O. Negm, B. MacKenzie, Mohamed R. Hamed, O.A.J. Ahmad, C. Shone, David Paul Humphreys, K. Acharya, Christine E. Loscher, I. Marszalowska, M. Lynch, Mark Wilcox, Tanya Monaghan
The prevalence of serum antibodies against Clostridium difficile (CD) toxins A and B in healthy populations have prompted interest in evaluating the therapeutic activity of intravenous immunoglobulin (IVIg) in individuals experiencing severe or recurrent C. difficile infection (CDI). Despite some promising case reports, a definitive clinical role for IVIg in CDI remains unclear. Contradictory results may be attributed to a lack of consensus regarding optimal dose, timing of administration and patient selection as well as variability in specific antibody content between commercial preparations. The purpose of this study was to investigate retrospectively the efficacy of three commercial preparations of IVIg for treating severe or recurrent CDI. In subsequent mechanistic studies using protein microarray and toxin neutralization assays, all IVIg preparations were analysed for specific binding and neutralizing antibodies (NAb) to CD antigens in vitro and the presence of anti‐toxin NAbs in vivo following IVIg infusion. A therapeutic response to IVIg was observed in 41% (10 of 17) of the CDI patients. Significant variability in multi‐isotype specific antibodies to a 7‐plex panel of CD antigens and toxin neutralization efficacies were observed between IVIg preparations and also in patient sera before and after IVIg administration. These results extend our current understanding of population immunity to CD and support the inclusion of surface layer proteins and binary toxin antigens in CD vaccines. Future strategies could enhance IVIg treatment response rates by using protein microarray to preselect donor plasma/serum with the highest levels of anti‐CD antibodies and/or anti‐toxin neutralizing capacities prior to fractionation.
{"title":"Protective antibodies against Clostridium difficile are present in intravenous immunoglobulin and are retained in humans following its administration","authors":"O. Negm, B. MacKenzie, Mohamed R. Hamed, O.A.J. Ahmad, C. Shone, David Paul Humphreys, K. Acharya, Christine E. Loscher, I. Marszalowska, M. Lynch, Mark Wilcox, Tanya Monaghan","doi":"10.1111/cei.12946","DOIUrl":"https://doi.org/10.1111/cei.12946","url":null,"abstract":"The prevalence of serum antibodies against Clostridium difficile (CD) toxins A and B in healthy populations have prompted interest in evaluating the therapeutic activity of intravenous immunoglobulin (IVIg) in individuals experiencing severe or recurrent C. difficile infection (CDI). Despite some promising case reports, a definitive clinical role for IVIg in CDI remains unclear. Contradictory results may be attributed to a lack of consensus regarding optimal dose, timing of administration and patient selection as well as variability in specific antibody content between commercial preparations. The purpose of this study was to investigate retrospectively the efficacy of three commercial preparations of IVIg for treating severe or recurrent CDI. In subsequent mechanistic studies using protein microarray and toxin neutralization assays, all IVIg preparations were analysed for specific binding and neutralizing antibodies (NAb) to CD antigens in vitro and the presence of anti‐toxin NAbs in vivo following IVIg infusion. A therapeutic response to IVIg was observed in 41% (10 of 17) of the CDI patients. Significant variability in multi‐isotype specific antibodies to a 7‐plex panel of CD antigens and toxin neutralization efficacies were observed between IVIg preparations and also in patient sera before and after IVIg administration. These results extend our current understanding of population immunity to CD and support the inclusion of surface layer proteins and binary toxin antigens in CD vaccines. Future strategies could enhance IVIg treatment response rates by using protein microarray to preselect donor plasma/serum with the highest levels of anti‐CD antibodies and/or anti‐toxin neutralizing capacities prior to fractionation.","PeriodicalId":10179,"journal":{"name":"Clinical & Experimental Immunology","volume":"22 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2017-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"85545471","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}
Yan Du, Xinyu Wu, Mo Chen, Wenwen Wang, Weihong Xv, Lv Ye, Di Wu, Jing Xue, Wenjia Sun, Judong Luo, Huaxiang Wu
Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by extensive immune response, including over‐activation of T and B cell development of pathogenic autoantibodies, organ damage induced by the formation and deposition of immune complex and the abnormal elevation of type I interferon. Semaphorin5A (Sema5A) is involved essentially in immune cell regulation and is also implicated in the pathogenesis of autoimmune disorders. We aimed to evaluate the role of Sema5A in patients with SLE. Serum levels of Sema5A were tested by enzyme‐linked immunosorbent assay (ELISA) in 152 SLE patients and 48 healthy controls. The message ribonucleic acid (mRNA) expression levels of Sema5A and ADAM metallopeptidase domain 17 (ADAM17) in the peripheral blood mononuclear cells (PBMC) from 43 patients with SLE and 19 healthy controls were detected by the real‐time–quantitative polymerase chain reaction (qPCR). Serum Sema5A levels were increased significantly in SLE patients compared with healthy controls (P < 0·001). Elevated levels of Sema5A were correlated positively with 24‐h proteinuria excretion (r = 0·558, P < 0·0001), SLE disease activity index (SLEDAI) (r = 0·278, P = 0·0006) and C‐reactive protein (CRP) (r = 0·266, P = 0·002), but negatively with planet (PLT) (r = –0·294, P = 0·0003) and complement 3 (C3) (r = –0·287, P = 0·0004) in SLE patients. Patients with elevated Sema5A levels showed higher incidence of rash, serositis and nephritis (P < 0·05 or P < 0·001). Patients with decreased PLT, C3 or positive for proteinuria also showed elevated Sema5A (P < 0·001 or P < 0·05). The mRNA ADAM17 was increased in SLE patients and correlated positively with serum Sema5A levels. Our data demonstrated that elevated serum Sema5A in SLE patients correlated with disease activity and are involved in kidney and blood system damage; ADAM17 might be involved in the release of secreted Sema5A.
