Shu-hui Chen, Qiao-Li Lv, Lei Hu, Ming‐Jing Peng, Gui-Hua Wang, Bao Sun
Although lupus is, by definition, associated with genetic and immunological factors, its molecular mechanisms remain unclear. The up‐to‐date research findings point out that various genetic and epigenetic factors, especially gene‐specific and site‐specific methylation, are believed to contribute to the initiation and development of systemic lupus erythematosus (SLE). This review presents and summarizes the association between abnormal DNA methylation of immune‐related cells and lupus‐like diseases, as well as the possible mechanisms of immune disorder caused by DNA methylation, aiming at a better understanding of the roles of aberrant DNA methylation in the initiation and development of certain forms of lupus and providing a new insight into promising therapeutic regimens in lupus‐like diseases.
{"title":"DNA methylation alterations in the pathogenesis of lupus","authors":"Shu-hui Chen, Qiao-Li Lv, Lei Hu, Ming‐Jing Peng, Gui-Hua Wang, Bao Sun","doi":"10.1111/cei.12877","DOIUrl":"https://doi.org/10.1111/cei.12877","url":null,"abstract":"Although lupus is, by definition, associated with genetic and immunological factors, its molecular mechanisms remain unclear. The up‐to‐date research findings point out that various genetic and epigenetic factors, especially gene‐specific and site‐specific methylation, are believed to contribute to the initiation and development of systemic lupus erythematosus (SLE). This review presents and summarizes the association between abnormal DNA methylation of immune‐related cells and lupus‐like diseases, as well as the possible mechanisms of immune disorder caused by DNA methylation, aiming at a better understanding of the roles of aberrant DNA methylation in the initiation and development of certain forms of lupus and providing a new insight into promising therapeutic regimens in lupus‐like diseases.","PeriodicalId":10179,"journal":{"name":"Clinical & Experimental Immunology","volume":"16 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2017-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"90317966","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. Wehling, Oliver Amon, Martin Bommer, Bernd Hoppe, Karim Kentouche, Gesa Schalk, R. Weimer, Michael S. Wiesener, Bernd Hohenstein, B. Tönshoff, Rainer Büscher, H. Fehrenbach, Ömer-Necmi Gök, M. Kirschfink
Various complement‐mediated renal disorders are treated currently with the complement inhibitor eculizumab. By blocking the cleavage of C5, this monoclonal antibody prevents cell damage caused by complement‐mediated inflammation. We included 23 patients with atypical haemolytic uraemic syndrome (aHUS, n = 12), C3 glomerulopathies (C3G, n = 9) and acute antibody‐mediated renal graft rejection (AMR, n = 2), treated with eculizumab in 12 hospitals in Germany. We explored the course of complement activation biomarkers and the benefit of therapeutic drug monitoring of eculizumab. Complement activation was assessed by analysing the haemolytic complement function of the classical (CH50) and the alternative pathway (APH50), C3 and the activation products C3d, C5a and sC5b‐9 prior to, 3 and 6 months after eculizumab treatment. Eculizumab concentrations were determined by a newly established specific enzyme‐linked immunosorbent assay (ELISA). Serum eculizumab concentrations up to 1082 μg/ml point to drug accumulation, especially in paediatric patients. Loss of the therapeutic antibody via urine with concentrations up to 56 μg/ml correlated with proteinuria. In aHUS patients, effective complement inhibition was demonstrated by significant reductions of CH50, APH50, C3d and sC5b‐9 levels, whereas C5a levels were only reduced significantly after 6 months' treatment. C3G patients presented increased C3d and consistently low C3 levels, reflecting ongoing complement activation and consumption at the C3 level, despite eculizumab treatment. A comprehensive complement analysis together with drug monitoring is required to distinguish mode of complement activation and efficacy of eculizumab treatment in distinct renal disorders. Accumulation of the anti‐C5 antibody points to the need for a patient‐orientated tailored therapy.
