Houyu Zhang, G. He, Y. Kong, Y. Chen, B. Wang, X. Sun, B. Jia, X. Xie, X. Wang, D. Chen, L. Wei, M. Zhang, H. Zeng, H. Chen
Regulating mechanisms underlying hepatic myeloid‐derived suppressor cell (MDSC) accumulation remain to be described. Here, we provide evidence for the involvement of tumour‐activated liver stromal cells in the process of hepatic MDSCs migration and accumulation. Our data showed an elevated frequency of MDSCs in the liver of tumour‐bearing mice. Moreover, tumour‐activated liver stromal cells promote MDSC migration into the liver site. Further investigation indicated higher levels of cytokine and chemokine expression in liver stromal cells after exposure to the tumour‐conditioned supernatant. Notably, the expression levels of proinflammatory factors, mainly including macrophage colony stimulating factor (M‐CSF), transforming growth factor‐β (TGF‐β), monocyte chemotactic protein‐1 (MCP‐1) and stromal‐derived factor‐1 (SDF‐1), increased after treatment with tumour‐conditioned supernatant, and blockade of MCP‐1 or SDF‐1 decreased the proportion of tumour infiltrated MDSCs in mice co‐transplanted with liver stromal cells and tumour cells, but not in mice with only tumour cells injection. These findings demonstrate that tumour‐activated liver stromal cells produce higher levels of chemokines and cytokines, which may contribute to MDSC accumulation into the liver site in patients with liver cancer.
{"title":"Tumour‐activated liver stromal cells regulate myeloid‐derived suppressor cells accumulation in the liver","authors":"Houyu Zhang, G. He, Y. Kong, Y. Chen, B. Wang, X. Sun, B. Jia, X. Xie, X. Wang, D. Chen, L. Wei, M. Zhang, H. Zeng, H. Chen","doi":"10.1111/cei.12917","DOIUrl":"https://doi.org/10.1111/cei.12917","url":null,"abstract":"Regulating mechanisms underlying hepatic myeloid‐derived suppressor cell (MDSC) accumulation remain to be described. Here, we provide evidence for the involvement of tumour‐activated liver stromal cells in the process of hepatic MDSCs migration and accumulation. Our data showed an elevated frequency of MDSCs in the liver of tumour‐bearing mice. Moreover, tumour‐activated liver stromal cells promote MDSC migration into the liver site. Further investigation indicated higher levels of cytokine and chemokine expression in liver stromal cells after exposure to the tumour‐conditioned supernatant. Notably, the expression levels of proinflammatory factors, mainly including macrophage colony stimulating factor (M‐CSF), transforming growth factor‐β (TGF‐β), monocyte chemotactic protein‐1 (MCP‐1) and stromal‐derived factor‐1 (SDF‐1), increased after treatment with tumour‐conditioned supernatant, and blockade of MCP‐1 or SDF‐1 decreased the proportion of tumour infiltrated MDSCs in mice co‐transplanted with liver stromal cells and tumour cells, but not in mice with only tumour cells injection. These findings demonstrate that tumour‐activated liver stromal cells produce higher levels of chemokines and cytokines, which may contribute to MDSC accumulation into the liver site in patients with liver cancer.","PeriodicalId":10179,"journal":{"name":"Clinical & Experimental Immunology","volume":"438 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2017-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"76775955","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Jeremy M. Clain, A. Hummel, John H. Stone, F. Fervenza, G. S. Hoffman, C. Kallenberg, C. Langford, W. J. Mccune, Peter A. Merkel, P. Monach, P. Seo, R. Spiera, E. Clair, S. Ytterberg, Ulrich Specks
Anti‐neutrophil cytoplasmic antibodies (ANCA) appear to play an important role in the pathogenesis of ANCA‐associated vasculitis (AAV). However, ANCA alone are not sufficient to generate disease, and some evidence suggests that infectious triggers may serve as inciting events for AAV disease activity. Antibodies of the immunoglobulin (Ig)M isotype often serve as markers of recent infection, and IgM ANCA have been identified previously in patients with AAV, although the frequency and clinical relevance of IgM ANCA is not well established. We sought to characterize IgM ANCA more clearly by creating a novel enzyme‐linked immunosorbent assay (ELISA) for IgM antibodies to proteinase 3 [IgM proteinase 3 (PR3)–ANCA], which we applied to two large, clinically well‐characterized trial cohorts of patients with granulomatosis with polyangiitis and microscopic polyangiitis. In the first cohort, IgM PR3–ANCA occurred with a frequency of 15·0%, and were associated with a higher degree of disease severity and a trend towards a higher rate of alveolar haemorrhage (29·6 versus 15·7%, P = 0·10). Analysis of follow‐up samples in this cohort showed that the presence of IgM PR3–ANCA was transient, but could recur. In the second cohort, IgM PR3–ANCA occurred with a frequency of 41·1%, and were also associated with a higher degree of disease severity. A higher rate of alveolar haemorrhage was observed among those with IgM PR3–ANCA (45·3 versus 15·8%; P < 0·001). The association of transient IgM PR3–ANCA with an acute respiratory manifestation of AAV suggests a possible link between an infectious trigger and AAV disease activity.
