D. Gómez-Martín, A. S. Galindo‐Feria, A. Barrera-Vargas, J. Merayo-Chalico, Guillermo Juárez-Vega, J. Torres-Ruiz, J. Alcocer-Varela
The presence of anti‐Ro52/tripartite motif 21 (Trim21) autoantibodies has been associated with a distinctive clinical profile and has gained value as a prognostic marker in idiopathic inflammatory myopathies (IIM). The aim of the present work was to analyse Ro52/Trim21 expression in different subsets of peripheral blood mononuclear cells (PBMCs) of patients with IIM, as well as the ubiquitination profile and its association with proinflammatory cytokine production. We included 18 patients with recent‐onset IIM and 18 age‐ and gender‐matched healthy donors. PBMCs were isolated and different subsets (CD4+, CD8+, CD14+) were purified by magnetic selection. The expression of Ro52/Trim21 in different PBMC subsets of patients with IIM and healthy donors was analysed by Western blot. We assessed the presence of myositis‐specific and associated autoantibodies by enzyme‐linked immunosorbent assay (ELISA). Cytokine levels were measured by cytometric bead array. Patients with IIM showed decreased protein expression of Ro52/Trim21 in comparison to healthy controls in PBMC (0·97 ± 0·60 versus 1·84 ± 0·92, P = 0·016), CD4+ lymphocytes (0·79 ± 0·54 versus 2·41 ± 0·78, P = 0·017), and monocytes (0·87 ± 0·35 versus 1·89 ± 0·20, P < 0·001). There were no significant differences among IIM groups. Also, a lower K48‐mediated ubiquitination profile was found, predominantly in CD4+ lymphocytes. Furthermore, after mitogenic stimulation, there was a higher synthesis of proinflammatory cytokines by T cells [interleukin (IL)‐17A and tumour necrosis factor (TNF)‐α] and monocytes [IL‐6 and interferon (IFN)‐α] from IIM patients compared with healthy controls. Our data suggest that patients with IIM, mainly DM, are characterized by a deficient expression of Ro52/TRIM21 in different PBMC subsets (CD4+ lymphocytes and monocytes), along with lower K48‐mediated ubiquitination, which is associated with a proinflammatory cytokine response.
{"title":"Ro52/TRIM21‐deficient expression and function in different subsets of peripheral blood mononuclear cells is associated with a proinflammatory cytokine response in patients with idiopathic inflammatory myopathies","authors":"D. Gómez-Martín, A. S. Galindo‐Feria, A. Barrera-Vargas, J. Merayo-Chalico, Guillermo Juárez-Vega, J. Torres-Ruiz, J. Alcocer-Varela","doi":"10.1111/cei.12914","DOIUrl":"https://doi.org/10.1111/cei.12914","url":null,"abstract":"The presence of anti‐Ro52/tripartite motif 21 (Trim21) autoantibodies has been associated with a distinctive clinical profile and has gained value as a prognostic marker in idiopathic inflammatory myopathies (IIM). The aim of the present work was to analyse Ro52/Trim21 expression in different subsets of peripheral blood mononuclear cells (PBMCs) of patients with IIM, as well as the ubiquitination profile and its association with proinflammatory cytokine production. We included 18 patients with recent‐onset IIM and 18 age‐ and gender‐matched healthy donors. PBMCs were isolated and different subsets (CD4+, CD8+, CD14+) were purified by magnetic selection. The expression of Ro52/Trim21 in different PBMC subsets of patients with IIM and healthy donors was analysed by Western blot. We assessed the presence of myositis‐specific and associated autoantibodies by enzyme‐linked immunosorbent assay (ELISA). Cytokine levels were measured by cytometric bead array. Patients with IIM showed decreased protein expression of Ro52/Trim21 in comparison to healthy controls in PBMC (0·97 ± 0·60 versus 1·84 ± 0·92, P = 0·016), CD4+ lymphocytes (0·79 ± 0·54 versus 2·41 ± 0·78, P = 0·017), and monocytes (0·87 ± 0·35 versus 1·89 ± 0·20, P < 0·001). There were no significant differences among IIM groups. Also, a lower K48‐mediated ubiquitination profile was found, predominantly in CD4+ lymphocytes. Furthermore, after mitogenic stimulation, there was a higher synthesis of proinflammatory cytokines by T cells [interleukin (IL)‐17A and tumour necrosis factor (TNF)‐α] and monocytes [IL‐6 and interferon (IFN)‐α] from IIM patients compared with healthy controls. Our data suggest that patients with IIM, mainly DM, are characterized by a deficient expression of Ro52/TRIM21 in different PBMC subsets (CD4+ lymphocytes and monocytes), along with lower K48‐mediated ubiquitination, which is associated with a proinflammatory cytokine response.","PeriodicalId":10179,"journal":{"name":"Clinical & Experimental Immunology","volume":"36 2 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2017-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"89432493","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}
