Sjögren's syndrome (SS) is an autoimmune disease and the second most common chronic systemic rheumatic disorder. Prevalence of primary SS in the general population has been estimated to be approximately 1–3%, whereas secondary SS has been observed in 10–20% of patients with rheumatoid arthritis, systemic lupus erythematosus (SLE) and scleroderma. Despite this, its exact aetiology and pathogenesis are largely unexplored. Nuclear factor‐kappa B (NF‐κB) signalling mechanisms provide central controls in SS, but how these pathways intersect the pathological features of this disease is unclear. The ubiquitin‐editing enzyme A20 (tumour necrosis factor‐α‐induced protein 3, TNFAIP3) serves as a critical inhibitor on NF‐κB signalling. In humans, polymorphisms in the A20 gene or a deregulated expression of A20 are often associated with several inflammatory disorders, including SS. Because A20 controls the ectodysplasin‐A1 (EDA‐A1)/ectodysplasin receptor (EDAR) signalling negatively, and the deletion of A20 results in excessive EDA1‐induced NF‐κB signalling, this work investigates the expression levels of EDA‐A1 and EDAR in SS human salivary glands epithelial cells (SGEC) and evaluates the hypothesis that SS SGEC‐specific deregulation of A20 results in excessive EDA1‐induced NF‐κB signalling in SS. Our approach, which combines the use of siRNA‐mediated gene silencing and quantitative pathway analysis, was used to elucidate the role of the A20 target gene in intracellular EDA‐A1/EDAR/NF‐κB pathway in SS SGEC, holding significant promise for compound selection in drug discovery.
{"title":"Downstream activation of NF‐κB in the EDA‐A1/EDAR signalling in Sjögren's syndrome and its regulation by the ubiquitin‐editing enzyme A20","authors":"M. Sisto, A. Barca, D. Lofrumento, S. Lisi","doi":"10.1111/cei.12764","DOIUrl":"https://doi.org/10.1111/cei.12764","url":null,"abstract":"Sjögren's syndrome (SS) is an autoimmune disease and the second most common chronic systemic rheumatic disorder. Prevalence of primary SS in the general population has been estimated to be approximately 1–3%, whereas secondary SS has been observed in 10–20% of patients with rheumatoid arthritis, systemic lupus erythematosus (SLE) and scleroderma. Despite this, its exact aetiology and pathogenesis are largely unexplored. Nuclear factor‐kappa B (NF‐κB) signalling mechanisms provide central controls in SS, but how these pathways intersect the pathological features of this disease is unclear. The ubiquitin‐editing enzyme A20 (tumour necrosis factor‐α‐induced protein 3, TNFAIP3) serves as a critical inhibitor on NF‐κB signalling. In humans, polymorphisms in the A20 gene or a deregulated expression of A20 are often associated with several inflammatory disorders, including SS. Because A20 controls the ectodysplasin‐A1 (EDA‐A1)/ectodysplasin receptor (EDAR) signalling negatively, and the deletion of A20 results in excessive EDA1‐induced NF‐κB signalling, this work investigates the expression levels of EDA‐A1 and EDAR in SS human salivary glands epithelial cells (SGEC) and evaluates the hypothesis that SS SGEC‐specific deregulation of A20 results in excessive EDA1‐induced NF‐κB signalling in SS. Our approach, which combines the use of siRNA‐mediated gene silencing and quantitative pathway analysis, was used to elucidate the role of the A20 target gene in intracellular EDA‐A1/EDAR/NF‐κB pathway in SS SGEC, holding significant promise for compound selection in drug discovery.","PeriodicalId":10179,"journal":{"name":"Clinical & Experimental Immunology","volume":"42 1 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2016-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"89520357","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}
R. Xing, Y. Jin, L. Sun, L. Yang, C. Li, Z. Li, X. Liu, J. Zhao
Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by synovial fibroblast hyperplasia and bone erosion. Fibroblast‐like synoviocytes (FLS) play a pivotal role in RA pathogenesis through aggressive migration and matrix invasion, and certain proinflammatory cytokines may affect synoviocyte invasion. Whether interleukin (IL)‐21 influences this process remains controversial. Here, we evaluated the potential regulatory effect of IL‐21 on the migration, invasion and matrix metalloproteinase (MMP) expression in RA‐FLS. We found that IL‐21 promoted the migration, invasion and MMP (MMP‐2, MMP‐3, MMP‐9, MMP‐13) production in RA‐FLS. Moreover, IL‐21 induced activation of the phosphoinositide 3‐kinase (PI3K), signal transducer and activator of transcription‐3 (STAT‐3) and extracellular signal‐regulated protein kinases 1 and 2 (ERK1/2) pathways, and blockage of these pathways [PI3K/protein kinase B (AKT) inhibitor LY294002, STAT‐3 inhibitor STA‐21 and ERK1/2 inhibitor PD98059] attenuated IL‐21‐induced migration and secretion of MMP‐3 and MMP‐9. In conclusion, our results suggest that IL‐21 promotes migration and invasion of RA‐FLS. Therefore, therapeutic strategies targeting IL‐21 might be effective for the treatment of RA.