目前，补体抑制剂eculizumab治疗多种补体介导的肾脏疾病。通过阻断C5的切割，该单克隆抗体可防止补体介导的炎症引起的细胞损伤。我们纳入了德国12家医院的23例非典型溶血性尿毒综合征(aHUS, n = 12)、C3肾小球病变(C3G, n = 9)和急性抗体介导的肾移植排斥反应(AMR, n = 2)患者，这些患者接受eculizumab治疗。我们探讨了补体活化生物标志物的过程和eculizumab治疗药物监测的益处。补体激活通过分析经典途径(CH50)和替代途径(APH50)、C3和激活产物C3d、C5a和sC5b‐9在eculizumab治疗前、3个月和6个月的溶血补体功能来评估。Eculizumab浓度由新建立的特异性酶联免疫吸附试验(ELISA)测定。血清eculizumab浓度高达1082 μg/ml指向药物积累，特别是在儿科患者中。治疗性抗体经尿丢失(浓度高达56 μg/ml)与蛋白尿相关。在aHUS患者中，补体抑制有效，CH50、APH50、C3d和sC5b‐9水平显著降低，而C5a水平在治疗6个月后才显著降低。C3G患者表现为C3d升高和持续的低C3水平，反映了补体激活和C3水平的持续消耗，尽管有eculizumab治疗。需要全面的补体分析和药物监测来区分补体激活模式和eculizumab治疗不同肾脏疾病的疗效。抗C5抗体的积累表明需要以患者为导向的定制治疗。
{"title":"Monitoring of complement activation biomarkers and eculizumab in complement‐mediated renal disorders","authors":"C. Wehling, Oliver Amon, Martin Bommer, Bernd Hoppe, Karim Kentouche, Gesa Schalk, R. Weimer, Michael S. Wiesener, Bernd Hohenstein, B. Tönshoff, Rainer Büscher, H. Fehrenbach, Ömer-Necmi Gök, M. Kirschfink","doi":"10.1111/cei.12890","DOIUrl":"https://doi.org/10.1111/cei.12890","url":null,"abstract":"Various complement‐mediated renal disorders are treated currently with the complement inhibitor eculizumab. By blocking the cleavage of C5, this monoclonal antibody prevents cell damage caused by complement‐mediated inflammation. We included 23 patients with atypical haemolytic uraemic syndrome (aHUS, n = 12), C3 glomerulopathies (C3G, n = 9) and acute antibody‐mediated renal graft rejection (AMR, n = 2), treated with eculizumab in 12 hospitals in Germany. We explored the course of complement activation biomarkers and the benefit of therapeutic drug monitoring of eculizumab. Complement activation was assessed by analysing the haemolytic complement function of the classical (CH50) and the alternative pathway (APH50), C3 and the activation products C3d, C5a and sC5b‐9 prior to, 3 and 6 months after eculizumab treatment. Eculizumab concentrations were determined by a newly established specific enzyme‐linked immunosorbent assay (ELISA). Serum eculizumab concentrations up to 1082 μg/ml point to drug accumulation, especially in paediatric patients. Loss of the therapeutic antibody via urine with concentrations up to 56 μg/ml correlated with proteinuria. In aHUS patients, effective complement inhibition was demonstrated by significant reductions of CH50, APH50, C3d and sC5b‐9 levels, whereas C5a levels were only reduced significantly after 6 months' treatment. C3G patients presented increased C3d and consistently low C3 levels, reflecting ongoing complement activation and consumption at the C3 level, despite eculizumab treatment. A comprehensive complement analysis together with drug monitoring is required to distinguish mode of complement activation and efficacy of eculizumab treatment in distinct renal disorders. Accumulation of the anti‐C5 antibody points to the need for a patient‐orientated tailored therapy.","PeriodicalId":10179,"journal":{"name":"Clinical & Experimental Immunology","volume":"81 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2017-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"86623599","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. Jones, A. Kermode, R. Lucas, W. Carroll, D. Nolan, P. Hart
Circulating T and B lymphocytes contribute to the pathogenesis of the neuroinflammatory autoimmune disease, multiple sclerosis (MS). Further progress in the development of MS treatments is dependent upon a greater understanding of the immunological disturbances that underlie the disease. Analyses of circulating immune cells by flow cytometry have revealed MS‐associated alterations in the composition and function of T and B cell subsets, including temporal changes associated with disease activity. Disturbances in circulating immune populations reflect those observed in the central nervous system and include skewing towards proinflammatory CD4+ and CD8+ T cells and B cells, greater proportions of follicular T helper cells and functional defects in the corresponding T and B regulatory subsets. Utilizing the analytical power of modern flow cytometers, researchers are now well positioned to monitor immunological changes associated with disease activity or intervention, describe immunological signatures with predictive value and identify targets for therapeutic drug development. This review discusses the contribution of various T and B lymphocyte subsets to MS pathogenesis, provides current and relevant phenotypical descriptions to assist in experimental design and highlights areas of future research.
