the roles of activation of iNKT cells by α-GalCer in GPI peptide-induced arthritis. Methods Arthritis was induced in susceptible DBA1 mice with GPI peptide and its severity was assessed clinically. The arthritic mice were treated with either the vehicle (DMSO) or α-GalCer. iNKT cells were detected in draining lymph nodes (dLNs) by flow cytometry, while serum anti-GPI antibody levels were measured by enzyme-linked immunosorbent assay. To evaluate GPI peptide-specific cytokine production from CD4+ T cells, immunized mice were euthanized and dLN CD4+ cells were re-stimulated by GPI-peptide in the presence of antigen-presenting cells. Results α-GalCer induced iNKT cell expansion in dLNs and significantly decreased the severity of GPI peptide-induced arthritis. In α-GalCer-treated mice, anti-GPI antibody production (total IgG, IgG1, IgG2b) and IL-17, IFN-γ, IL-2, and TNF-α produced by GPI peptide-specific T cells were significantly suppressed at day 10. Moreover, GPI-reactive T cells from mice immunized with GPI and α-GalCer did not generate any cytokines even when these cells were co-cultured with APC from mice immunized with GPI alone. In vitro depletion of iNKT cells did not alter the suppressive effect of α-GalCer on CD4+ T cells. Conclusion α-GalCer significantly suppressed GPI peptide-induced arthritis through the suppression of GPI-specific CD4+ T cells.

  • tumor necrosis factor α induced adipose related protein expression in experimental arthritis and in rheumatoid arthritis
    Arthritis Research & Therapy, 2009
    Co-Authors: Asuka Inoue, Isao Matsumoto, Keiichi Iwanami, Daisuke Goto, Satoshi Ito, Yoko Tanaka, Akihiro Kanamori, Naoyuki Ochiai, Takayuki Sumida
    Abstract:

    Introduction Tumor necrosis factor-alpha (TNFα) plays a pivotal role in rheumatoid arthritis (RA); however, the mechanism of action of TNFα antagonists in RA is poorly defined. Immunization of DBA/1 mice with Glucose-6-Phosphate Isomerase (GPI) induces severe acute arthritis. This arthritis can be controlled by TNFα antagonists, suggesting similar etiology to RA. In this study, we explored TNFα-related mechanisms of arthritis.

  • b cells play a crucial role as antigen presenting cells and collaborate with inflammatory cytokines in glucose 6 phosphate Isomerase induced arthritis
    Clinical and Experimental Immunology, 2009
    Co-Authors: Yoko Tanakawatanabe, Isao Matsumoto, Keiichi Iwanami, Asuka Inoue, Daisuke Goto, Satoshi Ito, Akito Tsutsumi, Takayuki Sumida
    Abstract:

    Anti-Glucose-6-Phosphate Isomerase (GPI) antibodies from K/BxN mice directly induce arthritis; however, the transfer of these antibodies from mice with GPI-induced arthritis does not induce arthritis. CD4(+) T cells play an important role in the induction and effector phase in this model; however, the roles of B cells and immunoglobulins (Igs) have not been elucidated. We investigated the roles of B cells and Igs in GPI-induced arthritis by using adoptive transfer system into SCID mice. Transfer of splenocytes of male DBA/1 mice immunized with GPI into SCID mice induced arthritis on day 6 in the latter, in association with the production of anti-GPI antibodies. Co-localization of C3 and IgG on the articular surface was identified in arthritic SCID mice. Inoculation of IgG (or anti-GPI antibodies) and CD19(+)-depleted splenocytes from arthritic DBA/1 mice induced arthritis in SCID mice, but not CD19(+)-depleted or CD4(+)-depleted splenocytes from DBA/1 mice. In vitro analysis of cytokine production by splenocytes from DBA/1 arthritic mice demonstrated production of large amounts of tumour necrosis factor (TNF)-alpha and interleukin (IL)-6 in an antigen-specific manner (P < 0.01), and production was dominated by CD19(+)-depleted than CD4(+)-depleted splenocytes (P < 0.05). Addition of IgG from DBA/1 arthritic mice to the culture enhanced TNF-alpha but not IL-6 production, and this effect was blocked by anti-Fcgamma receptor antibody. In vivo analysis of neutralization with TNF-alpha protected arthritis completely in SCID mice. Our results highlight the important role of B cells in GPI-induced arthritis as autoantibody producers, and these autoantibodies can trigger joint inflammation in orchestration with inflammatory cytokines, especially TNF-alpha.

  • arthritogenic t cell epitope in glucose 6 phosphate Isomerase induced arthritis
    Arthritis Research & Therapy, 2008
    Co-Authors: Keiichi Iwanami, Isao Matsumoto, Asuka Inoue, Daisuke Goto, Satoshi Ito, Akito Tsutsumi, Yoko Tanaka, Takayuki Sumida
    Abstract:

    Introduction Arthritis induced by immunisation with Glucose-6-Phosphate Isomerase (GPI) in DBA/1 mice was proven to be T helper (Th) 17 dependent. We undertook this study to identify GPI-specific T cell epitopes in DBA/1 mice (H-2q) and investigate the mechanisms of arthritis generation.