{"title":"Interleukin‐21 induces migration and invasion of fibroblast‐like synoviocytes from patients with rheumatoid arthritis","authors":"R. Xing, Y. Jin, L. Sun, L. Yang, C. Li, Z. Li, X. Liu, J. Zhao","doi":"10.1111/cei.12751","DOIUrl":"https://doi.org/10.1111/cei.12751","url":null,"abstract":"Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by synovial fibroblast hyperplasia and bone erosion. Fibroblast‐like synoviocytes (FLS) play a pivotal role in RA pathogenesis through aggressive migration and matrix invasion, and certain proinflammatory cytokines may affect synoviocyte invasion. Whether interleukin (IL)‐21 influences this process remains controversial. Here, we evaluated the potential regulatory effect of IL‐21 on the migration, invasion and matrix metalloproteinase (MMP) expression in RA‐FLS. We found that IL‐21 promoted the migration, invasion and MMP (MMP‐2, MMP‐3, MMP‐9, MMP‐13) production in RA‐FLS. Moreover, IL‐21 induced activation of the phosphoinositide 3‐kinase (PI3K), signal transducer and activator of transcription‐3 (STAT‐3) and extracellular signal‐regulated protein kinases 1 and 2 (ERK1/2) pathways, and blockage of these pathways [PI3K/protein kinase B (AKT) inhibitor LY294002, STAT‐3 inhibitor STA‐21 and ERK1/2 inhibitor PD98059] attenuated IL‐21‐induced migration and secretion of MMP‐3 and MMP‐9. In conclusion, our results suggest that IL‐21 promotes migration and invasion of RA‐FLS. Therefore, therapeutic strategies targeting IL‐21 might be effective for the treatment of RA.","PeriodicalId":10179,"journal":{"name":"Clinical & Experimental Immunology","volume":"143 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2016-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"78048150","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. Gunn, D. C. F. Sealey, F. Jamali, B. Meibohm, S. Ghosh, G. Shankar
Unlike conventional chemical drugs where immunogenicity typically does not occur, the development of anti‐drug antibodies following treatment with biologics has led to concerns about their impact on clinical safety and efficacy. Hence the elucidation of the immunogenicity of biologics is required for drug approval by health regulatory authorities worldwide. Published ADA ‘incidence’ rates can vary greatly between same‐class products and different patient populations. Such differences are due to disparate bioanalytical methods and interpretation approaches, as well as a plethora of product‐specific and patient‐specific factors that are not fully understood. Therefore, the incidence of ADA and their association with clinical consequences cannot be generalized across products. In this context, the intent of this review article is to discuss the complex nature of ADA and key nuances of the methodologies used for immunogenicity assessments, and to dispel some fallacies and myths.
{"title":"From the bench to clinical practice: understanding the challenges and uncertainties in immunogenicity testing for biopharmaceuticals","authors":"G. Gunn, D. C. F. Sealey, F. Jamali, B. Meibohm, S. Ghosh, G. Shankar","doi":"10.1111/cei.12742","DOIUrl":"https://doi.org/10.1111/cei.12742","url":null,"abstract":"Unlike conventional chemical drugs where immunogenicity typically does not occur, the development of anti‐drug antibodies following treatment with biologics has led to concerns about their impact on clinical safety and efficacy. Hence the elucidation of the immunogenicity of biologics is required for drug approval by health regulatory authorities worldwide. Published ADA ‘incidence’ rates can vary greatly between same‐class products and different patient populations. Such differences are due to disparate bioanalytical methods and interpretation approaches, as well as a plethora of product‐specific and patient‐specific factors that are not fully understood. Therefore, the incidence of ADA and their association with clinical consequences cannot be generalized across products. In this context, the intent of this review article is to discuss the complex nature of ADA and key nuances of the methodologies used for immunogenicity assessments, and to dispel some fallacies and myths.","PeriodicalId":10179,"journal":{"name":"Clinical & Experimental Immunology","volume":"1 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2016-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"83636689","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. Cantarini, V. Pucino, A. Vitale, R. Talarico, O. M. Lucherini, F. Magnotti, V. De Rosa, M. Galgani, C. Alviggi, G. Marone, M. Galeazzi, G. Matarese