The programmed death‐1 (PD‐1) receptor ligands, PD‐L1 and PD‐L2, are co‐stimulatory molecules that contribute to the negative regulation of T lymphocyte activation. It is still unclear whether there is correlation between PD‐L1 or PD‐L2 and tumour‐infiltrating dendritic cells (TIDCs) in cutaneous squamous cell carcinoma (CSCC). The aim of this study was to analyse PD‐L1 and PD‐L2 expression and dendritic cells infiltration in tumour tissue of CSCC patients and investigate their clinical significance. Immunohistochemical analysis was used to evaluate the expression of PD‐L1, PD‐L2, CD1a and CD83 in 61 CSCC tissues. The immunofluoresence double‐labelling technique was performed to detect the co‐expression of PD‐L1 or PD‐L2 and CD1a or CD83 in tumour tissues. We found that 25 of 61 cases CSCC (40·98%) exhibited positivity for PD‐L1, whereas 37 of 61 cases CSCC (60·66%) exhibited positivity for PD‐L2. A higher percentage of CD1a‐positive cases were observed on both PD‐L1‐positive and PD‐L2‐positive specimens compared with that of CD83‐positive cases (92·29% versus 37·60%, 83·20% versus 33·16%). The expression of PD‐L1 and PD‐L2 on CD1a+ cells was significantly higher than that on CD83+ cells in tumour tissues of CSCC patients. Furthermore, the expression rate of PD‐L1 was associated with UICC stage, and the expression rate of PD‐L2 was associated with predominant differentiation and tumour size in CSCC. Our results indicated that higher expression of PD‐L1 and PD‐L2 on CD1a+ cells than that on CD83+ cells in CSCC tumour tissues may contribute to negative regulation in anti‐tumour immune responses.
{"title":"Programmed death‐1 ligands 1 and 2 expression in cutaneous squamous cell carcinoma and their relationship with tumour‐ infiltrating dendritic cells","authors":"Q. Jiao, Cuiping Liu, Wenzhong Li, Wei Li, F. Fang, Qihong Qian, Xueguang Zhang","doi":"10.1111/cei.12921","DOIUrl":"https://doi.org/10.1111/cei.12921","url":null,"abstract":"The programmed death‐1 (PD‐1) receptor ligands, PD‐L1 and PD‐L2, are co‐stimulatory molecules that contribute to the negative regulation of T lymphocyte activation. It is still unclear whether there is correlation between PD‐L1 or PD‐L2 and tumour‐infiltrating dendritic cells (TIDCs) in cutaneous squamous cell carcinoma (CSCC). The aim of this study was to analyse PD‐L1 and PD‐L2 expression and dendritic cells infiltration in tumour tissue of CSCC patients and investigate their clinical significance. Immunohistochemical analysis was used to evaluate the expression of PD‐L1, PD‐L2, CD1a and CD83 in 61 CSCC tissues. The immunofluoresence double‐labelling technique was performed to detect the co‐expression of PD‐L1 or PD‐L2 and CD1a or CD83 in tumour tissues. We found that 25 of 61 cases CSCC (40·98%) exhibited positivity for PD‐L1, whereas 37 of 61 cases CSCC (60·66%) exhibited positivity for PD‐L2. A higher percentage of CD1a‐positive cases were observed on both PD‐L1‐positive and PD‐L2‐positive specimens compared with that of CD83‐positive cases (92·29% versus 37·60%, 83·20% versus 33·16%). The expression of PD‐L1 and PD‐L2 on CD1a+ cells was significantly higher than that on CD83+ cells in tumour tissues of CSCC patients. Furthermore, the expression rate of PD‐L1 was associated with UICC stage, and the expression rate of PD‐L2 was associated with predominant differentiation and tumour size in CSCC. Our results indicated that higher expression of PD‐L1 and PD‐L2 on CD1a+ cells than that on CD83+ cells in CSCC tumour tissues may contribute to negative regulation in anti‐tumour immune responses.","PeriodicalId":10179,"journal":{"name":"Clinical & Experimental Immunology","volume":"427 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2017-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"75904806","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}
Coronary heart disease (CHD) is one of the most common types of organ lesions caused by atherosclerosis, in which CD4+CD25+forkhead box protein 3 (FoxP3+) regulatory T cells (Treg) play an atheroprotective role. However, Treg cell numbers are decreased and their functions are impaired in atherosclerosis; the underlying mechanisms remain unclear. CD31 plays an important part in T cell response and contributes to maintaining T cell tolerance. The immunomodulatory effects of CD31 are also implicated in atherosclerosis. In this study, we found that decreased frequencies of the CD31+ subpopulation in Treg cells (CD31+Tr cells) correlated positively with decreased FoxP3 expression in CHD patients. Cell culture in vitro demonstrated CD31+Tr cells maintaining stable FoxP3 expression after activation and exhibited enhanced proliferation and immunosuppression compared with the CD31− subpopulation in Treg cells (CD31−Tr cells). We also confirmed impaired secretion of transforming growth factor (TGF)‐β1 and interleukin (IL)‐10 in CD31+Tr cells of CHD patients. Further analysis revealed reduced phospho‐SHP2 (associated with CD31 activation) and phospho‐signal transducer and activator of transcription‐5 (STAT‐5) (associated with FoxP3 transcription) levels in CD31+Tr cells of CHD patients, suggesting that decreased FoxP3 expression in CD31+Tr cells might be because of attenuated SHP2 and STAT‐5 activation. These data indicate that decreased frequencies and impaired functions of the CD31+Tr subpopulation associated with decreased FoxP3 expression give rise, at least in part, to Treg cell defects in CHD patients. Our findings emphasize the important role of the CD31+Tr subpopulation in maintaining Treg cell normal function and may provide a novel explanation for impaired immunoregulation of Treg cells in CHD.