系统性红斑狼疮(SLE)是一种以广泛的免疫反应为特征的自身免疫性疾病，包括致病性自身抗体的T和B细胞过度活化、免疫复合物的形成和沉积引起的器官损伤以及I型干扰素的异常升高。信号蛋白5a (Sema5A)主要参与免疫细胞调节，也涉及自身免疫性疾病的发病机制。我们旨在评估Sema5A在SLE患者中的作用。采用酶联免疫吸附试验(ELISA)检测了152例SLE患者和48例健康对照者的血清Sema5A水平。采用实时定量聚合酶链式反应(qPCR)检测了43例SLE患者和19例健康对照者外周血单个核细胞(PBMC)中Sema5A和ADAM金属肽酶结构域17 (ADAM17)信息核糖核酸(mRNA)表达水平。SLE患者血清Sema5A水平明显高于健康对照组(P < 0.001)。Sema5A水平升高与SLE患者24小时蛋白尿排泄(r = 0.558, P < 0.0001)、SLE疾病活动性指数(SLEDAI) (r = 0.278, P = 0.0006)、C反应蛋白(CRP) (r = 0.266, P = 0.002)呈正相关，与行星(PLT) (r = - 0.294, P = 0.0003)、补体3 (C3) (r = - 0.287, P = 0.0004)呈负相关。Sema5A水平升高的患者皮疹、浆液炎和肾炎的发生率较高(P < 0.05或P < 0.001)。PLT、C3降低或蛋白尿阳性患者的Sema5A水平升高(P < 0.001或P < 0.05)。mRNA ADAM17在SLE患者中升高，且与血清Sema5A水平呈正相关。我们的数据表明，SLE患者血清Sema5A升高与疾病活动性相关，并参与肾脏和血液系统损伤;ADAM17可能参与分泌的Sema5A的释放。
{"title":"Elevated semaphorin5A in systemic lupus erythematosus is in association with disease activity and lupus nephritis","authors":"Yan Du, Xinyu Wu, Mo Chen, Wenwen Wang, Weihong Xv, Lv Ye, Di Wu, Jing Xue, Wenjia Sun, Judong Luo, Huaxiang Wu","doi":"10.1111/cei.12924","DOIUrl":"https://doi.org/10.1111/cei.12924","url":null,"abstract":"Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by extensive immune response, including over‐activation of T and B cell development of pathogenic autoantibodies, organ damage induced by the formation and deposition of immune complex and the abnormal elevation of type I interferon. Semaphorin5A (Sema5A) is involved essentially in immune cell regulation and is also implicated in the pathogenesis of autoimmune disorders. We aimed to evaluate the role of Sema5A in patients with SLE. Serum levels of Sema5A were tested by enzyme‐linked immunosorbent assay (ELISA) in 152 SLE patients and 48 healthy controls. The message ribonucleic acid (mRNA) expression levels of Sema5A and ADAM metallopeptidase domain 17 (ADAM17) in the peripheral blood mononuclear cells (PBMC) from 43 patients with SLE and 19 healthy controls were detected by the real‐time–quantitative polymerase chain reaction (qPCR). Serum Sema5A levels were increased significantly in SLE patients compared with healthy controls (P < 0·001). Elevated levels of Sema5A were correlated positively with 24‐h proteinuria excretion (r = 0·558, P < 0·0001), SLE disease activity index (SLEDAI) (r = 0·278, P = 0·0006) and C‐reactive protein (CRP) (r = 0·266, P = 0·002), but negatively with planet (PLT) (r = –0·294, P = 0·0003) and complement 3 (C3) (r = –0·287, P = 0·0004) in SLE patients. Patients with elevated Sema5A levels showed higher incidence of rash, serositis and nephritis (P < 0·05 or P < 0·001). Patients with decreased PLT, C3 or positive for proteinuria also showed elevated Sema5A (P < 0·001 or P < 0·05). The mRNA ADAM17 was increased in SLE patients and correlated positively with serum Sema5A levels. Our data demonstrated that elevated serum Sema5A in SLE patients correlated with disease activity and are involved in kidney and blood system damage; ADAM17 might be involved in the release of secreted Sema5A.","PeriodicalId":10179,"journal":{"name":"Clinical & Experimental Immunology","volume":"68 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2017-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"87166504","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}
B. Dedeoglu, A. D. Weerd, Ling Huang, A. Langerak, Frank J. M. F. Dor, M. Klepper, W. Verschoor, Derek Reijerkerk, C. Baan, N. H. Litjens, M. Betjes
Ageing is associated with changes in the peripheral T cell immune system, which can be influenced significantly by latent cytomegalovirus (CMV) infection. To what extent changes in circulating T cell populations correlate with T cell composition of the lymph node (LN) is unclear, but is crucial for a comprehensive understanding of the T cell system. T cells from peripheral blood (PB) and LN of end‐stage renal disease patients were analysed for frequency of recent thymic emigrants using CD31 expression and T cell receptor excision circle content, relative telomere length and expression of differentiation markers. Compared with PB, LN contained relatively more CD4+ than CD8+ T cells (P < 0·001). The percentage of naive and central memory CD4+ and CD8+ T cells and thymic output parameters showed a strong linear correlation between PB and LN. Highly differentiated CD28null T cells, being CD27–, CD57+ or programmed death 1 (PD‐1+), were found almost exclusively in the circulation but not in LN. An age‐related decline in naive CD4+ and CD8+ T cell frequency was observed (P = 0·035 and P = 0·002, respectively) within LN, concomitant with an increase in central memory CD8+ T cells (P = 0·033). Latent CMV infection increased dramatically the frequency of circulating terminally differentiated T cells, but did not alter T cell composition and ageing parameters of LN significantly. Overall T cell composition and measures of thymic function in PB and LN are correlated strongly. However, highly differentiated CD28null T cells, which may comprise a large part of circulating T cells in CMV‐seropositive individuals, are found almost exclusively within the circulation.