Behcet's disease (BD) is a systemic inflammatory disease with a still unclear pathogenesis. Although several inflammatory molecules have been studied, current biomarkers are largely insensitive in BD and unable to predict disease progression and response to treatment. Our primary aim was to explore serum levels of soluble CD40 L (sCD40L), soluble intracellular adhesion molecule (sICAM‐1), monocyte chemoattractant protein‐1 (MCP‐1), myeloperoxidase (MPO), leptin, resistin, osteoprotegerin (OPG), soluble type 1 tumour necrosis factor receptor (sTNFR), interleukin (IL)−6 and serum amyloid A (SAA) serum concentration in a cohort of 27 BD patients. The secondary aim was to evaluate potential correlations between the putative circulating biomarkers, demographic profile of patients, the status of disease activity, the specific organ involvement at the time of sample collection and different therapeutic regimens. Serum concentrations of sTNFR (P = 0·008), leptin (P = 0·0011), sCD40L (P < 0·0001) and IL‐6 (P = 0·0154) were significantly higher in BD patients than in HC, while no difference was found in MCP‐1, MPO and resistin serum levels. Moreover, we observed significantly higher sTNFR serum concentrations in BD patients presenting inactive disease than HC (P = 0·0108). A correlation between sTNFR and age was also found, with higher levels in patients over 40 years than HC (P = 0·0329). Although further research is warranted to elucidate the role of circulating biomarkers, some of that may contribute to the understanding of the physiopathology processes underlying BD activity and damage as well as to provide useful tools for prognostic purposes and a personalized treatment approach.
{"title":"Immunometabolic biomarkers of inflammation in Behçet's disease: relationship with epidemiological profile, disease activity and therapeutic regimens","authors":"L. Cantarini, V. Pucino, A. Vitale, R. Talarico, O. M. Lucherini, F. Magnotti, V. De Rosa, M. Galgani, C. Alviggi, G. Marone, M. Galeazzi, G. Matarese","doi":"10.1111/cei.12768","DOIUrl":"https://doi.org/10.1111/cei.12768","url":null,"abstract":"Behcet's disease (BD) is a systemic inflammatory disease with a still unclear pathogenesis. Although several inflammatory molecules have been studied, current biomarkers are largely insensitive in BD and unable to predict disease progression and response to treatment. Our primary aim was to explore serum levels of soluble CD40 L (sCD40L), soluble intracellular adhesion molecule (sICAM‐1), monocyte chemoattractant protein‐1 (MCP‐1), myeloperoxidase (MPO), leptin, resistin, osteoprotegerin (OPG), soluble type 1 tumour necrosis factor receptor (sTNFR), interleukin (IL)−6 and serum amyloid A (SAA) serum concentration in a cohort of 27 BD patients. The secondary aim was to evaluate potential correlations between the putative circulating biomarkers, demographic profile of patients, the status of disease activity, the specific organ involvement at the time of sample collection and different therapeutic regimens. Serum concentrations of sTNFR (P = 0·008), leptin (P = 0·0011), sCD40L (P < 0·0001) and IL‐6 (P = 0·0154) were significantly higher in BD patients than in HC, while no difference was found in MCP‐1, MPO and resistin serum levels. Moreover, we observed significantly higher sTNFR serum concentrations in BD patients presenting inactive disease than HC (P = 0·0108). A correlation between sTNFR and age was also found, with higher levels in patients over 40 years than HC (P = 0·0329). Although further research is warranted to elucidate the role of circulating biomarkers, some of that may contribute to the understanding of the physiopathology processes underlying BD activity and damage as well as to provide useful tools for prognostic purposes and a personalized treatment approach.","PeriodicalId":10179,"journal":{"name":"Clinical & Experimental Immunology","volume":"125 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2016-02-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"74479697","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}
I. Melamed, S. Gupta, M. S. Stratford Bobbitt, N. Hyland, J. Moy
This open‐label multi‐centre study evaluated Gammaplex® 5%, a human intravenous immunoglobulin (IVIG) 5% liquid, in 25 children and adolescent patients (aged 3–16 years) with primary immunodeficiency diseases (PIDs). Subjects received Gammaplex 5% (at doses of 300–800 mg/kg/infusion) for 12 months, with a 3‐month follow‐up. The primary efficacy end‐point was the incidence of serious acute bacterial infections (SABIs) during the 12‐month treatment period. Secondary objectives assessed safety and tolerability. Nineteen males and six females were treated using the same infusion schedule as their prior IVIG treatment (14 and 11 subjects on 21‐ and 28‐day dosing schedules, respectively). Two SABIs of pneumonia were reported, resulting in an annual SABI event rate of 0·09 [upper one‐sided 99% confidence interval (CI) = 0·36]. Twenty‐one subjects (84%) experienced ≥ 1 infection during the study, with a median infective episode per subject/year of 3·08 (range = 0–10·4). Sixteen subjects (64%) missed ≥ 1 day of nursery or school because of infection or other illness. All trough immunoglobulin G levels exceeded 7·00 g/l after 15 weeks (mean = 9·69 g/l; range = 7·04–15·35 g/l). Product‐related adverse events occurred in 14 subjects (56%); none were serious. Of 368 total infusions, 97 (26%) were associated temporally with an adverse event (≤ 72 h after infusion), regardless of causality. Laboratory test results and adverse‐reaction data showed no evidence of product‐related haemolysis or thromboembolic events. These data demonstrate that Gammaplex 5% is effective in preventing SABIs and well tolerated in children and adolescents with PID.