{"title":"Immunoglobulin (Ig)M antibodies to proteinase 3 in granulomatosis with polyangiitis and microscopic polyangiitis","authors":"Jeremy M. Clain, A. Hummel, John H. Stone, F. Fervenza, G. S. Hoffman, C. Kallenberg, C. Langford, W. J. Mccune, Peter A. Merkel, P. Monach, P. Seo, R. Spiera, E. Clair, S. Ytterberg, Ulrich Specks","doi":"10.1111/cei.12925","DOIUrl":"https://doi.org/10.1111/cei.12925","url":null,"abstract":"Anti‐neutrophil cytoplasmic antibodies (ANCA) appear to play an important role in the pathogenesis of ANCA‐associated vasculitis (AAV). However, ANCA alone are not sufficient to generate disease, and some evidence suggests that infectious triggers may serve as inciting events for AAV disease activity. Antibodies of the immunoglobulin (Ig)M isotype often serve as markers of recent infection, and IgM ANCA have been identified previously in patients with AAV, although the frequency and clinical relevance of IgM ANCA is not well established. We sought to characterize IgM ANCA more clearly by creating a novel enzyme‐linked immunosorbent assay (ELISA) for IgM antibodies to proteinase 3 [IgM proteinase 3 (PR3)–ANCA], which we applied to two large, clinically well‐characterized trial cohorts of patients with granulomatosis with polyangiitis and microscopic polyangiitis. In the first cohort, IgM PR3–ANCA occurred with a frequency of 15·0%, and were associated with a higher degree of disease severity and a trend towards a higher rate of alveolar haemorrhage (29·6 versus 15·7%, P = 0·10). Analysis of follow‐up samples in this cohort showed that the presence of IgM PR3–ANCA was transient, but could recur. In the second cohort, IgM PR3–ANCA occurred with a frequency of 41·1%, and were also associated with a higher degree of disease severity. A higher rate of alveolar haemorrhage was observed among those with IgM PR3–ANCA (45·3 versus 15·8%; P < 0·001). The association of transient IgM PR3–ANCA with an acute respiratory manifestation of AAV suggests a possible link between an infectious trigger and AAV disease activity.","PeriodicalId":10179,"journal":{"name":"Clinical & Experimental Immunology","volume":"20 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2017-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"86891319","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
M. Yokosawa, Y. Kondo, Masahiro Tahara, Mana Iizuka-Koga, S. Segawa, Syunta Kaneko, H. Tsuboi, K. Yoh, Satoru Takahashi, I. Matsumoto, Takayuki Sumida
Various transcription factors are also known to enhance or suppress T helper type 17 (Th17) differentiation. We have shown previously that the development of collagen‐induced arthritis was suppressed in T‐bet transgenic (T‐bet Tg) mice, and T‐bet seemed to suppress Th17 differentiation through an interferon (IFN)‐γ‐independent pathway, although the precise mechanism remains to be clarified. The present study was designed to investigate further the mechanisms involved in the regulation of Th17 differentiation by T‐bet over‐expression, and we found the new relationship between T‐bet and aryl hydrocarbon receptor (AHR). Both T‐bet Tg mice and IFN‐γ–/–‐over‐expressing T‐bet (T‐bet Tg/IFN‐γ–/–) mice showed inhibition of retinoic acid‐related orphan receptor (ROR)γt expression and IL‐17 production by CD4+ T cells cultured under conditions that promote Th‐17 differentiation, and decreased IL‐6 receptor (IL‐6R) expression and signal transducer and activator of transcription‐3 (STAT‐3) phosphorylation in CD4+ T cells. The mRNA expression of ahr and rorc were suppressed in CD4+ T cells cultured under Th‐17 conditions from T‐bet Tg mice and T‐bet Tg/IFN‐γ–/– mice. CD4+ T cells of wild‐type (WT) and IFN‐γ–/– mice transduced with T‐bet‐expressing retrovirus also showed inhibition of IL‐17 production, whereas T‐bet transduction had no effect on IL‐6R expression and STAT‐3 phosphorylation. Interestingly, the mRNA expression of ahr and rorc were suppressed in CD4+ T cells with T‐bet transduction cultured under Th17 conditions. The enhancement of interleukin (IL)−17 production from CD4+ T cells by the addition of AHR ligand with Th17 conditions was cancelled by T‐bet over‐expression. Our findings suggest that T‐bet over‐expression‐induced suppression of Th17 differentiation is mediated through IFN‐γ‐independent AHR suppression.