{"title":"Circulating immune cells in multiple sclerosis","authors":"A. Jones, A. Kermode, R. Lucas, W. Carroll, D. Nolan, P. Hart","doi":"10.1111/cei.12878","DOIUrl":"https://doi.org/10.1111/cei.12878","url":null,"abstract":"Circulating T and B lymphocytes contribute to the pathogenesis of the neuroinflammatory autoimmune disease, multiple sclerosis (MS). Further progress in the development of MS treatments is dependent upon a greater understanding of the immunological disturbances that underlie the disease. Analyses of circulating immune cells by flow cytometry have revealed MS‐associated alterations in the composition and function of T and B cell subsets, including temporal changes associated with disease activity. Disturbances in circulating immune populations reflect those observed in the central nervous system and include skewing towards proinflammatory CD4+ and CD8+ T cells and B cells, greater proportions of follicular T helper cells and functional defects in the corresponding T and B regulatory subsets. Utilizing the analytical power of modern flow cytometers, researchers are now well positioned to monitor immunological changes associated with disease activity or intervention, describe immunological signatures with predictive value and identify targets for therapeutic drug development. This review discusses the contribution of various T and B lymphocyte subsets to MS pathogenesis, provides current and relevant phenotypical descriptions to assist in experimental design and highlights areas of future research.","PeriodicalId":10179,"journal":{"name":"Clinical & Experimental Immunology","volume":"118 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2017-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"79526155","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}
Adam A. Anas, Jack Yang, J. D. D. Boer, J. Roelofs, Baidong Hou, A. F. D. Vos, T. V. D. Poll
Asthma is a highly prevalent chronic allergic inflammatory disease of the airways affecting people worldwide. House dust mite (HDM) is the most common allergen implicated in human allergic asthma. HDM‐induced allergic responses are thought to depend upon activation of pathways involving Toll‐like receptors and their adaptor protein myeloid differentiation factor 88 (MyD88). We sought here to determine the role of MyD88 in myeloid and type II lung epithelial cells in the development of asthma‐like allergic disease using a mouse model. Repeated exposure to HDM caused allergic responses in control mice characterized by influx of eosinophils into the bronchoalveolar space and lung tissue, lung pathology and mucus production and protein leak into bronchoalveolar lavage fluid. All these responses were abrogated in mice with a general deficiency of MyD88 but unaltered in mice with MyD88 deficiency, specifically in myeloid or type II lung epithelial cells. We conclude that cells other than myeloid or type II lung epithelial cells are responsible for MyD88‐dependent HDM‐induced allergic airway inflammation.
{"title":"General, but not myeloid or type II lung epithelial cell, myeloid differentiation factor 88 deficiency abrogates house dust mite induced allergic lung inflammation","authors":"Adam A. Anas, Jack Yang, J. D. D. Boer, J. Roelofs, Baidong Hou, A. F. D. Vos, T. V. D. Poll","doi":"10.1111/cei.12867","DOIUrl":"https://doi.org/10.1111/cei.12867","url":null,"abstract":"Asthma is a highly prevalent chronic allergic inflammatory disease of the airways affecting people worldwide. House dust mite (HDM) is the most common allergen implicated in human allergic asthma. HDM‐induced allergic responses are thought to depend upon activation of pathways involving Toll‐like receptors and their adaptor protein myeloid differentiation factor 88 (MyD88). We sought here to determine the role of MyD88 in myeloid and type II lung epithelial cells in the development of asthma‐like allergic disease using a mouse model. Repeated exposure to HDM caused allergic responses in control mice characterized by influx of eosinophils into the bronchoalveolar space and lung tissue, lung pathology and mucus production and protein leak into bronchoalveolar lavage fluid. All these responses were abrogated in mice with a general deficiency of MyD88 but unaltered in mice with MyD88 deficiency, specifically in myeloid or type II lung epithelial cells. We conclude that cells other than myeloid or type II lung epithelial cells are responsible for MyD88‐dependent HDM‐induced allergic airway inflammation.","PeriodicalId":10179,"journal":{"name":"Clinical & Experimental Immunology","volume":"62 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2017-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"75081698","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}
L. Smyth, L. Smyth, L. Smyth, Lucy Meader, Fang Xiao, Martin Woodward, Hugh J. M. Brady, R. Lechler, Giovanna Lombardi
Anti‐apoptotic genes, including those of the Bcl‐2 family, have been shown to have dual functionality inasmuch as they inhibit cell death but also regulate inflammation. Several anti‐apoptotic molecules have been associated with endothelial cell (EC) survival following transplantation; however, their exact role has yet to be elucidated in respect to controlling inflammation. In this study we created mice expressing murine A1 (Bfl‐1), a Bcl‐2 family member, under the control of the human intercellular adhesion molecule 2 (ICAM‐2) promoter. Constitutive expression of A1 in murine vascular ECs conferred protection from cell death induced by the proinflammatory cytokine tumour necrosis factor (TNF)‐α. Importantly, in a mouse model of heart allograft transplantation, expression of A1 in vascular endothelium increased survival in the absence of CD8+ T cells. Better graft outcome in mice receiving an A1 transgenic heart correlated with a reduced immune infiltration, which may be related to increased EC survival and reduced expression of adhesion molecules on ECs. In conclusion, constitutive expression of the anti‐apoptotic molecule Bfl1 (A1) in murine vascular ECs leads to prolonged allograft survival due to modifying inflammation.