这项开放标签多中心研究评估了Gammaplex®5%，一种人静脉注射免疫球蛋白(IVIG) 5%液体，在25名患有原发性免疫缺陷疾病(ids)的儿童和青少年患者(3-16岁)中的应用。受试者接受Gammaplex 5%(剂量300 - 800mg /kg/次输注)治疗12个月，并进行3个月的随访。主要疗效终点是12个月治疗期间严重急性细菌感染(SABIs)的发生率。次要目标评估安全性和耐受性。19名男性和6名女性采用与先前IVIG治疗相同的输注方案(14名和11名受试者分别采用21天和28天的给药方案)。报告了2例肺炎SABI，导致每年SABI事件发生率为0.09[上单边99%可信区间(CI) = 0.36]。21名受试者(84%)在研究期间经历了≥1次感染，每位受试者/年的中位感染事件为3.08次(范围= 0 - 10.4)。16例(64%)因感染或其他疾病缺勤≥1天。15周后免疫球蛋白G水平均超过7·00 G /l(平均9·69 G /l;范围= 7.04 - 15.35 g/l)。14名受试者(56%)发生了与产品相关的不良事件;没有一个是认真的。在总共368次输注中，无论因果关系如何，97次(26%)与不良事件(输注后≤72小时)暂时相关。实验室检测结果和不良反应数据显示，没有证据表明产品相关的溶血或血栓栓塞事件。这些数据表明，Gammaplex 5%在预防sabi方面是有效的，并且在患有PID的儿童和青少年中耐受性良好。
{"title":"Efficacy and safety of Gammaplex® 5% in children and adolescents with primary immunodeficiency diseases","authors":"I. Melamed, S. Gupta, M. S. Stratford Bobbitt, N. Hyland, J. Moy","doi":"10.1111/cei.12760","DOIUrl":"https://doi.org/10.1111/cei.12760","url":null,"abstract":"This open‐label multi‐centre study evaluated Gammaplex® 5%, a human intravenous immunoglobulin (IVIG) 5% liquid, in 25 children and adolescent patients (aged 3–16 years) with primary immunodeficiency diseases (PIDs). Subjects received Gammaplex 5% (at doses of 300–800 mg/kg/infusion) for 12 months, with a 3‐month follow‐up. The primary efficacy end‐point was the incidence of serious acute bacterial infections (SABIs) during the 12‐month treatment period. Secondary objectives assessed safety and tolerability. Nineteen males and six females were treated using the same infusion schedule as their prior IVIG treatment (14 and 11 subjects on 21‐ and 28‐day dosing schedules, respectively). Two SABIs of pneumonia were reported, resulting in an annual SABI event rate of 0·09 [upper one‐sided 99% confidence interval (CI) = 0·36]. Twenty‐one subjects (84%) experienced ≥ 1 infection during the study, with a median infective episode per subject/year of 3·08 (range = 0–10·4). Sixteen subjects (64%) missed ≥ 1 day of nursery or school because of infection or other illness. All trough immunoglobulin G levels exceeded 7·00 g/l after 15 weeks (mean = 9·69 g/l; range = 7·04–15·35 g/l). Product‐related adverse events occurred in 14 subjects (56%); none were serious. Of 368 total infusions, 97 (26%) were associated temporally with an adverse event (≤ 72 h after infusion), regardless of causality. Laboratory test results and adverse‐reaction data showed no evidence of product‐related haemolysis or thromboembolic events. These data demonstrate that Gammaplex 5% is effective in preventing SABIs and well tolerated in children and adolescents with PID.","PeriodicalId":10179,"journal":{"name":"Clinical & Experimental Immunology","volume":"46 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2016-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"90959722","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
M. Guzmán, I. Keitelman, F. Sabbione, A. Trevani, M. Giordano, J. Galletti
Dry eye is an allegedly autoimmune disorder for which the initiating mechanisms and the targeted antigens in the ocular surface are not known, yet there is extensive evidence that a localized T helper type 1 (Th1)/Th17 effector T cell response is responsible for its pathogenesis. In this work, we explore the reconciling hypothesis that desiccating stress, which is usually considered an exacerbating factor, could actually be sufficient to skew the ocular surface's mucosal response to any antigen and therefore drive the disease. Using a mouse model of dry eye, we found that desiccating stress causes a nuclear factor kappa B (NF‐κB)‐ and time‐dependent disruption of the ocular surface's immune tolerance to exogenous ovalbumin. This pathogenic event is mediated by increased Th1 and Th17 T cells and reduced regulatory T cells in the draining lymph nodes. Conversely, topical NF‐κB inhibitors reduced corneal epithelial damage and interleukin (IL)‐1β and IL‐6 levels in the ocular surface of mice under desiccating stress. The observed effect was mediated by an augmented regulatory T cell response, a finding that highlights the role of mucosal tolerance disruption in dry eye pathogenesis. Remarkably, the NF‐κB pathway is also involved in mucosal tolerance disruption in other ocular surface disorders. Together, these results suggest that targeting of mucosal NF‐κB activation could have therapeutic potential in dry eye.