{"title":"T‐bet over‐expression regulates aryl hydrocarbon receptor‐mediated T helper type 17 differentiation through an interferon (IFN)γ‐independent pathway","authors":"M. Yokosawa, Y. Kondo, Masahiro Tahara, Mana Iizuka-Koga, S. Segawa, Syunta Kaneko, H. Tsuboi, K. Yoh, Satoru Takahashi, I. Matsumoto, Takayuki Sumida","doi":"10.1111/cei.12912","DOIUrl":"https://doi.org/10.1111/cei.12912","url":null,"abstract":"Various transcription factors are also known to enhance or suppress T helper type 17 (Th17) differentiation. We have shown previously that the development of collagen‐induced arthritis was suppressed in T‐bet transgenic (T‐bet Tg) mice, and T‐bet seemed to suppress Th17 differentiation through an interferon (IFN)‐γ‐independent pathway, although the precise mechanism remains to be clarified. The present study was designed to investigate further the mechanisms involved in the regulation of Th17 differentiation by T‐bet over‐expression, and we found the new relationship between T‐bet and aryl hydrocarbon receptor (AHR). Both T‐bet Tg mice and IFN‐γ–/–‐over‐expressing T‐bet (T‐bet Tg/IFN‐γ–/–) mice showed inhibition of retinoic acid‐related orphan receptor (ROR)γt expression and IL‐17 production by CD4+ T cells cultured under conditions that promote Th‐17 differentiation, and decreased IL‐6 receptor (IL‐6R) expression and signal transducer and activator of transcription‐3 (STAT‐3) phosphorylation in CD4+ T cells. The mRNA expression of ahr and rorc were suppressed in CD4+ T cells cultured under Th‐17 conditions from T‐bet Tg mice and T‐bet Tg/IFN‐γ–/– mice. CD4+ T cells of wild‐type (WT) and IFN‐γ–/– mice transduced with T‐bet‐expressing retrovirus also showed inhibition of IL‐17 production, whereas T‐bet transduction had no effect on IL‐6R expression and STAT‐3 phosphorylation. Interestingly, the mRNA expression of ahr and rorc were suppressed in CD4+ T cells with T‐bet transduction cultured under Th17 conditions. The enhancement of interleukin (IL)−17 production from CD4+ T cells by the addition of AHR ligand with Th17 conditions was cancelled by T‐bet over‐expression. Our findings suggest that T‐bet over‐expression‐induced suppression of Th17 differentiation is mediated through IFN‐γ‐independent AHR suppression.","PeriodicalId":10179,"journal":{"name":"Clinical & Experimental Immunology","volume":"196 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2017-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"77655000","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
M. Kluger, A. Nosko, T. Ramcke, Boeren Goerke, Matthias C. Meyer, C. Wegscheid, Michael Luig, G. Tiegs, R. A. Stahl, O. Steinmetz
Systemic lupus erythematosus (SLE) is a common autoimmune disorder with a complex and poorly understood immunopathogenesis. However, a pathogenic role for the T helper type 17 (Th17) axis was demonstrated by many studies, while regulatory T cells (Tregs) were shown to mediate protection. Recently, we and others characterized a novel and independent T cell population expressing both the Treg characteristic transcription factor forkhead box protein 3 (FoxP3) and the Th17‐defining retinoic acid receptor‐related orphan nuclear receptor γt (RORγt). Studies in a model of acute glomerulonephritis unveiled potent regulatory, but also proinflammatory, functions of RORγt+FoxP3+ Tregs. This bi‐functional nature prompted us to suggest the name ‘biTregs’. Importantly, the pathogenic biTreg effects were dependent upon expression of RORγt. We thus aimed to evaluate the contribution of RORγt+FoxP3+ biTregs to pristane‐induced SLE and explored the therapeutic potential of interference with RORγt activation. Our analyses revealed expansion of IL‐17 producing biTregs in a distinctive time–course and organ‐specific pattern, coincident with the development of autoimmunity and tissue injury. Importantly, specific ablation of RORγt activation in endogenous biTregs resulted in significant amelioration of pristane‐induced pulmonary vasculitis and lupus nephritis. As potential mechanisms underlying the observed protection, we found that secretion of IL‐17 by biTregs was abrogated completely in FoxP3Cre × RORCfl/fl mice. Furthermore, Tregs showed a more activated phenotype after cell‐specific inactivation of RORγt signalling. Finally, and remarkably, biTregs were found to potently suppress anti‐inflammatory Th2 immunity in a RORγt‐dependent manner. Our study thus identifies biTregs as novel players in SLE and advocates RORγt‐directed interventions as promising therapeutic strategies.