{"title":"Lymph node and circulating T cell characteristics are strongly correlated in end‐stage renal disease patients, but highly differentiated T cells reside within the circulation","authors":"B. Dedeoglu, A. D. Weerd, Ling Huang, A. Langerak, Frank J. M. F. Dor, M. Klepper, W. Verschoor, Derek Reijerkerk, C. Baan, N. H. Litjens, M. Betjes","doi":"10.1111/cei.12934","DOIUrl":"https://doi.org/10.1111/cei.12934","url":null,"abstract":"Ageing is associated with changes in the peripheral T cell immune system, which can be influenced significantly by latent cytomegalovirus (CMV) infection. To what extent changes in circulating T cell populations correlate with T cell composition of the lymph node (LN) is unclear, but is crucial for a comprehensive understanding of the T cell system. T cells from peripheral blood (PB) and LN of end‐stage renal disease patients were analysed for frequency of recent thymic emigrants using CD31 expression and T cell receptor excision circle content, relative telomere length and expression of differentiation markers. Compared with PB, LN contained relatively more CD4+ than CD8+ T cells (P < 0·001). The percentage of naive and central memory CD4+ and CD8+ T cells and thymic output parameters showed a strong linear correlation between PB and LN. Highly differentiated CD28null T cells, being CD27–, CD57+ or programmed death 1 (PD‐1+), were found almost exclusively in the circulation but not in LN. An age‐related decline in naive CD4+ and CD8+ T cell frequency was observed (P = 0·035 and P = 0·002, respectively) within LN, concomitant with an increase in central memory CD8+ T cells (P = 0·033). Latent CMV infection increased dramatically the frequency of circulating terminally differentiated T cells, but did not alter T cell composition and ageing parameters of LN significantly. Overall T cell composition and measures of thymic function in PB and LN are correlated strongly. However, highly differentiated CD28null T cells, which may comprise a large part of circulating T cells in CMV‐seropositive individuals, are found almost exclusively within the circulation.","PeriodicalId":10179,"journal":{"name":"Clinical & Experimental Immunology","volume":"396 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2017-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"79441292","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, R. Gupta, V. Negi, L. Rajasekhar, R. Misra, P. Singh, V. Chaturvedi, S. Sinha
The study was aimed at identification by proteomics and validation by enzyme‐linked immunosorbent assay (ELISA) of potential urinary biomarkers for lupus nephritis. Study subjects comprised 88 systemic lupus erythematosus (SLE) patients and 60 controls (rheumatoid arthritis, diabetes mellitus and healthy individuals). Based on the SLE disease activity index (SLEDAI), patients were classified as active renal (AR), active non‐renal (ANR) or inactive disease (ID). Urinary proteins from a group of patients with AR or ID were resolved by two‐dimensional gel electrophoresis and identified by matrix‐assisted laser desorption ionization–time of flight–mass spectrometry (MALDI‐TOF‐MS/MS). The selected biomarkers were validated by ELISA using samples from all patients and controls. AR patients were followed‐up for 12 months after start of therapy. Three urinary proteins, alpha‐1 anti‐chymotrypsin (ACT), haptoglobin (HAP) and retinol binding protein (RBP), were detected in patients with AR and not ID. Upon validation, ACT levels were higher in AR patients than the other groups (P < 0·001) and showed good correlation with renal SLEDAI (r = 0·577, P < 0·001) as well as SLEDAI (r = 0·461, P < 0·001). Similarly, HAP levels were > 10‐fold higher in AR than other groups (P < 0·001) and correlated well with renal SLEDAI (r = 0·594, P < 0·001) and SLEDAI (r = 0·371, P < 0·01). RBP levels were also higher in AR patients than in other groups (P < 0·05), except diabetes, and showed moderate correlation with renal SLEDAI (r = 0·284, P < 0·008) and SLEDAI (r = 0·316, P < 0·003). Upon follow‐up with treatment, levels of all three proteins declined at 6 and 12 months (P < 0·01). Multiple logistic regression identified ACT as the best marker to differentiate AR from ANR. Urinary HAP, ACT and RBP are potential biomarkers for lupus nephritis activity.