{"title":"Desiccating stress‐induced disruption of ocular surface immune tolerance drives dry eye disease","authors":"M. Guzmán, I. Keitelman, F. Sabbione, A. Trevani, M. Giordano, J. Galletti","doi":"10.1111/cei.12759","DOIUrl":"https://doi.org/10.1111/cei.12759","url":null,"abstract":"Dry eye is an allegedly autoimmune disorder for which the initiating mechanisms and the targeted antigens in the ocular surface are not known, yet there is extensive evidence that a localized T helper type 1 (Th1)/Th17 effector T cell response is responsible for its pathogenesis. In this work, we explore the reconciling hypothesis that desiccating stress, which is usually considered an exacerbating factor, could actually be sufficient to skew the ocular surface's mucosal response to any antigen and therefore drive the disease. Using a mouse model of dry eye, we found that desiccating stress causes a nuclear factor kappa B (NF‐κB)‐ and time‐dependent disruption of the ocular surface's immune tolerance to exogenous ovalbumin. This pathogenic event is mediated by increased Th1 and Th17 T cells and reduced regulatory T cells in the draining lymph nodes. Conversely, topical NF‐κB inhibitors reduced corneal epithelial damage and interleukin (IL)‐1β and IL‐6 levels in the ocular surface of mice under desiccating stress. The observed effect was mediated by an augmented regulatory T cell response, a finding that highlights the role of mucosal tolerance disruption in dry eye pathogenesis. Remarkably, the NF‐κB pathway is also involved in mucosal tolerance disruption in other ocular surface disorders. Together, these results suggest that targeting of mucosal NF‐κB activation could have therapeutic potential in dry eye.","PeriodicalId":10179,"journal":{"name":"Clinical & Experimental Immunology","volume":"18 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2016-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"89812430","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}
I. Pągowska-Klimek, A. Świerzko, M. Michalski, E. Głowacka, A. Szala-Poździej, A. Sokołowska, M. Moll, W. Krajewski, J. Romak, M. Cedzyński
The systemic inflammatory response is a challenge in the management of paediatric patients undergoing cardiac surgery. Although multi‐factorial, a contribution by the lectin pathway of complement activation has been postulated. We therefore investigated the changes in serum levels of mannose binding lectin (MBL) and activities of MBL–MBL‐associated serine protease (MASP)‐1 and MBL–MASP‐2 complexes immediately before and during surgery, throughout the first postoperative day and at discharge from the hospital. These changes were analysed in relation to postoperative complications. Blood samples were obtained from 185 children with congenital heart disease undergoing surgical correction with the use of cardiopulmonary bypass: preoperatively (MBL‐1), 15 min after initiation of cardiopulmonary bypass (CPB) (MBL‐E), 30 min (MBL‐2), 4 h (MBL‐3), 12 h (MBL‐4) and 24 h (MBL‐5) post‐CPB and at discharge from hospital (MBL‐K). Alterations in serum MBL levels were calculated as a ratio of its serum level at subsequent time‐points (MBL‐2, ‐3, ‐4, ‐5) to the preoperative (MBL‐1) value. Decreases in MBL and MBL–MASP complexes were observed in all samples, correlating with a decrease in C4 and increase in C4a, confirming activation of the lectin pathway. Changes in MBL levels between children with an uncomplicated postoperative course and those suffering from infection or low cardiac output syndrome did not differ significantly, but significant differences were observed between the SIRS and non‐SIRS groups. Paediatric cardiac surgery with the use of cardiopulmonary bypass activates the complement system via the lectin pathway and the latter contributes to the development of the post‐bypass systemic inflammatory response.