{"title":"Decreased frequencies and impaired functions of the CD31+ subpopulation in Treg cells associated with decreased FoxP3 expression and enhanced Treg cell defects in patients with coronary heart disease","authors":"Liya Huang, Yingxia Zheng, Xiangliang Yuan, Yanhui Ma, Guo-hua Xie, Weiwei Wang, Hui Chen, Lisong Shen","doi":"10.1111/cei.12897","DOIUrl":"https://doi.org/10.1111/cei.12897","url":null,"abstract":"Coronary heart disease (CHD) is one of the most common types of organ lesions caused by atherosclerosis, in which CD4+CD25+forkhead box protein 3 (FoxP3+) regulatory T cells (Treg) play an atheroprotective role. However, Treg cell numbers are decreased and their functions are impaired in atherosclerosis; the underlying mechanisms remain unclear. CD31 plays an important part in T cell response and contributes to maintaining T cell tolerance. The immunomodulatory effects of CD31 are also implicated in atherosclerosis. In this study, we found that decreased frequencies of the CD31+ subpopulation in Treg cells (CD31+Tr cells) correlated positively with decreased FoxP3 expression in CHD patients. Cell culture in vitro demonstrated CD31+Tr cells maintaining stable FoxP3 expression after activation and exhibited enhanced proliferation and immunosuppression compared with the CD31− subpopulation in Treg cells (CD31−Tr cells). We also confirmed impaired secretion of transforming growth factor (TGF)‐β1 and interleukin (IL)‐10 in CD31+Tr cells of CHD patients. Further analysis revealed reduced phospho‐SHP2 (associated with CD31 activation) and phospho‐signal transducer and activator of transcription‐5 (STAT‐5) (associated with FoxP3 transcription) levels in CD31+Tr cells of CHD patients, suggesting that decreased FoxP3 expression in CD31+Tr cells might be because of attenuated SHP2 and STAT‐5 activation. These data indicate that decreased frequencies and impaired functions of the CD31+Tr subpopulation associated with decreased FoxP3 expression give rise, at least in part, to Treg cell defects in CHD patients. Our findings emphasize the important role of the CD31+Tr subpopulation in maintaining Treg cell normal function and may provide a novel explanation for impaired immunoregulation of Treg cells in CHD.","PeriodicalId":10179,"journal":{"name":"Clinical & Experimental Immunology","volume":"26 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2017-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"73977015","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}
Mingming Sun, Chong He, Wei Wu, Guangxi Zhou, Fenghua Liu, Y. Cong, Zhanju Liu
Intestinal epithelial cells (IECs), an important barrier to gut microbiota, are subject to low oxygen tension, particularly during intestinal inflammation. Hypoxia inducible factor‐1α (HIF‐1α) is expressed highly in the inflamed mucosa of inflammatory bowel disease (IBD) and functions as a key regulator in maintenance of intestinal homeostasis. However, how IEC‐derived HIF‐1α regulates intestinal immune responses in IBD is still not understood completely. We report here that the expression of HIF‐1α and IL‐33 was increased significantly in the inflamed mucosa of IBD patients as well as mice with colitis induced by dextran sulphate sodium (DSS). The levels of interleukin (IL)−33 were correlated positively with that of HIF‐1α. A HIF‐1α‐interacting element was identified in the promoter region of IL‐33, indicating that HIF‐1α activity regulates IL‐33 expression. Furthermore, tumour necrosis factor (TNF) facilitated the HIF‐1α‐dependent IL‐33 expression in IEC. Our data thus demonstrate that HIF‐1α‐dependent IL‐33 in IEC functions as a regulatory cytokine in inflamed mucosa of IBD, thereby regulating the intestinal inflammation and maintaining mucosal homeostasis.