{"title":"Constitutive expression of the anti‐apoptotic Bcl‐2 family member A1 in murine endothelial cells leads to transplant tolerance","authors":"L. Smyth, L. Smyth, L. Smyth, Lucy Meader, Fang Xiao, Martin Woodward, Hugh J. M. Brady, R. Lechler, Giovanna Lombardi","doi":"10.1111/cei.12931","DOIUrl":"https://doi.org/10.1111/cei.12931","url":null,"abstract":"Anti‐apoptotic genes, including those of the Bcl‐2 family, have been shown to have dual functionality inasmuch as they inhibit cell death but also regulate inflammation. Several anti‐apoptotic molecules have been associated with endothelial cell (EC) survival following transplantation; however, their exact role has yet to be elucidated in respect to controlling inflammation. In this study we created mice expressing murine A1 (Bfl‐1), a Bcl‐2 family member, under the control of the human intercellular adhesion molecule 2 (ICAM‐2) promoter. Constitutive expression of A1 in murine vascular ECs conferred protection from cell death induced by the proinflammatory cytokine tumour necrosis factor (TNF)‐α. Importantly, in a mouse model of heart allograft transplantation, expression of A1 in vascular endothelium increased survival in the absence of CD8+ T cells. Better graft outcome in mice receiving an A1 transgenic heart correlated with a reduced immune infiltration, which may be related to increased EC survival and reduced expression of adhesion molecules on ECs. In conclusion, constitutive expression of the anti‐apoptotic molecule Bfl1 (A1) in murine vascular ECs leads to prolonged allograft survival due to modifying inflammation.","PeriodicalId":10179,"journal":{"name":"Clinical & Experimental Immunology","volume":"273 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2017-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"75781029","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}
This special issue of Clinical and Experimental Immunology is dedicated to immunosenescence. It covers a wide range of topics related to immunosenescence, from basic research and animal models to applied topics such as vaccines for elderly people and interventions to rejuvenate the immune system. The reviews in this issue highlight some of the topics discussed at the Satellite Symposium ‘Immunosenescence: Hot Topics and Interventions’, which took place on 5–6 September 2015 in Vienna, Austria, preceding the 4th European Congress of Immunology. The symposium was organized by Birgit Weinberger, Beatrix GrubeckLoebenstein (both University of Innsbruck, Innsbruck, Austria), Daniela Frasca, Bonnie Blomberg (both University of Miami, Miami, FL, USA), Arne N. Akbar (University College London, London, UK), Graham Pawelec (University of T€ ubingen, T€ ubingen, Germany), Rebecca Fuldner (National Institute on Aging, Bethesda, ND, USA) and Elizabeth J. Kovacs (Loyola University, Chicago, IL, USA). The world is undergoing a substantial shift in demographics, as the number of individuals aged more than 60 years is increasing dramatically. The immune system undergoes typical age-related changes, which are collectively termed ‘immunosenescence’. The incidence and severity of various infections increases with age; concomitantly, the immunogenicity and efficacy of many vaccines is lower in elderly people, making protection of this vulnerable population a challenge. With increasing age, the innate immune system exhibits a diminished ability to respond to and clear infections. The incidence of lung infections is high in older adults and severe disease is observed frequently. A more detailed understanding of local and systemic immune responses to pneumonia and the impact of age is essential in order to design age-specific therapies. Alveolar macrophages and neutrophils are the first line of defence against bacterial pneumonia, but alterations in Toll-like receptor signalling, cytokine and chemokine production and defects in effector functions, such as clearance of cell debris and bactericidal activity, limit their effect in elderly people. Dendritic cells and natural killer cells in the lung play an important role in the defence against viral infections such as influenza and respiratory syncytial virus, but migration to lymph nodes and stimulation of T cells by dendritic cells as well as the capacity of natural killer cells to eliminate infected cells are diminished in old age [1]. Cell-intrinsic defects of aged T cells have been investigated extensively. The review by Kim et al. [2] summarizes the details of vaccine-induced T cell responses, including activation, expansion, differentiation into effector cells and generation of T cell memory, and highlights the importance of these findings for vaccine development. Most approaches to improve vaccination responses in old age concentrate on activating the innate immune system by adjuvants in order to improve the induct