{"title":"Activation of the lectin pathway of complement by cardiopulmonary bypass contributes to the development of systemic inflammatory response syndrome after paediatric cardiac surgery","authors":"I. Pągowska-Klimek, A. Świerzko, M. Michalski, E. Głowacka, A. Szala-Poździej, A. Sokołowska, M. Moll, W. Krajewski, J. Romak, M. Cedzyński","doi":"10.1111/cei.12763","DOIUrl":"https://doi.org/10.1111/cei.12763","url":null,"abstract":"The systemic inflammatory response is a challenge in the management of paediatric patients undergoing cardiac surgery. Although multi‐factorial, a contribution by the lectin pathway of complement activation has been postulated. We therefore investigated the changes in serum levels of mannose binding lectin (MBL) and activities of MBL–MBL‐associated serine protease (MASP)‐1 and MBL–MASP‐2 complexes immediately before and during surgery, throughout the first postoperative day and at discharge from the hospital. These changes were analysed in relation to postoperative complications. Blood samples were obtained from 185 children with congenital heart disease undergoing surgical correction with the use of cardiopulmonary bypass: preoperatively (MBL‐1), 15 min after initiation of cardiopulmonary bypass (CPB) (MBL‐E), 30 min (MBL‐2), 4 h (MBL‐3), 12 h (MBL‐4) and 24 h (MBL‐5) post‐CPB and at discharge from hospital (MBL‐K). Alterations in serum MBL levels were calculated as a ratio of its serum level at subsequent time‐points (MBL‐2, ‐3, ‐4, ‐5) to the preoperative (MBL‐1) value. Decreases in MBL and MBL–MASP complexes were observed in all samples, correlating with a decrease in C4 and increase in C4a, confirming activation of the lectin pathway. Changes in MBL levels between children with an uncomplicated postoperative course and those suffering from infection or low cardiac output syndrome did not differ significantly, but significant differences were observed between the SIRS and non‐SIRS groups. Paediatric cardiac surgery with the use of cardiopulmonary bypass activates the complement system via the lectin pathway and the latter contributes to the development of the post‐bypass systemic inflammatory response.","PeriodicalId":10179,"journal":{"name":"Clinical & Experimental Immunology","volume":"184 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2016-02-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"85677927","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}
Marie-Astrid Boutet, Marie-Astrid Boutet, Géraldine Bart, Géraldine Bart, Mélanie Gahier Penhoat, Mélanie Gahier Penhoat, J. Amiaud, J. Amiaud, B. Brulin, B. Brulin, Céline Charrier, Céline Charrier, Franck Morel, J. Lecron, M. Rolli-Derkinderen, Arnaud Bourreille, S. Vigne, C. Gabay, G. Palmer, B. L. Goff, B. L. Goff, Frédéric Blanchard, Frédéric Blanchard
Interleukin (IL)‐36α, IL‐36β and IL‐36γ are expressed highly in skin and are involved in the pathogenesis of psoriasis, while the antagonists IL‐36Ra or IL‐38, another potential IL‐36 inhibitor, limit uncontrolled inflammation. The expression and role of IL‐36 cytokines in rheumatoid arthritis (RA) and Crohn's disease (CD) is currently debated. Here, we observed that during imiquimod‐induced mouse skin inflammation and in human psoriasis, expression of IL‐36α, γ and IL‐36Ra, but not IL‐36β and IL‐38 mRNA, was induced and correlated with IL‐1β and T helper type 17 (Th17) cytokines (IL‐17A, IL‐22, IL‐23, CCL20). In mice with collagen‐induced arthritis and in the synovium of patients with RA, IL‐36α, β, γ, IL‐36Ra and IL‐38 were all elevated and correlated with IL‐1β, CCL3, CCL4 and macrophage colony‐stimulating factor (M‐CSF), but not with Th17 cytokines. In the colon of mice with dextran sulphate sodium‐induced colitis and in patients with CD, only IL‐36α, γ and IL‐38 were induced at relatively low levels and correlated with IL‐1β and IL‐17A. We suggest that only a minor subgroup of patients with RA (17–29%) or CD (25%) had an elevated IL‐36 agonists/antagonists ratio, versus 93% of patients with psoriasis. By immunohistochemistry, IL‐36 cytokines were produced by various cell types in skin, synovium and colonic mucosa such as keratinocytes, CD68+ macrophages, dendritic/Langerhans cells and CD79α+ plasma cells. In primary cultures of monocytes or inflammatory macrophages (M1), IL‐36β and IL‐36Ra were produced constitutively, but IL‐36α, γ and IL‐38 were produced after lipopolysaccharide stimulation. These distinct expression profiles may help to explain why only subgroups of RA and CD patients have a potentially elevated IL‐36 agonists/antagonists ratio.