{"title":"Hypoxia inducible factor‐1α‐induced interleukin‐33 expression in intestinal epithelia contributes to mucosal homeostasis in inflammatory bowel disease","authors":"Mingming Sun, Chong He, Wei Wu, Guangxi Zhou, Fenghua Liu, Y. Cong, Zhanju Liu","doi":"10.1111/cei.12896","DOIUrl":"https://doi.org/10.1111/cei.12896","url":null,"abstract":"Intestinal epithelial cells (IECs), an important barrier to gut microbiota, are subject to low oxygen tension, particularly during intestinal inflammation. Hypoxia inducible factor‐1α (HIF‐1α) is expressed highly in the inflamed mucosa of inflammatory bowel disease (IBD) and functions as a key regulator in maintenance of intestinal homeostasis. However, how IEC‐derived HIF‐1α regulates intestinal immune responses in IBD is still not understood completely. We report here that the expression of HIF‐1α and IL‐33 was increased significantly in the inflamed mucosa of IBD patients as well as mice with colitis induced by dextran sulphate sodium (DSS). The levels of interleukin (IL)−33 were correlated positively with that of HIF‐1α. A HIF‐1α‐interacting element was identified in the promoter region of IL‐33, indicating that HIF‐1α activity regulates IL‐33 expression. Furthermore, tumour necrosis factor (TNF) facilitated the HIF‐1α‐dependent IL‐33 expression in IEC. Our data thus demonstrate that HIF‐1α‐dependent IL‐33 in IEC functions as a regulatory cytokine in inflamed mucosa of IBD, thereby regulating the intestinal inflammation and maintaining mucosal homeostasis.","PeriodicalId":10179,"journal":{"name":"Clinical & Experimental Immunology","volume":"60 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2017-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"85865396","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}
H. Jaïdane, Aymen Halouani, H. Jmii, F. Elmastour, S. Abdelkefi, Gwennaëlle Bodart, H. Michaux, T. Chakroun, F. Sane, M. Mokni, V. Geenen, D. Hober, M. Aouni
Type B coxsackievirus (CV‐B) infections are involved frequently in the triggering of several autoimmune diseases such as myocarditis, dilated cardiomyopathy, pericarditis, pancreatitis, type 1 diabetes, encephalitis, thyroiditis or Sjögren's syndrome. Serological and virological evidence suggests that maternal infections during pregnancy can play a role in the appearance of these diseases in offspring. The current study aims to explore the effect of an in‐utero CV‐B infection on the fetal thymus, the central site for programming immunological self‐tolerance. In this perspective, female Swiss albino mice were inoculated intraperitoneally or orally with the diabetogenic CV‐B4 E2 strain at gestational days 10 or 17. Offspring were killed at different post‐inoculation times, and their thymuses were analysed for evidence of infection and alterations in thymic T cell subsets. In‐utero CV‐B infection of the thymus was demonstrated during the course of vertical transmission, as attested by viral RNA and infectious virus detection in most analysed samples. No histopathological changes were evident. Thymic T cells were not depleted, despite being positive for viral RNA. As evidenced by flow cytometry analysis, CV‐B infection of the fetal thymus induced significant changes of thymic T cell populations, particularly with maternal inoculation at gestational day 10. Altogether, these findings suggest that CV‐B infection of the fetal thymus may play an important role in the genesis of autoimmune diseases.
{"title":"In‐utero coxsackievirus B4 infection of the mouse thymus","authors":"H. Jaïdane, Aymen Halouani, H. Jmii, F. Elmastour, S. Abdelkefi, Gwennaëlle Bodart, H. Michaux, T. Chakroun, F. Sane, M. Mokni, V. Geenen, D. Hober, M. Aouni","doi":"10.1111/cei.12893","DOIUrl":"https://doi.org/10.1111/cei.12893","url":null,"abstract":"Type B coxsackievirus (CV‐B) infections are involved frequently in the triggering of several autoimmune diseases such as myocarditis, dilated cardiomyopathy, pericarditis, pancreatitis, type 1 diabetes, encephalitis, thyroiditis or Sjögren's syndrome. Serological and virological evidence suggests that maternal infections during pregnancy can play a role in the appearance of these diseases in offspring. The current study aims to explore the effect of an in‐utero CV‐B infection on the fetal thymus, the central site for programming immunological self‐tolerance. In this perspective, female Swiss albino mice were inoculated intraperitoneally or orally with the diabetogenic CV‐B4 E2 strain at gestational days 10 or 17. Offspring were killed at different post‐inoculation times, and their thymuses were analysed for evidence of infection and alterations in thymic T cell subsets. In‐utero CV‐B infection of the thymus was demonstrated during the course of vertical transmission, as attested by viral RNA and infectious virus detection in most analysed samples. No histopathological changes were evident. Thymic T cells were not depleted, despite being positive for viral RNA. As evidenced by flow cytometry analysis, CV‐B infection of the fetal thymus induced significant changes of thymic T cell populations, particularly with maternal inoculation at gestational day 10. Altogether, these findings suggest that CV‐B infection of the fetal thymus may play an important role in the genesis of autoimmune diseases.","PeriodicalId":10179,"journal":{"name":"Clinical & Experimental Immunology","volume":"13 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2017-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"89387031","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}