该研究旨在通过蛋白质组学鉴定和酶联免疫吸附试验(ELISA)验证狼疮肾炎的潜在尿液生物标志物。研究对象包括88例系统性红斑狼疮(SLE)患者和60例对照(类风湿关节炎、糖尿病和健康个体)。根据SLE疾病活动性指数(SLEDAI)，将患者分为活动性肾脏(AR)、活动性非肾脏(ANR)和非活动性疾病(ID)。采用二维凝胶电泳和基质辅助激光解吸电离飞行时间质谱法(MALDI - TOF - MS/MS)对一组AR或ID患者的尿蛋白进行了鉴定。选择的生物标志物通过ELISA对所有患者和对照组的样本进行验证。AR患者在治疗开始后随访12个月。在AR患者而非ID患者中检测到三种尿蛋白，α - 1抗凝乳胰蛋白酶(ACT)、触珠蛋白(HAP)和视黄醇结合蛋白(RBP)。经验证，AR患者的ACT水平高于其他组(P < 0.001)，且与肾脏SLEDAI (r = 0.594, P < 0.001)和SLEDAI (r = 0.371, P < 0.01)有良好的相关性。除糖尿病外，AR患者RBP水平均高于其他组(P < 0.05)，且与肾脏SLEDAI (r = 0.284, P < 0.008)和SLEDAI (r = 0.316, P < 0.003)呈中度相关。治疗后随访6个月和12个月，三种蛋白水平均下降(P < 0.01)。多元逻辑回归发现ACT是区分AR和ANR的最佳标记。尿HAP、ACT和RBP是红斑狼疮肾炎活动性的潜在生物标志物。
{"title":"Urinary haptoglobin, alpha‐1 anti‐chymotrypsin and retinol binding protein identified by proteomics as potential biomarkers for lupus nephritis","authors":"A. Aggarwal, R. Gupta, V. Negi, L. Rajasekhar, R. Misra, P. Singh, V. Chaturvedi, S. Sinha","doi":"10.1111/cei.12930","DOIUrl":"https://doi.org/10.1111/cei.12930","url":null,"abstract":"The study was aimed at identification by proteomics and validation by enzyme‐linked immunosorbent assay (ELISA) of potential urinary biomarkers for lupus nephritis. Study subjects comprised 88 systemic lupus erythematosus (SLE) patients and 60 controls (rheumatoid arthritis, diabetes mellitus and healthy individuals). Based on the SLE disease activity index (SLEDAI), patients were classified as active renal (AR), active non‐renal (ANR) or inactive disease (ID). Urinary proteins from a group of patients with AR or ID were resolved by two‐dimensional gel electrophoresis and identified by matrix‐assisted laser desorption ionization–time of flight–mass spectrometry (MALDI‐TOF‐MS/MS). The selected biomarkers were validated by ELISA using samples from all patients and controls. AR patients were followed‐up for 12 months after start of therapy. Three urinary proteins, alpha‐1 anti‐chymotrypsin (ACT), haptoglobin (HAP) and retinol binding protein (RBP), were detected in patients with AR and not ID. Upon validation, ACT levels were higher in AR patients than the other groups (P < 0·001) and showed good correlation with renal SLEDAI (r = 0·577, P < 0·001) as well as SLEDAI (r = 0·461, P < 0·001). Similarly, HAP levels were > 10‐fold higher in AR than other groups (P < 0·001) and correlated well with renal SLEDAI (r = 0·594, P < 0·001) and SLEDAI (r = 0·371, P < 0·01). RBP levels were also higher in AR patients than in other groups (P < 0·05), except diabetes, and showed moderate correlation with renal SLEDAI (r = 0·284, P < 0·008) and SLEDAI (r = 0·316, P < 0·003). Upon follow‐up with treatment, levels of all three proteins declined at 6 and 12 months (P < 0·01). Multiple logistic regression identified ACT as the best marker to differentiate AR from ANR. Urinary HAP, ACT and RBP are potential biomarkers for lupus nephritis activity.","PeriodicalId":10179,"journal":{"name":"Clinical & Experimental Immunology","volume":"1 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2017-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"72835061","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. Speake, Elizabeth Whalen, V. Gersuk, Damien Chaussabel, Jared M. Odegard, Carla J. Greenbaum
Blood transcriptional profiles could serve as biomarkers of clinical changes in subjects at‐risk for or diagnosed with diabetes. However, transcriptional variation over time is poorly understood due to the impracticality of frequent longitudinal phlebotomy in large patient cohorts. We have developed a novel transcriptome assessment method that could be applied to fingerstick blood samples self‐collected by study volunteers. Fifteen μL of blood from a fingerstick yielded sufficient RNA to analyse > 176 transcripts by high‐throughput quantitative polymerase chain reaction (PCR). We enrolled 13 subjects with type 1 diabetes and 14 controls to perform weekly collections at home for a period of 6 months. Subjects returned an average of 24 of 26 total weekly samples, and transcript data were obtained successfully for > 99% of samples returned. A high degree of correlation between fingerstick data and data from a standard 3 mL venipuncture sample was observed. Increases in interferon‐stimulated gene expression were associated with self‐reported respiratory infections, indicating that real‐world transcriptional changes can be detected using this assay. In summary, we show that longitudinal monitoring of gene expression is feasible using ultra‐low‐volume blood samples self‐collected by study participants at home, and can be used to monitor changes in gene expression frequently over extended periods.