{"title":"RORγt expression in Tregs promotes systemic lupus erythematosus via IL‐17 secretion, alteration of Treg phenotype and suppression of Th2 responses","authors":"M. Kluger, A. Nosko, T. Ramcke, Boeren Goerke, Matthias C. Meyer, C. Wegscheid, Michael Luig, G. Tiegs, R. A. Stahl, O. Steinmetz","doi":"10.1111/cei.12905","DOIUrl":"https://doi.org/10.1111/cei.12905","url":null,"abstract":"Systemic lupus erythematosus (SLE) is a common autoimmune disorder with a complex and poorly understood immunopathogenesis. However, a pathogenic role for the T helper type 17 (Th17) axis was demonstrated by many studies, while regulatory T cells (Tregs) were shown to mediate protection. Recently, we and others characterized a novel and independent T cell population expressing both the Treg characteristic transcription factor forkhead box protein 3 (FoxP3) and the Th17‐defining retinoic acid receptor‐related orphan nuclear receptor γt (RORγt). Studies in a model of acute glomerulonephritis unveiled potent regulatory, but also proinflammatory, functions of RORγt+FoxP3+ Tregs. This bi‐functional nature prompted us to suggest the name ‘biTregs’. Importantly, the pathogenic biTreg effects were dependent upon expression of RORγt. We thus aimed to evaluate the contribution of RORγt+FoxP3+ biTregs to pristane‐induced SLE and explored the therapeutic potential of interference with RORγt activation. Our analyses revealed expansion of IL‐17 producing biTregs in a distinctive time–course and organ‐specific pattern, coincident with the development of autoimmunity and tissue injury. Importantly, specific ablation of RORγt activation in endogenous biTregs resulted in significant amelioration of pristane‐induced pulmonary vasculitis and lupus nephritis. As potential mechanisms underlying the observed protection, we found that secretion of IL‐17 by biTregs was abrogated completely in FoxP3Cre × RORCfl/fl mice. Furthermore, Tregs showed a more activated phenotype after cell‐specific inactivation of RORγt signalling. Finally, and remarkably, biTregs were found to potently suppress anti‐inflammatory Th2 immunity in a RORγt‐dependent manner. Our study thus identifies biTregs as novel players in SLE and advocates RORγt‐directed interventions as promising therapeutic strategies.","PeriodicalId":10179,"journal":{"name":"Clinical & Experimental Immunology","volume":"58 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2017-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"91338594","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Sjögren's syndrome is the second most common rheumatic disease in which autoimmune response targets exocrine glands (salivary and lacrimal glands) result in clinical symptoms of dry mouth and dry eye. Inflammation of the lacrimal gland induces tear abnormalities that contribute to the inflammation of the ocular surface, which includes ocular mucosa. Thrombospondin‐1 (TSP‐1) plays a critical regulatory role in the ocular mucosa and as such TSP‐1–/– mice develop spontaneously chronic ocular surface inflammation associated with Sjögren's syndrome. The autoimmune pathology is also accompanied by a peripheral imbalance in regulatory (Treg) and inflammatory Th17 effectors. In this study, we demonstrate an in‐vitro effect of a CD47‐binding TSP‐derived peptide in the induction of transforming growth factor (TGF)‐β1‐secreting forkhead box protein 2 (Foxp3+) Tregs from activated CD4+CD25– T cells and the inhibition of pathogenic T helper type 17 (Th17)‐promoting interleukin (IL)‐23 derived from antigen‐presenting cells. The in‐vivo administration of this peptide promotes Foxp3+ Treg induction and inhibition of Th17 development. Consistent with these results, topical administration of CD47‐binding TSP peptide, both before and after the onset of the disease, attenuates clinical symptoms of SS‐associated dry eye in TSP‐1–/– mice. Augmented expression of Foxp3 detected in the draining lymph nodes of TSP peptide ‐treated mice compared to those treated with control peptide suggests the ability of TSP peptide to restore peripheral immune imbalance. Thus, our results suggest that TSP‐derived peptide attenuates Sjögren's syndrome‐associated dry eye and autoimmune inflammation by preventing Th17 development while promoting the induction of Tregs. Collectively, our data identify TSP‐derived peptide as a novel therapeutic option to treat autoimmune diseases.
{"title":"Thrombospondin‐derived peptide attenuates Sjögren's syndrome‐associated ocular surface inflammation in mice","authors":"L. C. Ruiz, F. Mir, B. Turpie, S. Masli","doi":"10.1111/cei.12919","DOIUrl":"https://doi.org/10.1111/cei.12919","url":null,"abstract":"Sjögren's syndrome is the second most common rheumatic disease in which autoimmune response targets exocrine glands (salivary and lacrimal glands) result in clinical symptoms of dry mouth and dry eye. Inflammation of the lacrimal gland induces tear abnormalities that contribute to the inflammation of the ocular surface, which includes ocular mucosa. Thrombospondin‐1 (TSP‐1) plays a critical regulatory role in the ocular mucosa and as such TSP‐1–/– mice develop spontaneously chronic ocular surface inflammation associated with Sjögren's syndrome. The autoimmune pathology is also accompanied by a peripheral imbalance in regulatory (Treg) and inflammatory Th17 effectors. In this study, we demonstrate an in‐vitro effect of a CD47‐binding TSP‐derived peptide in the induction of transforming growth factor (TGF)‐β1‐secreting forkhead box protein 2 (Foxp3+) Tregs from activated CD4+CD25– T cells and the inhibition of pathogenic T helper type 17 (Th17)‐promoting interleukin (IL)‐23 derived from antigen‐presenting cells. The in‐vivo administration of this peptide promotes Foxp3+ Treg induction and