G. L. V. D. Oliveira, A. F. Ferreira, Elainy Patrícia Lino Gasparotto, Simone Kashima, D. Covas, C. T. Guerreiro, D. Brum, A. A. Barreira, J. Voltarelli, B. Simões, M. C. Oliveira, F. A. D. Castro, K. Malmegrim
Defective apoptosis might be involved in the pathogenesis of multiple sclerosis (MS). We evaluated apoptosis‐related molecules in MS patients before and after autologous haematopoietic stem cell transplantation (AHSCT) using BCNU, Etoposide, AraC and Melphalan (BEAM) or cyclophosphamide (CY)‐based conditioning regimens. Patients were followed for clinical and immunological parameters for 2 years after AHSCT. At baseline, MS patients had decreased proapoptotic BAD, BAX and FASL and increased A1 gene expression when compared with healthy counterparts. In the BEAM group, BAK, BIK, BIMEL, FAS, FASL, A1, BCL2, BCLXL, CFLIPL and CIAP2 genes were up‐regulated after AHSCT. With the exception of BIK, BIMEL and A1, all genes reached levels similar to controls at day + 720 post‐transplantation. Furthermore, in these patients, we observed increased CD8+ Fas+ T cell frequencies after AHSCT when compared to baseline. In the CY group, we observed increased BAX, BCLW, CFLIPL and CIAP1 and decreased BIK and BID gene expressions after transplantation. At day + 720 post‐AHSCT, the expression of BAX, FAS, FASL, BCL2, BCLXL and CIAP1 was similar to that of controls. Protein analyses showed increased Bcl‐2 expression before transplantation. At 1 year post‐AHSCT, expression of Bak, Bim, Bcl‐2, Bcl‐xL and cFlip‐L was decreased when compared to baseline values. In summary, our findings suggest that normalization of apoptosis‐related molecules is associated with the early therapeutic effects of AHSCT in MS patients. These mechanisms may be involved in the re‐establishment of immune tolerance during the first 2 years post‐transplantation.
{"title":"Defective expression of apoptosis‐related molecules in multiple sclerosis patients is normalized early after autologous haematopoietic stem cell transplantation","authors":"G. L. V. D. Oliveira, A. F. Ferreira, Elainy Patrícia Lino Gasparotto, Simone Kashima, D. Covas, C. T. Guerreiro, D. Brum, A. A. Barreira, J. Voltarelli, B. Simões, M. C. Oliveira, F. A. D. Castro, K. Malmegrim","doi":"10.1111/cei.12895","DOIUrl":"https://doi.org/10.1111/cei.12895","url":null,"abstract":"Defective apoptosis might be involved in the pathogenesis of multiple sclerosis (MS). We evaluated apoptosis‐related molecules in MS patients before and after autologous haematopoietic stem cell transplantation (AHSCT) using BCNU, Etoposide, AraC and Melphalan (BEAM) or cyclophosphamide (CY)‐based conditioning regimens. Patients were followed for clinical and immunological parameters for 2 years after AHSCT. At baseline, MS patients had decreased proapoptotic BAD, BAX and FASL and increased A1 gene expression when compared with healthy counterparts. In the BEAM group, BAK, BIK, BIMEL, FAS, FASL, A1, BCL2, BCLXL, CFLIPL and CIAP2 genes were up‐regulated after AHSCT. With the exception of BIK, BIMEL and A1, all genes reached levels similar to controls at day + 720 post‐transplantation. Furthermore, in these patients, we observed increased CD8+ Fas+ T cell frequencies after AHSCT when compared to baseline. In the CY group, we observed increased BAX, BCLW, CFLIPL and CIAP1 and decreased BIK and BID gene expressions after transplantation. At day + 720 post‐AHSCT, the expression of BAX, FAS, FASL, BCL2, BCLXL and CIAP1 was similar to that of controls. Protein analyses showed increased Bcl‐2 expression before transplantation. At 1 year post‐AHSCT, expression of Bak, Bim, Bcl‐2, Bcl‐xL and cFlip‐L was decreased when compared to baseline values. In summary, our findings suggest that normalization of apoptosis‐related molecules is associated with the early therapeutic effects of AHSCT in MS patients. These mechanisms may be involved in the re‐establishment of immune tolerance during the first 2 years post‐transplantation.","PeriodicalId":10179,"journal":{"name":"Clinical & Experimental Immunology","volume":"225 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2017-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"72866839","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}
Pooja Arora, M. Malik, R. Sachdeva, Latika Saxena, Joy Das, Vishnampettai G. Ramachandran, Rahul Pal