{"title":"Immunosenescence: the importance of considering age in health and disease","authors":"B. Weinberger","doi":"10.1111/cei.12879","DOIUrl":"https://doi.org/10.1111/cei.12879","url":null,"abstract":"This special issue of Clinical and Experimental Immunology is dedicated to immunosenescence. It covers a wide range of topics related to immunosenescence, from basic research and animal models to applied topics such as vaccines for elderly people and interventions to rejuvenate the immune system. The reviews in this issue highlight some of the topics discussed at the Satellite Symposium ‘Immunosenescence: Hot Topics and Interventions’, which took place on 5–6 September 2015 in Vienna, Austria, preceding the 4th European Congress of Immunology. The symposium was organized by Birgit Weinberger, Beatrix GrubeckLoebenstein (both University of Innsbruck, Innsbruck, Austria), Daniela Frasca, Bonnie Blomberg (both University of Miami, Miami, FL, USA), Arne N. Akbar (University College London, London, UK), Graham Pawelec (University of T€ ubingen, T€ ubingen, Germany), Rebecca Fuldner (National Institute on Aging, Bethesda, ND, USA) and Elizabeth J. Kovacs (Loyola University, Chicago, IL, USA). The world is undergoing a substantial shift in demographics, as the number of individuals aged more than 60 years is increasing dramatically. The immune system undergoes typical age-related changes, which are collectively termed ‘immunosenescence’. The incidence and severity of various infections increases with age; concomitantly, the immunogenicity and efficacy of many vaccines is lower in elderly people, making protection of this vulnerable population a challenge. With increasing age, the innate immune system exhibits a diminished ability to respond to and clear infections. The incidence of lung infections is high in older adults and severe disease is observed frequently. A more detailed understanding of local and systemic immune responses to pneumonia and the impact of age is essential in order to design age-specific therapies. Alveolar macrophages and neutrophils are the first line of defence against bacterial pneumonia, but alterations in Toll-like receptor signalling, cytokine and chemokine production and defects in effector functions, such as clearance of cell debris and bactericidal activity, limit their effect in elderly people. Dendritic cells and natural killer cells in the lung play an important role in the defence against viral infections such as influenza and respiratory syncytial virus, but migration to lymph nodes and stimulation of T cells by dendritic cells as well as the capacity of natural killer cells to eliminate infected cells are diminished in old age [1]. Cell-intrinsic defects of aged T cells have been investigated extensively. The review by Kim et al. [2] summarizes the details of vaccine-induced T cell responses, including activation, expansion, differentiation into effector cells and generation of T cell memory, and highlights the importance of these findings for vaccine development. Most approaches to improve vaccination responses in old age concentrate on activating the innate immune system by adjuvants in order to improve the induct","PeriodicalId":10179,"journal":{"name":"Clinical & Experimental Immunology","volume":"27 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2017-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"84108821","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}
J. Basile, Denise Kviatcovsky, M. M. Romero, L. Balboa, Johana Monteserin, Viviana Ritacco, Briceida Lopez, C. S. Y. García, A. García, Marisa Vescovo, P. G. Montaner, Domingo Palmero, M. Sasiain, S. Barrera
We have reported previously that T cells from patients with multi‐drug‐resistant tuberculosis (MDR‐TB) express high levels of interleukin (IL)‐17 in response to the MDR strain M (Haarlem family) of Mycobacterium tuberculosis (M. tuberculosis). Herein, we explore the pathways involved in the induction of Th17 cells in MDR‐TB patients and healthy tuberculin reactors [purified protein derivative healthy donors (PPD+ HD)] by the M strain and the laboratory strain H37Rv. Our results show that IL‐1β and IL‐6 are crucial for the H37Rv and M‐induced expansion of IL‐17+interferon (IFN)‐γ– and IL‐17+IFN‐γ+ in CD4+ T cells from MDR‐TB and PPD+ HD. IL‐23 plays an ambiguous role in T helper type 1 (Th1) and Th17 profiles: alone, IL‐23 is responsible for M. tuberculosis‐induced IL‐17 and IFN‐γ expression in CD4+ T cells from PPD+ HD whereas, together with transforming growth factor (TGF‐β), it promotes IL‐17+IFN‐γ– expansion in MDR‐TB. In fact, spontaneous and M. tuberculosis‐induced TGF‐β secretion is increased in cells from MDR‐TB, the M strain being the highest inducer. Interestingly, Toll‐like receptor (TLR)‐2 signalling mediates the expansion of IL‐17+IFN‐γ– cells and the enhancement of latency‐associated protein (LAP) expression in CD14+ and CD4+ T cells from MDR‐TB, which suggests that the M strain promotes IL‐17+IFN‐γ– T cells through a strong TLR‐2‐dependent TGF‐β production by antigen‐presenting cells and CD4+ T cells. Finally, CD4+ T cells from MDR‐TB patients infected with MDR Haarlem strains show higher IL‐17+IFN‐γ– and lower IL‐17+IFN‐γ+ levels than LAM‐infected patients. The present findings deepen our understanding of the role of IL‐17 in MDR‐TB and highlight the influence of the genetic background of the infecting M. tuberculosis strain on the ex‐vivo Th17 response.