{"title":"Distinct expression of interleukin (IL)‐36α, β and γ, their antagonist IL‐36Ra and IL‐38 in psoriasis, rheumatoid arthritis and Crohn's disease","authors":"Marie-Astrid Boutet, Marie-Astrid Boutet, Géraldine Bart, Géraldine Bart, Mélanie Gahier Penhoat, Mélanie Gahier Penhoat, J. Amiaud, J. Amiaud, B. Brulin, B. Brulin, Céline Charrier, Céline Charrier, Franck Morel, J. Lecron, M. Rolli-Derkinderen, Arnaud Bourreille, S. Vigne, C. Gabay, G. Palmer, B. L. Goff, B. L. Goff, Frédéric Blanchard, Frédéric Blanchard","doi":"10.1111/cei.12761","DOIUrl":"https://doi.org/10.1111/cei.12761","url":null,"abstract":"Interleukin (IL)‐36α, IL‐36β and IL‐36γ are expressed highly in skin and are involved in the pathogenesis of psoriasis, while the antagonists IL‐36Ra or IL‐38, another potential IL‐36 inhibitor, limit uncontrolled inflammation. The expression and role of IL‐36 cytokines in rheumatoid arthritis (RA) and Crohn's disease (CD) is currently debated. Here, we observed that during imiquimod‐induced mouse skin inflammation and in human psoriasis, expression of IL‐36α, γ and IL‐36Ra, but not IL‐36β and IL‐38 mRNA, was induced and correlated with IL‐1β and T helper type 17 (Th17) cytokines (IL‐17A, IL‐22, IL‐23, CCL20). In mice with collagen‐induced arthritis and in the synovium of patients with RA, IL‐36α, β, γ, IL‐36Ra and IL‐38 were all elevated and correlated with IL‐1β, CCL3, CCL4 and macrophage colony‐stimulating factor (M‐CSF), but not with Th17 cytokines. In the colon of mice with dextran sulphate sodium‐induced colitis and in patients with CD, only IL‐36α, γ and IL‐38 were induced at relatively low levels and correlated with IL‐1β and IL‐17A. We suggest that only a minor subgroup of patients with RA (17–29%) or CD (25%) had an elevated IL‐36 agonists/antagonists ratio, versus 93% of patients with psoriasis. By immunohistochemistry, IL‐36 cytokines were produced by various cell types in skin, synovium and colonic mucosa such as keratinocytes, CD68+ macrophages, dendritic/Langerhans cells and CD79α+ plasma cells. In primary cultures of monocytes or inflammatory macrophages (M1), IL‐36β and IL‐36Ra were produced constitutively, but IL‐36α, γ and IL‐38 were produced after lipopolysaccharide stimulation. These distinct expression profiles may help to explain why only subgroups of RA and CD patients have a potentially elevated IL‐36 agonists/antagonists ratio.","PeriodicalId":10179,"journal":{"name":"Clinical & Experimental Immunology","volume":"31 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2015-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"81083684","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
M. Sorice, B. Buttari, A. Capozzi, E. Profumo, F. Facchiano, S. Truglia, S. Recalchi, C. Alessandri, F. Conti, R. Misasi, G. Valesini, R. Riganò
Anti‐phospholipid antibody syndrome (APS) is a systemic autoimmune disease characterized clinically by arterial and/or venous thromboses, recurrent abortions or fetal loss and serologically by the presence of ‘anti‐phospholipid antibodies’ (aPL). The main target antigen of the antibodies is β2glycoprotein I (β2GPI). Post‐translational oxidative modifications of the protein have been widely described. In this study we aimed to analyse sera reactivity to glucose‐modified β2GPI (G‐β2GPI). Sera collected from 43 patients with APS [15 primary APS (PAPS) and 28 APS associated with systemic lupus erythematosus (SLE) (SAPS)], 30 with SLE, 30 with rheumatoid arthritis (RA) and 40 healthy subjects were analysed by an enzyme‐linked immunosorbent assay (ELISA) using a G‐β2GPI. Nine of 15 consecutive PAPS out‐patients (60%) and 16 of 28 SAPS (57.1%) showed serum antibodies [immunoglobulin (Ig)G class] against G‐β2GPI (anti‐G‐β2GPI) by ELISA. The occurrence of anti‐G‐β2GPI was significantly higher in APS patients compared to patients suffering from SLE. No RA patients or control healthy subjects resulted positive for anti‐G‐β2GPI. Of note, aG‐β2GPI prompted to identify some APS patients (four PAPS and seven SAPS), who were negative in the classical anti‐β2GPI test. Moreover, in APS patients, anti‐G‐β2GPI titre was associated significantly with venous thrombosis and seizure in APS patients. This study demonstrates that G‐β2GPI is a target antigen of humoral immune response in patients with APS, suggesting that β2GPI glycation products may contain additional epitopes for anti‐β2GPI reactivity. Searching for these antibodies may be useful for evaluating the risk of clinical manifestations.