While apoptotic debris is believed to constitute the original antigenic insult in lupus (which is characterized by a time‐dependent diversification of autoreactivity), whether such debris and autoantibodies specifically recognizing its constituents mediate differential effects on innate and humoral responses in lupus‐prone mice is currently unknown. Apoptotic blebs (as opposed to cellular lysate) enhanced preferentially the maturation of dendritic cells (DCs) from bone marrow precursors drawn from lupus‐prone mice. Murine, somatically mutated, apoptotic cell‐reactive immunoglobulin (Ig)G monoclonal antibodies demonstrated enhanced recognition of DCs and also displayed a prominent lupus strain‐specific bias in mediating DC maturation. Further, immunization of such antibodies specifically in lupus‐prone mice resulted in widespread humoral autoreactivity; hypergammaglobulinaemia (a hallmark of systemic autoimmunity) was observed, accompanied by enhanced antibody titres to cellular moieties. Induced antibodies recognized antigens distinct from those recognized by the antibodies employed for immunization; in particular, nephritis‐associated anti‐double stranded (ds) DNA antibodies and neonatal lupus‐associated anti‐Ro60 antibodies were elicited by a non‐dsDNA, non‐Ro60 reactive antibody, and Sm was a favoured target. Further, only in lupus‐prone mice did such immunization enhance the kinetics of humoral anti‐self responses, resulting in the advanced onset of glomerulosclerosis. These studies reveal that preferential innate and humoral recognition of the products of cell death in a lupus milieu influence the indices associated with autoimmune pathology.
{"title":"Innate and humoral recognition of the products of cell death: differential antigenicity and immunogenicity in lupus","authors":"Pooja Arora, M. Malik, R. Sachdeva, Latika Saxena, Joy Das, Vishnampettai G. Ramachandran, Rahul Pal","doi":"10.1111/cei.12889","DOIUrl":"https://doi.org/10.1111/cei.12889","url":null,"abstract":"While apoptotic debris is believed to constitute the original antigenic insult in lupus (which is characterized by a time‐dependent diversification of autoreactivity), whether such debris and autoantibodies specifically recognizing its constituents mediate differential effects on innate and humoral responses in lupus‐prone mice is currently unknown. Apoptotic blebs (as opposed to cellular lysate) enhanced preferentially the maturation of dendritic cells (DCs) from bone marrow precursors drawn from lupus‐prone mice. Murine, somatically mutated, apoptotic cell‐reactive immunoglobulin (Ig)G monoclonal antibodies demonstrated enhanced recognition of DCs and also displayed a prominent lupus strain‐specific bias in mediating DC maturation. Further, immunization of such antibodies specifically in lupus‐prone mice resulted in widespread humoral autoreactivity; hypergammaglobulinaemia (a hallmark of systemic autoimmunity) was observed, accompanied by enhanced antibody titres to cellular moieties. Induced antibodies recognized antigens distinct from those recognized by the antibodies employed for immunization; in particular, nephritis‐associated anti‐double stranded (ds) DNA antibodies and neonatal lupus‐associated anti‐Ro60 antibodies were elicited by a non‐dsDNA, non‐Ro60 reactive antibody, and Sm was a favoured target. Further, only in lupus‐prone mice did such immunization enhance the kinetics of humoral anti‐self responses, resulting in the advanced onset of glomerulosclerosis. These studies reveal that preferential innate and humoral recognition of the products of cell death in a lupus milieu influence the indices associated with autoimmune pathology.","PeriodicalId":10179,"journal":{"name":"Clinical & Experimental Immunology","volume":"17 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2017-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"74309726","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}
Ageing of the innate and adaptive immune system, collectively termed immune senescence, is a complex process. One method to understand the components of ageing involves dissociating the effects of ageing on the cells of the immune system, on the microenvironment in lymphoid organs and tissues where immune cells reside and on the circulating factors that interact with both immune cells and their microenvironment. Heterochronic parabiosis, a surgical union of two organisms of disparate ages, is ideal for this type of study, as it has the power to dissociate the age of the cell and the age of the microenvironment into which the cell resides or is migrating. So far, however, it has been used sparingly to study immune ageing. Here we review the limited literature on homeostatic innate immune cell trafficking in ageing in the absence of chronic inflammation. We also review our own recent data on trafficking of innate immune subsets between primary and secondary lymphoid organs in heterochronic parabiosis. We found no systemic bias in retention or acceptance of neutrophils, macrophages, dendritic cells or natural killer cells with ageing in primary and secondary lymphoid organs. We conclude that these four innate immune cell types migrate to and populate lymphoid organs (peripheral lymph nodes, spleen and bone marrow), regardless of their own age and of the age of lymphoid organs.