inhibition of Th17 development. Consistent with these results, topical administration of CD47‐binding TSP peptide, both before and after the onset of the disease, attenuates clinical symptoms of SS‐associated dry eye in TSP‐1–/– mice. Augmented expression of Foxp3 detected in the draining lymph nodes of TSP peptide ‐treated mice compared to those treated with control peptide suggests the ability of TSP peptide to restore peripheral immune imbalance. Thus, our results suggest that TSP‐derived peptide attenuates Sjögren's syndrome‐associated dry eye and autoimmune inflammation by preventing Th17 development while promoting the induction of Tregs. Collectively, our data identify TSP‐derived peptide as a novel therapeutic option to treat autoimmune diseases.","PeriodicalId":10179,"journal":{"name":"Clinical & Experimental Immunology","volume":"40 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2017-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"72760034","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
K. Hernández-Flores, A. Calderón-Garcidueñas, G. Mellado-Sánchez, R. Ruiz-Ramos, L. A. Sánchez-Vargas, P. Thomas-Dupont, I. Y. Izaguirre-Hernández, J. Téllez-Sosa, J. Martínez-Barnetche, L. Wood, Y. Paterson, L. Cedillo-Barrón, Ó. López-Franco, H. Vivanco-Cid
Listeriolysin O (LLO) has been proposed as a potential carrier or adjuvant molecule in the vaccination field. However, the cytotoxic and pro‐apoptotic effects of LLO are the major limitations for this purpose. Here, we have performed a preclinical safety evaluation and characterized a new potential adjuvant application for a non‐cytolytic LLO mutant (dtLLO) to enhance and modulate the immune response against the envelope (E) protein from dengue virus. In addition, we have studied the adjuvant effects of dtLLO on human immune cells and the role of membrane cholesterol for the binding and proinflammatory property of the toxoid. Our in‐vivo results in the murine model confirmed that dtLLO is a safer molecule than wild‐type LLO (wtLLO), with a significantly increased survival rate for mice challenged with dtLLO compared with mice challenged with wtLLO (P < 0·001). Histopathological analysis showed non‐toxic effects in key target organs such as brain, heart, liver, spleen, kidney and lung after challenge with dtLLO. In vitro, dtLLO retained the capacity of binding to plasma membrane cholesterol on the surface of murine and human immune cells. Immunization of 6–8‐week‐old female BALB/c mice with a combination of dtLLO mixed with E protein elicited a robust specific humoral response with isotype diversification of immunoglobulin (Ig)G antibodies (IgG1 and IgG2a). Finally, we demonstrated that cholesterol and lipid raft integrity are required to induce a proinflammatory response by human cells. Taken together, these findings support a potential use of the dtLLO mutant as a safe and effective adjuvant molecule in vaccination.
李斯特菌素O (Listeriolysin O, LLO)被认为是疫苗接种领域潜在的载体或佐剂分子。然而，LLO的细胞毒性和促凋亡作用是实现这一目的的主要限制。在这里，我们进行了临床前安全性评估，并描述了一种新的潜在佐剂应用于非细胞溶解性LLO突变体(dtLLO)，以增强和调节针对登革热病毒包膜(E)蛋白的免疫反应。此外，我们还研究了dtLLO对人体免疫细胞的佐剂作用以及膜胆固醇在类毒素结合和促炎特性中的作用。我们在小鼠模型中的体内实验结果证实，dtLLO是一种比野生型LLO (wtLLO)更安全的分子，与wtLLO相比，dtLLO攻击小鼠的存活率显著提高(P < 0.001)。组织病理学分析显示，dtLLO对脑、心、肝、脾、肾和肺等关键靶器官无毒性作用。在体外实验中，dtLLO保留了与小鼠和人免疫细胞表面的质膜胆固醇结合的能力。dtLLO与E蛋白的组合免疫6-8周龄雌性BALB/c小鼠，引起了免疫球蛋白(Ig)G抗体(IgG1和IgG2a)同种型多样化的强大特异性体液反应。最后，我们证明了胆固醇和脂质筏完整性是诱导人类细胞促炎反应所必需的。综上所述，这些发现支持dtLLO突变体作为疫苗接种中安全有效的佐剂分子的潜在用途。
{"title":"Evaluation of the safety and adjuvant effect of a detoxified listeriolysin O mutant on the humoral response to dengue virus antigens","authors":"K. Hernández-Flores, A. Calderón-Garcidueñas, G. Mellado-Sánchez, R. Ruiz-Ramos, L. A. Sánchez-Vargas, P. Thomas-Dupont, I. Y. Izaguirre-Hernández, J. Téllez-Sosa, J. Martínez-Barnetche, L. Wood, Y. Paterson, L. Cedillo-Barrón, Ó. López-Franco, H. Vivanco-Cid","doi":"10.1111/cei.12906","DOIUrl":"https://doi.org/10.1111/cei.12906","url":null,"abstract":"Listeriolysin O (LLO) has been proposed as a potential carrier or adjuvant molecule in the vaccination field. However, the cytotoxic and pro‐apoptotic effects of LLO are the major limitations for this purpose. Here, we have performed a preclinical safety evaluation and characterized a new potential adjuvant application for a non‐cytolytic LLO mutant (dtLLO) to enhance and modulate the immune response against the envelope (E) protein from dengue virus. In addition, we have studied the adjuvant effects of dtLLO on human immune cells and the role of membrane cholesterol for the binding and proinflammatory property of the toxoid. Our in‐vivo results in the murine model confirmed that dtLLO is a safer molecule than wild‐type LLO (wtLLO), with a significantly increased survival rate for mice challenged with dtLLO compared with mice challenged with wtLLO (P < 0·001). Histopathological analysis showed non‐toxic effects in key target organs such as brain, heart, liver, spleen, kidney and lung after challenge with dtLLO. In vitro, dtLLO retained the capacity of binding to plasma membrane cholesterol on the surface of murine and human immune cells. Immunization of 6–8‐week‐old female BALB/c mice with a combination of dtLLO mixed with E protein elicited a robust specific humoral response with isotype diversification of immunoglobulin (Ig)G antibodies (IgG1 and IgG2a). Finally, we demonstrated that cholesterol and lipid raft integrity are required to induce a proinflammatory response by human cells. Taken together, these findings support a potential use of the dtLLO mutant as a safe and effective adjuvant molecule in vaccination.","PeriodicalId":10179,"journal":{"name":"Clinical & Experimental Immunology","volume":"58 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2017-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"83905453","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