{"title":"Longitudinal monitoring of gene expression in ultra‐low‐volume blood samples self‐collected at home","authors":"C. Speake, Elizabeth Whalen, V. Gersuk, Damien Chaussabel, Jared M. Odegard, Carla J. Greenbaum","doi":"10.1111/cei.12916","DOIUrl":"https://doi.org/10.1111/cei.12916","url":null,"abstract":"Blood transcriptional profiles could serve as biomarkers of clinical changes in subjects at‐risk for or diagnosed with diabetes. However, transcriptional variation over time is poorly understood due to the impracticality of frequent longitudinal phlebotomy in large patient cohorts. We have developed a novel transcriptome assessment method that could be applied to fingerstick blood samples self‐collected by study volunteers. Fifteen μL of blood from a fingerstick yielded sufficient RNA to analyse > 176 transcripts by high‐throughput quantitative polymerase chain reaction (PCR). We enrolled 13 subjects with type 1 diabetes and 14 controls to perform weekly collections at home for a period of 6 months. Subjects returned an average of 24 of 26 total weekly samples, and transcript data were obtained successfully for > 99% of samples returned. A high degree of correlation between fingerstick data and data from a standard 3 mL venipuncture sample was observed. Increases in interferon‐stimulated gene expression were associated with self‐reported respiratory infections, indicating that real‐world transcriptional changes can be detected using this assay. In summary, we show that longitudinal monitoring of gene expression is feasible using ultra‐low‐volume blood samples self‐collected by study participants at home, and can be used to monitor changes in gene expression frequently over extended periods.","PeriodicalId":10179,"journal":{"name":"Clinical & Experimental Immunology","volume":"393 1 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2017-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"73147088","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}
F. Verhoeven, P. Totoson, K. Maguin-Gaté, A. Prigent-Tessier, C. Marie, Daniel Wendling, J. Moretto, C. Prati, C. Demougeot
To determine the effect of glucocorticoids (GCs) on endothelial dysfunction (ED) and on traditional cardiovascular (CV) risk factors in the adjuvant‐induced arthritis (AIA) rat model. At the first signs of AIA, a high dose (HD) [10 mg/kg/day, intraperitoneally (i.p.), GC‐HD] or low dose (LD) (1 mg/kg/day, i.p., GC‐LD) of prednisolone was administered for 3 weeks. Endothelial function was studied in aortic rings relaxed with acetylcholine (Ach) with or without inhibitors of nitric oxide synthase (NOS), cyclooxygenase 2 (COX‐2), arginase, endothelium derived hyperpolarizing factor (EDHF) and superoxide anions ( O2– °) production. Aortic expression of endothelial NOS (eNOS), Ser1177‐phospho‐eNOS, COX‐2, arginase‐2, p22phox and p47phox was evaluated by Western blotting analysis. Arthritis scores, blood pressure, heart rate and blood levels of cytokines, triglycerides, cholesterol and glucose were measured. GC‐HD but not GC‐LD reduced arthritis score significantly and improved Ach‐induced relaxation (P < 0·05). The positive effect of GC‐HD resulted from increased NOS activity and EDHF production and decreased COX‐2/arginase activities and O2– ° production. These functional effects relied upon increased phospho‐eNOS expression and decreased COX‐2, arginase‐2 and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase expression. Despite the lack of effect of GC‐LD on ED, it increased NOS and EDHF and down‐regulated O2– ° pathways but did not change arginase and COX‐2 pathways. GC‐HD increased triglycerides levels and blood pressure significantly (P < 0·05). Both doses of GCs decreased to the same extent as plasma interleukin (IL)‐1β and tumour necrosis factor (TNF)‐α levels (P < 0·05). Our data demonstrated that subchronic treatment with prednisolone improved endothelial function in AIA via pleiotropic effects on endothelial pathways. These effects occurred independently of the deleterious cardiometabolic effects and the impact of prednisolone on systemic inflammation.