{"title":"Homeostatic migration and distribution of innate immune cells in primary and secondary lymphoid organs with ageing","authors":"J. Nikolich-Žugich, John Davies","doi":"10.1111/cei.12920","DOIUrl":"https://doi.org/10.1111/cei.12920","url":null,"abstract":"Ageing of the innate and adaptive immune system, collectively termed immune senescence, is a complex process. One method to understand the components of ageing involves dissociating the effects of ageing on the cells of the immune system, on the microenvironment in lymphoid organs and tissues where immune cells reside and on the circulating factors that interact with both immune cells and their microenvironment. Heterochronic parabiosis, a surgical union of two organisms of disparate ages, is ideal for this type of study, as it has the power to dissociate the age of the cell and the age of the microenvironment into which the cell resides or is migrating. So far, however, it has been used sparingly to study immune ageing. Here we review the limited literature on homeostatic innate immune cell trafficking in ageing in the absence of chronic inflammation. We also review our own recent data on trafficking of innate immune subsets between primary and secondary lymphoid organs in heterochronic parabiosis. We found no systemic bias in retention or acceptance of neutrophils, macrophages, dendritic cells or natural killer cells with ageing in primary and secondary lymphoid organs. We conclude that these four innate immune cell types migrate to and populate lymphoid organs (peripheral lymph nodes, spleen and bone marrow), regardless of their own age and of the age of lymphoid organs.","PeriodicalId":10179,"journal":{"name":"Clinical & Experimental Immunology","volume":"25 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2017-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"91186822","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}
E. Storjord, J. A. Dahl, A. Landsem, H. Fure, J. Ludviksen, S. Goldbeck-Wood, B. Karlsen, K. Berg, T. Mollnes, E. W Nielsen, O. Brekke
This study aimed to examine whether acute intermittent porphyria (AIP) is associated with systemic inflammation and whether the inflammation correlates with disease activity. A case–control study with 50 AIP cases and age‐, sex‐ and place of residence‐matched controls was performed. Plasma cytokines, insulin and C‐peptide were analysed after an overnight fast using multiplex assay. Long pentraxin‐3 (PTX3) and complement activation products (C3bc and TCC) were analysed using enzyme‐linked immunosorbent assay (ELISA). Urine porphobilinogen ratio (U‐PBG, µmol/mmol creatinine), haematological and biochemical tests were performed using routine methods. Questionnaires were used to register AIP symptoms, medication and other diseases. All 27 cytokines, chemokines and growth factors investigated were increased significantly in symptomatic AIP cases compared with controls (P < 0·0004). Hierarchical cluster analyses revealed a cluster with high visfatin levels and several highly expressed cytokines including interleukin (IL)‐17, suggesting a T helper type 17 (Th17) inflammatory response in a group of AIP cases. C3bc (P = 0·002) and serum immunoglobulin (Ig)G levels (P = 0·03) were increased significantly in cases with AIP. The U‐PBG ratio correlated positively with PTX3 (r = 0·38, P = 0·006), and with terminal complement complex (TCC) levels (r = 0·33, P = 0·02). PTX3 was a significant predictor of the biochemical disease activity marker U‐PBG in AIP cases after adjustment for potential confounders in multiple linear regression analyses (P = 0·032). Prealbumin, C‐peptide, insulin and kidney function were all decreased in the symptomatic AIP cases, but not in the asymptomatic cases. These results indicate that AIP is associated with systemic inflammation. Decreased C‐peptide levels in symptomatic AIP cases indicate that reduced insulin release is associated with enhanced disease activity and reduced kidney function.