A. Troldborg, A. Hansen, Søren Hansen, J. Jensenius, Kristian Stengaard-Pedersen, S. Thiel
Since the discovery of the lectin pathway of complement activation, numerous clinical cohorts have been examined for one or more proteins, with the intention of uncovering the functions of the proteins or with the aim of discovering new biomarkers or diagnostic tools. To unveil the abnormal, it is pivotal to know the normal. Our aim was to describe the concentrations of the 11 known proteins of the lectin pathway in serum and plasma and to uncover possible gender differences, age and diurnal variations, which must be taken into account for investigation in different cohorts. We examined the concentrations of all lectin pathway proteins mannan‐binding lectin (MBL), H‐ficolin, L‐ficolin, M‐ficolin, collectin‐K1, collectin‐L1, MBL‐associated serine protease 2 (MASP‐2), MASP‐3, MBL‐associated protein of 44 kDa (MAp44) and MAp19 in 300 Danish blood donors in serum and ethylenediamine tetraacetic acid (EDTA) plasma in established assays, and we further developed a new assay to measure MASP‐1 in the same samples. We found significant differences in concentrations between serum and plasma for all proteins except for MBL and MASP‐3. H‐ficolin, M‐ficolin and MAp19 displayed convincing diurnal variation. H‐ficolin, in particular, halved from morning to the middle of the night. There were gender differences for most proteins, whereas age did not seem to influence concentration. The present study underlines the necessity of considering which material to use, correct matching and a trial design that takes the nature of the protein into account in order for the outcome of cohort studies to have significant relevance.
{"title":"Lectin complement pathway proteins in healthy individuals","authors":"A. Troldborg, A. Hansen, Søren Hansen, J. Jensenius, Kristian Stengaard-Pedersen, S. Thiel","doi":"10.1111/cei.12909","DOIUrl":"https://doi.org/10.1111/cei.12909","url":null,"abstract":"Since the discovery of the lectin pathway of complement activation, numerous clinical cohorts have been examined for one or more proteins, with the intention of uncovering the functions of the proteins or with the aim of discovering new biomarkers or diagnostic tools. To unveil the abnormal, it is pivotal to know the normal. Our aim was to describe the concentrations of the 11 known proteins of the lectin pathway in serum and plasma and to uncover possible gender differences, age and diurnal variations, which must be taken into account for investigation in different cohorts. We examined the concentrations of all lectin pathway proteins mannan‐binding lectin (MBL), H‐ficolin, L‐ficolin, M‐ficolin, collectin‐K1, collectin‐L1, MBL‐associated serine protease 2 (MASP‐2), MASP‐3, MBL‐associated protein of 44 kDa (MAp44) and MAp19 in 300 Danish blood donors in serum and ethylenediamine tetraacetic acid (EDTA) plasma in established assays, and we further developed a new assay to measure MASP‐1 in the same samples. We found significant differences in concentrations between serum and plasma for all proteins except for MBL and MASP‐3. H‐ficolin, M‐ficolin and MAp19 displayed convincing diurnal variation. H‐ficolin, in particular, halved from morning to the middle of the night. There were gender differences for most proteins, whereas age did not seem to influence concentration. The present study underlines the necessity of considering which material to use, correct matching and a trial design that takes the nature of the protein into account in order for the outcome of cohort studies to have significant relevance.","PeriodicalId":10179,"journal":{"name":"Clinical & Experimental Immunology","volume":"8 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2017-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"73821071","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
C. S. Horjus Talabur Horje, C. Smids, J. Meijer, M. Groenen, M. Rijnders, E. V. van Lochem, P. Wahab
Naive and central memory T lymphocytes (TN and TCM) can infiltrate the inflamed gut mucosa in inflammatory bowel disease (IBD) patients. Homing of these subsets to the gut might be explained by ectopic formation of tertiary lymphoid organs (TLOs), containing high endothelial venules (HEVs). We aimed to evaluate the presence of HEVs and TLOs in inflamed intestinal mucosa of newly diagnosed, untreated IBD patients in relation to the presence of TN and TCM lymphocytes. IBD patients (n = 39) and healthy controls (n = 8) were included prospectively. Biopsy samples of inflamed and normal intestine, respectively, were analysed by immunohistochemistry for lymphocytes (CD3/CD20), blood vessels (CD31) and peripheral lymph node addressin (PNAd) expression (MECA‐79). TN and TCM lymphocyte subsets were identified by flow cytometric immunophenotyping. A higher number of HEVs was found in the inflamed colon of patients with ulcerative colitis [median 3·05 HEV/mm2; interquartile range (IQR) = 0–6·39] and ileum of Crohn's disease patients (1·40; 0‐4·34) compared to healthy controls (both 0; P = 0·033). A high density of colonic HEVs (HEVhigh) was associated with increased infiltration of TN and TCM in the inflamed gut (median 87%; IQR = 82–93% of T cell population), compared to HEVlow patients (58%; 38–81%; P = 0·003). The number of colonic follicles was higher in HEVhigh patients (median 0·54/mm2; IQR 0·28–0·84) compared to HEVlow patients (0·25/mm2; 0·08–0·45; P = 0·031) and controls (0·31/mm2; 0·23–0·45; P = 0·043). Increased homing of TN and TCM lymphocytes to inflamed gut tissue in IBD patients might be facilitated by ectopic formation of extrafollicular HEVs and TLOs in a subgroup of patients.