{"title":"Glucocorticoids improve endothelial function in rheumatoid arthritis: a study in rats with adjuvant‐induced arthritis","authors":"F. Verhoeven, P. Totoson, K. Maguin-Gaté, A. Prigent-Tessier, C. Marie, Daniel Wendling, J. Moretto, C. Prati, C. Demougeot","doi":"10.1111/cei.12938","DOIUrl":"https://doi.org/10.1111/cei.12938","url":null,"abstract":"To determine the effect of glucocorticoids (GCs) on endothelial dysfunction (ED) and on traditional cardiovascular (CV) risk factors in the adjuvant‐induced arthritis (AIA) rat model. At the first signs of AIA, a high dose (HD) [10 mg/kg/day, intraperitoneally (i.p.), GC‐HD] or low dose (LD) (1 mg/kg/day, i.p., GC‐LD) of prednisolone was administered for 3 weeks. Endothelial function was studied in aortic rings relaxed with acetylcholine (Ach) with or without inhibitors of nitric oxide synthase (NOS), cyclooxygenase 2 (COX‐2), arginase, endothelium derived hyperpolarizing factor (EDHF) and superoxide anions ( O2– °) production. Aortic expression of endothelial NOS (eNOS), Ser1177‐phospho‐eNOS, COX‐2, arginase‐2, p22phox and p47phox was evaluated by Western blotting analysis. Arthritis scores, blood pressure, heart rate and blood levels of cytokines, triglycerides, cholesterol and glucose were measured. GC‐HD but not GC‐LD reduced arthritis score significantly and improved Ach‐induced relaxation (P < 0·05). The positive effect of GC‐HD resulted from increased NOS activity and EDHF production and decreased COX‐2/arginase activities and O2– ° production. These functional effects relied upon increased phospho‐eNOS expression and decreased COX‐2, arginase‐2 and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase expression. Despite the lack of effect of GC‐LD on ED, it increased NOS and EDHF and down‐regulated O2– ° pathways but did not change arginase and COX‐2 pathways. GC‐HD increased triglycerides levels and blood pressure significantly (P < 0·05). Both doses of GCs decreased to the same extent as plasma interleukin (IL)‐1β and tumour necrosis factor (TNF)‐α levels (P < 0·05). Our data demonstrated that subchronic treatment with prednisolone improved endothelial function in AIA via pleiotropic effects on endothelial pathways. These effects occurred independently of the deleterious cardiometabolic effects and the impact of prednisolone on systemic inflammation.","PeriodicalId":10179,"journal":{"name":"Clinical & Experimental Immunology","volume":"61 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2017-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"76510760","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}
V. Willis, N. Banda, K. N. Cordova, P. Chandra, W. Robinson, D. C. Cooper, D. Lugo, G. Mehta, S. Taylor, P. Tak, R. Prinjha, H. Lewis, V. Holers
Citrullination of joint proteins by the protein arginine deiminase (PAD) family of enzymes is recognized increasingly as a key process in the pathogenesis of rheumatoid arthritis. This present study was undertaken to explore the efficacy of a novel PAD4‐selective inhibitor, GSK199, in the murine collagen‐induced arthritis model of rheumatoid arthritis. Mice were dosed daily from the time of collagen immunization with GSK199. Efficacy was assessed against a wide range of end‐points, including clinical disease scores, joint histology and immunohistochemistry, serum and joint citrulline levels and quantification of synovial autoantibodies using a proteomic array containing joint peptides. Administration of GSK199 at 30 mg/kg led to significant effects on arthritis, assessed both by global clinical disease activity and by histological analyses of synovial inflammation, pannus formation and damage to cartilage and bone. In addition, significant decreases in complement C3 deposition in both synovium and cartilage were observed robustly with GSK199 at 10 mg/kg. Neither the total levels of citrulline measurable in joint and serum, nor levels of circulating collagen antibodies, were affected significantly by treatment with GSK199 at any dose level. In contrast, a subset of serum antibodies reactive against citrullinated and non‐citrullinated joint peptides were reduced with GSK199 treatment. These data extend our previous demonstration of efficacy with the pan‐PAD inhibitor Cl‐amidine and demonstrate robustly that PAD4 inhibition alone is sufficient to block murine arthritis clinical and histopathological end‐points.
{"title":"Protein arginine deiminase 4 inhibition is sufficient for the amelioration of collagen‐induced arthritis","authors":"V. Willis, N. Banda, K. N. Cordova, P. Chandra, W. Robinson, D. C. Cooper, D. Lugo, G. Mehta, S. Taylor, P. Tak, R. Prinjha, H. Lewis, V. Holers","doi":"10.1111/cei.12932","DOIUrl":"https://doi.org/10.1111/cei.12932","url":null,"abstract":"Citrullination of joint proteins by the protein arginine deiminase (PAD) family of enzymes is recognized increasingly as a key process in the pathogenesis of rheumatoid arthritis. This present study was undertaken to explore the efficacy of a novel PAD4‐selective inhibitor, GSK199, in the murine collagen‐induced arthritis model of rheumatoid arthritis. Mice were dosed daily from the time of collagen immunization with GSK199. Efficacy was assessed against a wide range of end‐points, including clinical disease scores, joint histology and immunohistochemistry, serum and joint citrulline levels and quantification of synovial autoantibodies using a proteomic array containing joint peptides. Administration of GSK199 at 30 mg/kg led to significant effects on arthritis, assessed both by global clinical disease activity and by histological analyses of synovial inflammation, pannus formation and damage to cartilage and bone. In addition, significant decreases in complement C3 deposition in both synovium and cartilage were observed robustly with GSK199 at 10 mg/kg. Neither the total levels of citrulline measurable in joint and serum, nor levels of circulating collagen antibodies, were affected significantly by treatment with GSK199 at any dose level. In contrast, a subset of serum antibodies reactive against citrullinated and non‐citrullinated joint peptides were reduced with GSK199 treatment. These data extend our previous demonstration of efficacy with the pan‐PAD inhibitor Cl‐amidine and demonstrate robustly that PAD4 inhibition alone is sufficient to block murine arthritis clinical and histopathological end‐points.","PeriodicalId":10179,"journal":{"name":"Clinical & Experimental Immunology","volume":"19 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2017-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"88424505","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}