{"title":"Systemic inflammation in acute intermittent porphyria: a case–control study","authors":"E. Storjord, J. A. Dahl, A. Landsem, H. Fure, J. Ludviksen, S. Goldbeck-Wood, B. Karlsen, K. Berg, T. Mollnes, E. W Nielsen, O. Brekke","doi":"10.1111/cei.12899","DOIUrl":"https://doi.org/10.1111/cei.12899","url":null,"abstract":"This study aimed to examine whether acute intermittent porphyria (AIP) is associated with systemic inflammation and whether the inflammation correlates with disease activity. A case–control study with 50 AIP cases and age‐, sex‐ and place of residence‐matched controls was performed. Plasma cytokines, insulin and C‐peptide were analysed after an overnight fast using multiplex assay. Long pentraxin‐3 (PTX3) and complement activation products (C3bc and TCC) were analysed using enzyme‐linked immunosorbent assay (ELISA). Urine porphobilinogen ratio (U‐PBG, µmol/mmol creatinine), haematological and biochemical tests were performed using routine methods. Questionnaires were used to register AIP symptoms, medication and other diseases. All 27 cytokines, chemokines and growth factors investigated were increased significantly in symptomatic AIP cases compared with controls (P < 0·0004). Hierarchical cluster analyses revealed a cluster with high visfatin levels and several highly expressed cytokines including interleukin (IL)‐17, suggesting a T helper type 17 (Th17) inflammatory response in a group of AIP cases. C3bc (P = 0·002) and serum immunoglobulin (Ig)G levels (P = 0·03) were increased significantly in cases with AIP. The U‐PBG ratio correlated positively with PTX3 (r = 0·38, P = 0·006), and with terminal complement complex (TCC) levels (r = 0·33, P = 0·02). PTX3 was a significant predictor of the biochemical disease activity marker U‐PBG in AIP cases after adjustment for potential confounders in multiple linear regression analyses (P = 0·032). Prealbumin, C‐peptide, insulin and kidney function were all decreased in the symptomatic AIP cases, but not in the asymptomatic cases. These results indicate that AIP is associated with systemic inflammation. Decreased C‐peptide levels in symptomatic AIP cases indicate that reduced insulin release is associated with enhanced disease activity and reduced kidney function.","PeriodicalId":10179,"journal":{"name":"Clinical & Experimental Immunology","volume":"14 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2017-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"81742127","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. Aggarwal, A. N. Sarangi, P. Gaur, Anuj Shukla, R. Aggarwal
In Asia, enthesitis‐related arthritis (ERA) is the most frequent category of juvenile idiopathic arthritis. ERA has a strong association with human leucocyte antigen (HLA)‐B27 and subclinical gut inflammation. In an HLA‐B27 transgenic rat model, the presence of Bacteroides bacteria in the gut appears to cause spondyloarthropathy (SpA). Thus, we studied gut microbiota in children with ERA. Stool specimens from 33 patients with ERA and 14 age‐matched healthy controls were studied; none had any gastrointestinal symptom, or had received a drug known to affect gut motility or microbiota in the preceding 6 weeks. From each specimen, a cDNA library for the V3 region of bacterial 16S rRNA was subjected to high‐throughput, massively parallel sequencing. Relationship of the specimens was studied using principal co‐ordinate analysis (PCoA), and abundances of various bacterial taxa and alpha diversity were compared between groups. In eight patients, a repeat faecal specimen was studied after 12 weeks of probiotic therapy. The 55 specimens yielded a median (range) of 397 315 (102 093–1 502 380) high‐quality reads each. In PCoA, gut microbiota from ERA showed a wider dispersion than those from controls. In patients, families Bacteroidaceae and Enterobacteriaceae were more abundant and Prevotellaceae were less abundant than in controls. Also, genera Bacteroides, Entercoccus and Klebsiella were over‐represented and genus Prevotella was under‐represented in ERA patients. Probiotic therapy led to a non‐significant increase in Prevotellaceae. Patients with ERA have a dysbiosis in the gut, with increased abundance of Bacteroides and reduction of Prevotella. Probiotic supplementation in a subset of patients did not reverse these changes significantly.
{"title":"Gut microbiome in children with enthesitis‐related arthritis in a developing country and the effect of probiotic administration","authors":"A. Aggarwal, A. N. Sarangi, P. Gaur, Anuj Shukla, R. Aggarwal","doi":"10.1111/cei.12900","DOIUrl":"https://doi.org/10.1111/cei.12900","url":null,"abstract":"In Asia, enthesitis‐related arthritis (ERA) is the most frequent category of juvenile idiopathic arthritis. ERA has a strong association with human leucocyte antigen (HLA)‐B27 and subclinical gut inflammation. In an HLA‐B27 transgenic rat model, the presence of Bacteroides bacteria in the gut appears to cause spondyloarthropathy (SpA). Thus, we studied gut microbiota in children with ERA. Stool specimens from 33 patients with ERA and 14 age‐matched healthy controls were studied; none had any gastrointestinal symptom, or had received a drug known to affect gut motility or microbiota in the preceding 6 weeks. From each specimen, a cDNA library for the V3 region of bacterial 16S rRNA was subjected to high‐throughput, massively parallel sequencing. Relationship of the specimens was studied using principal co‐ordinate analysis (PCoA), and abundances of various bacterial taxa and alpha diversity were compared between groups. In eight patients, a repeat faecal specimen was studied after 12 weeks of probiotic therapy. The 55 specimens yielded a median (range) of 397 315 (102 093–1 502 380) high‐quality reads each. In PCoA, gut microbiota from ERA showed a wider dispersion than those from controls. In patients, families Bacteroidaceae and Enterobacteriaceae were more abundant and Prevotellaceae were less abundant than in controls. Also, genera Bacteroides, Entercoccus and Klebsiella were over‐represented and genus Prevotella was under‐represented in ERA patients. Probiotic therapy led to a non‐significant increase in Prevotellaceae. Patients with ERA have a dysbiosis in the gut, with increased abundance of Bacteroides and reduction of Prevotella. Probiotic supplementation in a subset of patients did not reverse these changes significantly.","PeriodicalId":10179,"journal":{"name":"Clinical & Experimental Immunology","volume":"1 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2017-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"89812419","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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