{"title":"Mycobacterium tuberculosis multi‐drug‐resistant strain M induces IL‐17+IFNγ– CD4+ T cell expansion through an IL‐23 and TGF‐β‐dependent mechanism in patients with MDR‐TB tuberculosis","authors":"J. Basile, Denise Kviatcovsky, M. M. Romero, L. Balboa, Johana Monteserin, Viviana Ritacco, Briceida Lopez, C. S. Y. García, A. García, Marisa Vescovo, P. G. Montaner, Domingo Palmero, M. Sasiain, S. Barrera","doi":"10.1111/cei.12873","DOIUrl":"https://doi.org/10.1111/cei.12873","url":null,"abstract":"We have reported previously that T cells from patients with multi‐drug‐resistant tuberculosis (MDR‐TB) express high levels of interleukin (IL)‐17 in response to the MDR strain M (Haarlem family) of Mycobacterium tuberculosis (M. tuberculosis). Herein, we explore the pathways involved in the induction of Th17 cells in MDR‐TB patients and healthy tuberculin reactors [purified protein derivative healthy donors (PPD+ HD)] by the M strain and the laboratory strain H37Rv. Our results show that IL‐1β and IL‐6 are crucial for the H37Rv and M‐induced expansion of IL‐17+interferon (IFN)‐γ– and IL‐17+IFN‐γ+ in CD4+ T cells from MDR‐TB and PPD+ HD. IL‐23 plays an ambiguous role in T helper type 1 (Th1) and Th17 profiles: alone, IL‐23 is responsible for M. tuberculosis‐induced IL‐17 and IFN‐γ expression in CD4+ T cells from PPD+ HD whereas, together with transforming growth factor (TGF‐β), it promotes IL‐17+IFN‐γ– expansion in MDR‐TB. In fact, spontaneous and M. tuberculosis‐induced TGF‐β secretion is increased in cells from MDR‐TB, the M strain being the highest inducer. Interestingly, Toll‐like receptor (TLR)‐2 signalling mediates the expansion of IL‐17+IFN‐γ– cells and the enhancement of latency‐associated protein (LAP) expression in CD14+ and CD4+ T cells from MDR‐TB, which suggests that the M strain promotes IL‐17+IFN‐γ– T cells through a strong TLR‐2‐dependent TGF‐β production by antigen‐presenting cells and CD4+ T cells. Finally, CD4+ T cells from MDR‐TB patients infected with MDR Haarlem strains show higher IL‐17+IFN‐γ– and lower IL‐17+IFN‐γ+ levels than LAM‐infected patients. The present findings deepen our understanding of the role of IL‐17 in MDR‐TB and highlight the influence of the genetic background of the infecting M. tuberculosis strain on the ex‐vivo Th17 response.","PeriodicalId":10179,"journal":{"name":"Clinical & Experimental Immunology","volume":"17 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2017-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"86003041","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}
S. Jolles, E. Carne, M. Brouns, T. El-shanawany, P. Williams, C. Marshall, P. Fielding
Common variable immunodeficiency (CVID) is the most common severe adult primary immunodeficiency and is characterized by a failure to produce antibodies leading to recurrent predominantly sinopulmonary infections. Improvements in the prevention and treatment of infection with immunoglobulin replacement and antibiotics have resulted in malignancy, autoimmune, inflammatory and lymphoproliferative disorders emerging as major clinical challenges in the management of patients who have CVID. In a proportion of CVID patients, inflammation manifests as granulomas that frequently involve the lungs, lymph nodes, spleen and liver and may affect almost any organ. Granulomatous lymphocytic interstitial lung disease (GLILD) is associated with a worse outcome. Its underlying pathogenic mechanisms are poorly understood and there is limited evidence to inform how best to monitor, treat or select patients to treat. We describe the use of combined 2‐[(18)F]‐fluoro‐2‐deoxy‐d‐glucose positron emission tomography and computed tomography (FDG PET‐CT) scanning for the assessment and monitoring of response to treatment in a patient with GLILD. This enabled a synergistic combination of functional and anatomical imaging in GLILD and demonstrated a widespread and high level of metabolic activity in the lungs and lymph nodes. Following treatment with rituximab and mycophenolate there was almost complete resolution of the previously identified high metabolic activity alongside significant normalization in lymph node size and lung architecture. The results support the view that GLILD represents one facet of a multi‐systemic metabolically highly active lymphoproliferative disorder and suggests potential utility of this imaging modality in this subset of patients with CVID.