B. Smolková, J. Tulinská, L. P. Murinova, Verona Buocikova, A. Líšková, K. Rausova, M. Kuricová, H. Patayová, Maria Sustrova, E. N. Svorcova, Silvia Ilavská, M. Szabová, Tomáš Nemessányi, Eva Jahnova, Maria Dusinska, P. Ciznar, Laurence J. Fuortes
This cross‐sectional study was designed to investigate the extent of genetic susceptibility by targeting variants in interleukin (IL)−4/IL‐13 signalling pathways leading to atopic disease in early childhood. We evaluated involvement of five single nucleotide polymorphisms IL4 C‐590T, IL13 C‐1055T, IL13 Arg130Gln, IL4RA Ile50Val and IL4RA Gln576Arg, in the control of serum total and antigen‐specific immunoglobulin (Ig)E levels. Furthermore, we analysed their association with changes in gene expression of five cytokines having key roles in inflammatory and anti‐inflammatory immune response [IL‐4, IL‐13, interferon (IFN)‐γ, IL‐8 and IL‐10]. Total and antigen‐specific IgE levels in serum and gene expression of selected cytokines in peripheral blood were measured in 386 children aged 1–8 years. TaqMan allelic discrimination, amplification refractory mutation system–polymerase chain reaction (ARMS–PCR) and restriction fragment length polymorphisms (RFLP) methods validated by sequencing were used for genotyping. All genotypes for children with total and antigen‐specific IgE levels in the normal range were in Hardy–Weinberg equilibrium. Gene expression analyses were carried out using TaqMan gene expression assays. We found elevated total IgE levels in carriers of IL13 Arg130Gln variant allele [odds ratio (OR) = 1·84; 95% confidence interval (CI) = 1·16‐2·93]. This effect was more apparent for boys (OR = 2·31; 95% CI = 1·25‐4·28). However, no significant association was observed for the other four variants examined. We found up‐regulation of IFN‐γ in children with elevated serum total IgE levels carrying the Arg130 allele (P = 0·005). No differences were found for IL4, IL8 or IL10, while IL13 gene expression was under the detection limit. IL13 Arg130Gln genotypes can play a role in genetic susceptibility to allergy via regulation of serum total IgE levels and affecting IFN‐γ gene expression.
{"title":"Impact of interleukin 13 (IL13) genetic polymorphism Arg130Gln on total serum immunoglobulin (IgE) levels and interferon (IFN)‐γ gene expression","authors":"B. Smolková, J. Tulinská, L. P. Murinova, Verona Buocikova, A. Líšková, K. Rausova, M. Kuricová, H. Patayová, Maria Sustrova, E. N. Svorcova, Silvia Ilavská, M. Szabová, Tomáš Nemessányi, Eva Jahnova, Maria Dusinska, P. Ciznar, Laurence J. Fuortes","doi":"10.1111/cei.12923","DOIUrl":"https://doi.org/10.1111/cei.12923","url":null,"abstract":"This cross‐sectional study was designed to investigate the extent of genetic susceptibility by targeting variants in interleukin (IL)−4/IL‐13 signalling pathways leading to atopic disease in early childhood. We evaluated involvement of five single nucleotide polymorphisms IL4 C‐590T, IL13 C‐1055T, IL13 Arg130Gln, IL4RA Ile50Val and IL4RA Gln576Arg, in the control of serum total and antigen‐specific immunoglobulin (Ig)E levels. Furthermore, we analysed their association with changes in gene expression of five cytokines having key roles in inflammatory and anti‐inflammatory immune response [IL‐4, IL‐13, interferon (IFN)‐γ, IL‐8 and IL‐10]. Total and antigen‐specific IgE levels in serum and gene expression of selected cytokines in peripheral blood were measured in 386 children aged 1–8 years. TaqMan allelic discrimination, amplification refractory mutation system–polymerase chain reaction (ARMS–PCR) and restriction fragment length polymorphisms (RFLP) methods validated by sequencing were used for genotyping. All genotypes for children with total and antigen‐specific IgE levels in the normal range were in Hardy–Weinberg equilibrium. Gene expression analyses were carried out using TaqMan gene expression assays. We found elevated total IgE levels in carriers of IL13 Arg130Gln variant allele [odds ratio (OR) = 1·84; 95% confidence interval (CI) = 1·16‐2·93]. This effect was more apparent for boys (OR = 2·31; 95% CI = 1·25‐4·28). However, no significant association was observed for the other four variants examined. We found up‐regulation of IFN‐γ in children with elevated serum total IgE levels carrying the Arg130 allele (P = 0·005). No differences were found for IL4, IL8 or IL10, while IL13 gene expression was under the detection limit. IL13 Arg130Gln genotypes can play a role in genetic susceptibility to allergy via regulation of serum total IgE levels and affecting IFN‐γ gene expression.","PeriodicalId":10179,"journal":{"name":"Clinical & Experimental Immunology","volume":"142 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2017-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"75148510","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. Koutsonikoli, M. Trachana, E. Farmaki, V. Tzimouli, P. Pratsidou-Gertsi, N. Printza, A. Garyphallos, V. Galanopoulou, F. Kanakoudi‐Tsakalidou, F. Papachristou
The discovery of serum biomarkers specific for paediatric lupus nephritis (pLN) will facilitate the non‐invasive diagnosis, follow‐up and more appropriate use of treatment. The aim of this study was to explore the role of serum high‐mobility group box 1 (HMGB1) protein, antibodies against nucleosomes (anti‐NCS), complement factor C1q (anti‐C1q) and glomerular basement membrane (anti‐GBM) in pLN. Serum samples of 42 patients with paediatric systemic lupus erythematosus (pSLE) (22 with pLN and 20 without renal involvement), 15 patients with other autoimmune nephritis (AN) and 26 healthy controls (HCs) were examined using enzyme‐linked immunosorbent assay (ELISA). The activity of both pSLE and pLN was assessed by the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) tool. The levels of all four biomarkers were significantly higher in pLN compared to AN and to HCs. The anti‐NCS, anti‐GBM and HMGB1 serum levels were significantly higher in pLN than in pSLE without renal involvement. The anti‐C1q and the HMGB1 serum levels were correlated positively with pSLE activity. The HMGB1 serum levels were also correlated positively with pLN activity. These findings suggest that serum anti‐NCS, anti‐GBM and HMGB1 may serve as biomarkers specific for the presence of nephritis in pSLE. HMGB1 emerged as a useful biomarker for the assessment of pLN and pSLE activity, whereas anti‐C1q only of pSLE activity.