{"title":"High endothelial venules associated with T cell subsets in the inflamed gut of newly diagnosed inflammatory bowel disease patients","authors":"C. S. Horjus Talabur Horje, C. Smids, J. Meijer, M. Groenen, M. Rijnders, E. V. van Lochem, P. Wahab","doi":"10.1111/cei.12918","DOIUrl":"https://doi.org/10.1111/cei.12918","url":null,"abstract":"Naive and central memory T lymphocytes (TN and TCM) can infiltrate the inflamed gut mucosa in inflammatory bowel disease (IBD) patients. Homing of these subsets to the gut might be explained by ectopic formation of tertiary lymphoid organs (TLOs), containing high endothelial venules (HEVs). We aimed to evaluate the presence of HEVs and TLOs in inflamed intestinal mucosa of newly diagnosed, untreated IBD patients in relation to the presence of TN and TCM lymphocytes. IBD patients (n = 39) and healthy controls (n = 8) were included prospectively. Biopsy samples of inflamed and normal intestine, respectively, were analysed by immunohistochemistry for lymphocytes (CD3/CD20), blood vessels (CD31) and peripheral lymph node addressin (PNAd) expression (MECA‐79). TN and TCM lymphocyte subsets were identified by flow cytometric immunophenotyping. A higher number of HEVs was found in the inflamed colon of patients with ulcerative colitis [median 3·05 HEV/mm2; interquartile range (IQR) = 0–6·39] and ileum of Crohn's disease patients (1·40; 0‐4·34) compared to healthy controls (both 0; P = 0·033). A high density of colonic HEVs (HEVhigh) was associated with increased infiltration of TN and TCM in the inflamed gut (median 87%; IQR = 82–93% of T cell population), compared to HEVlow patients (58%; 38–81%; P = 0·003). The number of colonic follicles was higher in HEVhigh patients (median 0·54/mm2; IQR 0·28–0·84) compared to HEVlow patients (0·25/mm2; 0·08–0·45; P = 0·031) and controls (0·31/mm2; 0·23–0·45; P = 0·043). Increased homing of TN and TCM lymphocytes to inflamed gut tissue in IBD patients might be facilitated by ectopic formation of extrafollicular HEVs and TLOs in a subgroup of patients.","PeriodicalId":10179,"journal":{"name":"Clinical & Experimental Immunology","volume":"10 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2017-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"75375815","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Given the possible importance of anti‐citrullinated peptide/protein antibodies (ACPA) for initiation and progression of rheumatoid arthritis (RA), extended knowledge about the different isotypes and subclasses is important. In the present study, we analysed the immunoglobulin (Ig)G subclasses regarding reactivity against cyclic citrullinated peptides (anti‐CCP) among 504 clinically well‐characterized patients with recent‐onset RA in relation to smoking habits, shared epitope (SE) status and IgA and pan‐IgG anti‐CCP antibodies. All patients, regardless of pan‐IgG anti‐CCP status, were analysed for IgG1–4 CCP reactivity. Sixty‐nine per cent were positive in any IgG anti‐CCP subclass, and of these 67% tested positive regarding IgG1, 35% IgG2, 32% IgG3, and 59% IgG4 anti‐CCP. Among ever‐smokers the percentages of IgG2 anti‐CCP (P = 0·01) and IgA anti‐CCP (P = 0·002)‐positive cases were significantly higher compared to never‐smokers. A positive IgG anti‐CCP subclass ‐negative cases. Combining SE and smoking data revealed that IgG1 and IgG4 anti‐CCP were the IgG anti‐CCP isotypes associated with expression of SE, although the lower number of patients positive for IgG2 or IgG3 anti‐CCP could, however, have influenced the results. High levels of IgG2 anti‐CCP were shown to correlate with expression of the ‘non‐SE’ allele human leucocyte antigen (HLA)‐DRB1*15. In conclusion, in this study we describe different risk factor characteristics across the IgG anti‐CCP subclasses, where IgG2 appears similar to IgA anti‐CCP regarding the predominant association with smoking, while IgG1 and IgG4 related more distinctly to the carriage of SE genes.