{"title":"FDG PET‐CT imaging of therapeutic response in granulomatous lymphocytic interstitial lung disease (GLILD) in common variable immunodeficiency (CVID)","authors":"S. Jolles, E. Carne, M. Brouns, T. El-shanawany, P. Williams, C. Marshall, P. Fielding","doi":"10.1111/cei.12856","DOIUrl":"https://doi.org/10.1111/cei.12856","url":null,"abstract":"Common variable immunodeficiency (CVID) is the most common severe adult primary immunodeficiency and is characterized by a failure to produce antibodies leading to recurrent predominantly sinopulmonary infections. Improvements in the prevention and treatment of infection with immunoglobulin replacement and antibiotics have resulted in malignancy, autoimmune, inflammatory and lymphoproliferative disorders emerging as major clinical challenges in the management of patients who have CVID. In a proportion of CVID patients, inflammation manifests as granulomas that frequently involve the lungs, lymph nodes, spleen and liver and may affect almost any organ. Granulomatous lymphocytic interstitial lung disease (GLILD) is associated with a worse outcome. Its underlying pathogenic mechanisms are poorly understood and there is limited evidence to inform how best to monitor, treat or select patients to treat. We describe the use of combined 2‐[(18)F]‐fluoro‐2‐deoxy‐d‐glucose positron emission tomography and computed tomography (FDG PET‐CT) scanning for the assessment and monitoring of response to treatment in a patient with GLILD. This enabled a synergistic combination of functional and anatomical imaging in GLILD and demonstrated a widespread and high level of metabolic activity in the lungs and lymph nodes. Following treatment with rituximab and mycophenolate there was almost complete resolution of the previously identified high metabolic activity alongside significant normalization in lymph node size and lung architecture. The results support the view that GLILD represents one facet of a multi‐systemic metabolically highly active lymphoproliferative disorder and suggests potential utility of this imaging modality in this subset of patients with CVID.","PeriodicalId":10179,"journal":{"name":"Clinical & Experimental Immunology","volume":"12 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2017-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"72749020","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}
Immunotherapy is now experiencing unprecedented successes in treating various cancers based on new understandings of cancer immunopathogenesis. Nonetheless, although ageing is the biggest risk factor for cancer, the majority of cancer immunotherapy preclinical studies are conducted in young hosts. This review will explore age‐related changes in immunity as they relate to cancer immune surveillance, immunopathogenesis and responses to immunotherapy. Although it is recognized that declining T cell function with age poses a great challenge to developing effective age‐related cancer immunotherapies, examples of successful approaches to overcome this hurdle have been developed. Further, it is now recognized that immune functions do not simply decline with age, but rather change in ways than can be detrimental. For example, with age, specific immune cell populations with detrimental functions can become predominant (such as cells producing proinflammatory cytokines), suppressive cells can become more numerous or more suppressive (such as myeloid‐derived suppressor cells), drugs can affect aged immune cells distinctly and the aged microenvironment is becoming recognized as a significant barrier to address. Key developments in these and other areas will be surveyed as they relate to cancer immunotherapy in aged hosts, and areas in need of more study will be assessed with some speculations for the future. We propose the term ‘age‐related immune dysfunction’ (ARID) as best representative of age‐associated changes in immunity.
{"title":"Considerations for successful cancer immunotherapy in aged hosts","authors":"V. Hurez, A. Padron, R. Svatek, T. Curiel","doi":"10.1111/cei.12875","DOIUrl":"https://doi.org/10.1111/cei.12875","url":null,"abstract":"Immunotherapy is now experiencing unprecedented successes in treating various cancers based on new understandings of cancer immunopathogenesis. Nonetheless, although ageing is the biggest risk factor for cancer, the majority of cancer immunotherapy preclinical studies are conducted in young hosts. This review will explore age‐related changes in immunity as they relate to cancer immune surveillance, immunopathogenesis and responses to immunotherapy. Although it is recognized that declining T cell function with age poses a great challenge to developing effective age‐related cancer immunotherapies, examples of successful approaches to overcome this hurdle have been developed. Further, it is now recognized that immune functions do not simply decline with age, but rather change in ways than can be detrimental. For example, with age, specific immune cell populations with detrimental functions can become predominant (such as cells producing proinflammatory cytokines), suppressive cells can become more numerous or