{"title":"Novel biomarkers for the assessment of paediatric systemic lupus erythematosus nephritis","authors":"A. Koutsonikoli, M. Trachana, E. Farmaki, V. Tzimouli, P. Pratsidou-Gertsi, N. Printza, A. Garyphallos, V. Galanopoulou, F. Kanakoudi‐Tsakalidou, F. Papachristou","doi":"10.1111/cei.12913","DOIUrl":"https://doi.org/10.1111/cei.12913","url":null,"abstract":"The discovery of serum biomarkers specific for paediatric lupus nephritis (pLN) will facilitate the non‐invasive diagnosis, follow‐up and more appropriate use of treatment. The aim of this study was to explore the role of serum high‐mobility group box 1 (HMGB1) protein, antibodies against nucleosomes (anti‐NCS), complement factor C1q (anti‐C1q) and glomerular basement membrane (anti‐GBM) in pLN. Serum samples of 42 patients with paediatric systemic lupus erythematosus (pSLE) (22 with pLN and 20 without renal involvement), 15 patients with other autoimmune nephritis (AN) and 26 healthy controls (HCs) were examined using enzyme‐linked immunosorbent assay (ELISA). The activity of both pSLE and pLN was assessed by the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) tool. The levels of all four biomarkers were significantly higher in pLN compared to AN and to HCs. The anti‐NCS, anti‐GBM and HMGB1 serum levels were significantly higher in pLN than in pSLE without renal involvement. The anti‐C1q and the HMGB1 serum levels were correlated positively with pSLE activity. The HMGB1 serum levels were also correlated positively with pLN activity. These findings suggest that serum anti‐NCS, anti‐GBM and HMGB1 may serve as biomarkers specific for the presence of nephritis in pSLE. HMGB1 emerged as a useful biomarker for the assessment of pLN and pSLE activity, whereas anti‐C1q only of pSLE activity.","PeriodicalId":10179,"journal":{"name":"Clinical & Experimental Immunology","volume":"67 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2017-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"85727642","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}
Mesenchymal stromal cells (MSC) have emerged as promising cell therapies for multiple conditions based on demonstrations of their potent immunomodulatory and regenerative capacities in models of inflammatory disease. Understanding the effects of MSC on T cells has dominated the majority of work carried out in this field to date; recently, however, a number of studies have shown that the therapeutic effect of MSC requires the presence of macrophages. It is timely to review the mechanisms and manner by which MSC modulate macrophage populations in order to design more effective MSC therapies and clinical studies. A complex cross‐talk exists through which MSC and macrophages communicate, a communication that is not controlled exclusively by MSC. Here, we examine the evidence that suggests that MSC not only respond to inflammatory macrophages and adjust their secretome accordingly, but also that macrophages respond to encounters with MSC, creating a feedback loop which contributes to the immune regulation observed following MSC therapy. Future studies examining the effects of MSC on macrophages should consider the antagonistic role that macrophages play in this exchange.
{"title":"The influence of macrophages on mesenchymal stromal cell therapy: passive or aggressive agents?","authors":"F. Carty, B. Mahon, K. English","doi":"10.1111/cei.12929","DOIUrl":"https://doi.org/10.1111/cei.12929","url":null,"abstract":"Mesenchymal stromal cells (MSC) have emerged as promising cell therapies for multiple conditions based on demonstrations of their potent immunomodulatory and regenerative capacities in models of inflammatory disease. Understanding the effects of MSC on T cells has dominated the majority of work carried out in this field to date; recently, however, a number of studies have shown that the therapeutic effect of MSC requires the presence of macrophages. It is timely to review the mechanisms and manner by which MSC modulate macrophage populations in order to design more effective MSC therapies and clinical studies. A complex cross‐talk exists through which MSC and macrophages communicate, a communication that is not controlled exclusively by MSC. Here, we examine the evidence that suggests that MSC not only respond to inflammatory macrophages and adjust their secretome accordingly, but also that macrophages respond to encounters with MSC, creating a feedback loop which contributes to the immune regulation observed following MSC therapy. Future studies examining the effects of MSC on macrophages should consider the antagonistic role that macrophages play in this exchange.","PeriodicalId":10179,"journal":{"name":"Clinical & Experimental Immunology","volume":"3 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2017-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"82132480","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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