{"title":"Immunoglobulin (Ig)G1 and IgG4 anti‐cyclic citrullinated peptide (CCP) associate with shared epitope, whereas IgG2 anti‐CCP associates with smoking in patients with recent‐onset rheumatoid arthritis (the Swedish TIRA project)","authors":"K. Martinsson, A. Johansson, A. Kastbom, T. Skogh","doi":"10.1111/cei.12901","DOIUrl":"https://doi.org/10.1111/cei.12901","url":null,"abstract":"Given the possible importance of anti‐citrullinated peptide/protein antibodies (ACPA) for initiation and progression of rheumatoid arthritis (RA), extended knowledge about the different isotypes and subclasses is important. In the present study, we analysed the immunoglobulin (Ig)G subclasses regarding reactivity against cyclic citrullinated peptides (anti‐CCP) among 504 clinically well‐characterized patients with recent‐onset RA in relation to smoking habits, shared epitope (SE) status and IgA and pan‐IgG anti‐CCP antibodies. All patients, regardless of pan‐IgG anti‐CCP status, were analysed for IgG1–4 CCP reactivity. Sixty‐nine per cent were positive in any IgG anti‐CCP subclass, and of these 67% tested positive regarding IgG1, 35% IgG2, 32% IgG3, and 59% IgG4 anti‐CCP. Among ever‐smokers the percentages of IgG2 anti‐CCP (P = 0·01) and IgA anti‐CCP (P = 0·002)‐positive cases were significantly higher compared to never‐smokers. A positive IgG anti‐CCP subclass ‐negative cases. Combining SE and smoking data revealed that IgG1 and IgG4 anti‐CCP were the IgG anti‐CCP isotypes associated with expression of SE, although the lower number of patients positive for IgG2 or IgG3 anti‐CCP could, however, have influenced the results. High levels of IgG2 anti‐CCP were shown to correlate with expression of the ‘non‐SE’ allele human leucocyte antigen (HLA)‐DRB1*15. In conclusion, in this study we describe different risk factor characteristics across the IgG anti‐CCP subclasses, where IgG2 appears similar to IgA anti‐CCP regarding the predominant association with smoking, while IgG1 and IgG4 related more distinctly to the carriage of SE genes.","PeriodicalId":10179,"journal":{"name":"Clinical & Experimental Immunology","volume":"39 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2017-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"74650952","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Umang Jain, Craig Midgen, Trent M. Woodruff, Wilhelm J. Schwaeble, C. Stover, Andrew W. Stadnyk
Intestinal mucositis is a serious complication of chemotherapy that leads to significant morbidity that may require dose or drug adjustments. Specific mitigating strategies for mucositis are unavailable, due partly to an incomplete understanding of the pathogenic mechanisms. We have previously shown an effect of properdin, a positive regulator of complement activation, in models of colitis. Here we use properdin‐deficient (PKO) mice to interrogate the role of properdin and complement in small intestinal mucositis. Mucositis was induced by five daily injections of 5‐fluorouracil (5‐FU) in wild‐type (WT), PKO, interleukin (IL)‐10–/– and properdin/IL‐10–/– double knock‐out (DKO) mice. At the time of euthanasia their jejunum was collected for histology, immunohistochemistry and cytokine and complement activation measurements. Complement became activated in mice receiving 5‐FU, indicated by increased intestinal levels of C3a and C5a. Compared to WT, PKO mice experienced significantly less mucositis, despite C3a levels as high as inflamed WT mice and slightly less C5a. Conversely, PKO mice had higher intestinal levels of IL‐10. IL‐10 expression was mainly by epithelial cells in both uninflamed and inflamed PKO mice. IL‐10–/– mice proved to be highly susceptible to mucositis and DKO mice were equally susceptible, demonstrating that a lack of properdin does not protect mice lacking IL‐10. We interpret our findings to indicate that, to a significant extent, the inflammation of mucositis is properdin‐dependent but complement activation‐independent. Additionally, the benefit achieved in the absence of properdin is associated with increased IL‐10 levels, and IL‐10 is important in limiting mucositis.
{"title":"Properdin deficiency protects from 5‐fluorouracil‐induced small intestinal mucositis in a complement activation‐independent, interleukin‐10‐dependent mechanism","authors":"Umang Jain, Craig Midgen, Trent M. Woodruff, Wilhelm J. Schwaeble, C. Stover, Andrew W. Stadnyk","doi":"10.1111/cei.12922","DOIUrl":"https://doi.org/10.1111/cei.12922","url":null,"abstract":"Intestinal mucositis is a serious complication of chemotherapy that leads to significant morbidity that may require dose or drug adjustments. Specific mitigating strategies for mucositis are unavailable, due partly to an incomplete understanding of the pathogenic mechanisms. We have previously shown an effect of properdin, a positive regulator of complement activation, in models of colitis. Here we use properdin‐deficient (PKO) mice to interrogate the role of properdin and complement in small intestinal mucositis. Mucositis was induced by five daily injections of 5‐fluorouracil (5‐FU) in wild‐type (WT), PKO, interleukin (IL)‐10–/– and properdin/IL‐10–/– double knock‐out (DKO) mice. At the time of euthanasia their jejunum was collected for histology, immunohistochemistry and cytokine and complement activation measurements. Complement became activated in mice receiving 5‐FU, indicated by increased intestinal levels of C3a and C5a. Compared to WT, PKO mice experienced significantly less mucositis, despite C3a levels as high as inflamed WT mice and slightly less C5a. Conversely, PKO mice had higher intestinal levels of IL‐10. IL‐10 expression was mainly by epithelial cells in both uninflamed and inflamed PKO mice. IL‐10–/– mice proved to be highly susceptible to mucositis and DKO mice were equally susceptible, demonstrating that a lack of properdin does not protect mice lacking IL‐10. We interpret our findings to indicate that, to a significant extent, the inflammation of mucositis is properdin‐dependent but complement activation‐independent. Additionally, the benefit achieved in the absence of properdin is associated with increased IL‐10 levels, and IL‐10 is important in limiting mucositis.","PeriodicalId":10179,"journal":{"name":"Clinical & Experimental Immunology","volume":"16 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2017-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"82747455","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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