more suppressive (such as myeloid‐derived suppressor cells), drugs can affect aged immune cells distinctly and the aged microenvironment is becoming recognized as a significant barrier to address. Key developments in these and other areas will be surveyed as they relate to cancer immunotherapy in aged hosts, and areas in need of more study will be assessed with some speculations for the future. We propose the term ‘age‐related immune dysfunction’ (ARID) as best representative of age‐associated changes in immunity.","PeriodicalId":10179,"journal":{"name":"Clinical & Experimental Immunology","volume":"53 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2017-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"73027719","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}
Anna Głobińska, Malgorzata Pawelczyk, Aleksandra Piechota-Polanczyk, A. Olszewska-Ziąber, S. Moskwa, A. Mikołajczyk, A. Jabłońska, Piotr K. Zakrzewski, M. Brauncajs, M. Jarzębska, S. Taka, N. G. Papadopoulos, M. L. Kowalski
The aim of this study was to assess the immune response to parainfluenza virus type 3 (PIV3), rhinovirus 1B (RV1B) and intracellular Toll‐like receptors (TLR) agonists in nasal epithelial cells (NECs) from patients with allergic rhinitis and healthy controls. NECs were obtained from eight patients with allergic rhinitis (AR) and 11 non‐atopic healthy controls (HC) by nasal scraping, grown to confluence and exposed to PIV3, RV1B infection or TLR‐3 and TLR‐7/8 agonists. Interferon (IFN)‐λ1, IFN‐α, IFN‐β and regulated on activation, normal T expressed and secreted (RANTES) release into the cell culture supernatants was assessed at 8, 24 and 48 h upon infection or 8 and 24 h after stimulation with poly(I:C) and R848. mRNA levels of IFNs, RANTES, interferon regulatory transcription factor (IRF)3, IRF7 and viral gene copy number were determined using real‐time polymerase chain reaction (RT‐PCR). PIV3 but not RV1B replication 48 h after infection was significantly lower (P < 0·01) in NECs from AR patients compared to HC. PIV3 infection induced significantly less IFN‐λ1 (both protein and mRNA) in NECs from AR compared to HC. IFN‐β mRNA expression and RANTES protein release and mRNA expression tended to be smaller in AR compared HC cells in response to both viruses. Stimulation with TLR‐3 agonist [poly (I:C)] induced similar IFN‐λ1 and RANTES generation in AR and HC subjects. Viral infections in NECs induced IRF7 expression, which correlated with IFN and RANTES expression. These data suggest that virus proliferation rates and the immune response profile are different in nasal epithelial cells from patients with allergic rhinitis compared to healthy individuals.
{"title":"Impaired virus replication and decreased innate immune responses to viral infections in nasal epithelial cells from patients with allergic rhinitis","authors":"Anna Głobińska, Malgorzata Pawelczyk, Aleksandra Piechota-Polanczyk, A. Olszewska-Ziąber, S. Moskwa, A. Mikołajczyk, A. Jabłońska, Piotr K. Zakrzewski, M. Brauncajs, M. Jarzębska, S. Taka, N. G. Papadopoulos, M. L. Kowalski","doi":"10.1111/cei.12869","DOIUrl":"https://doi.org/10.1111/cei.12869","url":null,"abstract":"The aim of this study was to assess the immune response to parainfluenza virus type 3 (PIV3), rhinovirus 1B (RV1B) and intracellular Toll‐like receptors (TLR) agonists in nasal epithelial cells (NECs) from patients with allergic rhinitis and healthy controls. NECs were obtained from eight patients with allergic rhinitis (AR) and 11 non‐atopic healthy controls (HC) by nasal scraping, grown to confluence and exposed to PIV3, RV1B infection or TLR‐3 and TLR‐7/8 agonists. Interferon (IFN)‐λ1, IFN‐α, IFN‐β and regulated on activation, normal T expressed and secreted (RANTES) release into the cell culture supernatants was assessed at 8, 24 and 48 h upon infection or 8 and 24 h after stimulation with poly(I:C) and R848. mRNA levels of IFNs, RANTES, interferon regulatory transcription factor (IRF)3, IRF7 and viral gene copy number were determined using real‐time polymerase chain reaction (RT‐PCR). PIV3 but not RV1B replication 48 h after infection was significantly lower (P < 0·01) in NECs from AR patients compared to HC. PIV3 infection induced significantly less IFN‐λ1 (both protein and mRNA) in NECs from AR compared to HC. IFN‐β mRNA expression and RANTES protein release and mRNA expression tended to be smaller in AR compared HC cells in response to both viruses. Stimulation with TLR‐3 agonist [poly (I:C)] induced similar IFN‐λ1 and RANTES generation in AR and HC subjects. Viral infections in NECs induced IRF7 expression, which correlated with IFN and RANTES expression. These data suggest that virus proliferation rates and the immune response profile are different in nasal epithelial cells from patients with allergic rhinitis compared to healthy individuals.","PeriodicalId":10179,"journal":{"name":"Clinical & Experimental Immunology","volume":"40 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2017-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"85447207","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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