{"title":"Antibodies to age‐β2glycoprotein I in patients with anti‐phospholipid antibody syndrome","authors":"M. Sorice, B. Buttari, A. Capozzi, E. Profumo, F. Facchiano, S. Truglia, S. Recalchi, C. Alessandri, F. Conti, R. Misasi, G. Valesini, R. Riganò","doi":"10.1111/cei.12762","DOIUrl":"https://doi.org/10.1111/cei.12762","url":null,"abstract":"Anti‐phospholipid antibody syndrome (APS) is a systemic autoimmune disease characterized clinically by arterial and/or venous thromboses, recurrent abortions or fetal loss and serologically by the presence of ‘anti‐phospholipid antibodies’ (aPL). The main target antigen of the antibodies is β2glycoprotein I (β2GPI). Post‐translational oxidative modifications of the protein have been widely described. In this study we aimed to analyse sera reactivity to glucose‐modified β2GPI (G‐β2GPI). Sera collected from 43 patients with APS [15 primary APS (PAPS) and 28 APS associated with systemic lupus erythematosus (SLE) (SAPS)], 30 with SLE, 30 with rheumatoid arthritis (RA) and 40 healthy subjects were analysed by an enzyme‐linked immunosorbent assay (ELISA) using a G‐β2GPI. Nine of 15 consecutive PAPS out‐patients (60%) and 16 of 28 SAPS (57.1%) showed serum antibodies [immunoglobulin (Ig)G class] against G‐β2GPI (anti‐G‐β2GPI) by ELISA. The occurrence of anti‐G‐β2GPI was significantly higher in APS patients compared to patients suffering from SLE. No RA patients or control healthy subjects resulted positive for anti‐G‐β2GPI. Of note, aG‐β2GPI prompted to identify some APS patients (four PAPS and seven SAPS), who were negative in the classical anti‐β2GPI test. Moreover, in APS patients, anti‐G‐β2GPI titre was associated significantly with venous thrombosis and seizure in APS patients. This study demonstrates that G‐β2GPI is a target antigen of humoral immune response in patients with APS, suggesting that β2GPI glycation products may contain additional epitopes for anti‐β2GPI reactivity. Searching for these antibodies may be useful for evaluating the risk of clinical manifestations.","PeriodicalId":10179,"journal":{"name":"Clinical & Experimental Immunology","volume":"22 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2015-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"87307054","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}
Pub Date : 2002-02-01DOI: 10.1046/j.1365-2249.2002.01752.x
Id Dimitriou, E. Kapsogeorgou, H. Moutsopoulos, M. Manoussakis
CD40 has been identified in an expanding list of haematopoietic and non‐haematopoietic cells and has received an increased interest based on its role in a variety of cell‐mediated responses and its potential to participate in the pathogenesis of chronic inflammatory disorders. Sjögren’s syndrome (SS) is an autoimmune exocrinopathy, which is characterized by chronic lymphocytic infiltration of exocrine glands and aberrant activation of epithelial tissues. We studied the expression of CD40 protein in cultured non‐neoplastic salivary gland epithelial cell (SGEC) lines as well as in minor SG biopsies obtained from 17 SS patients and 12 controls. Immunocytochemical and flow cytometric analyses had revealed the occurrence of constitutively expressed CD40 molecules on the surface of long‐term cultured SGEC lines, which could be further induced by interferon‐gamma (IFN‐γ) and IL‐1β cytokines, but not tumour necrosis factor‐alpha (TNF‐α), IL‐4, IL‐6, granulocyte‐macrophage colony‐stimulating factor (GM‐CSF) or IFN‐α. Triggering of SGEC through CD40 enhanced the surface expression of the adhesion molecule intercellular adhesion molecule‐1 (ICAM‐1)/CD54, but not MHC class I and class II (HLA‐DR) molecules. Spontaneous CD40 expression was significantly higher in SGEC lines derived from SS patients, compared with controls (P < 0·001), which is suggestive of their intrinsically activated status. In SG biopsies, CD40 was constitutively expressed by lymphocytes, ductal epithelial cells and endothelial cells but not by other glandular cell types, such as acinar cells, myoepithelial cells and fibroblasts. In addition, CD40L staining was also detected in 30–50% of the infiltrating lymphocytes in the biopsies of SS patients. Our findings indicate the immunoregulatory potential of SGEC and lend further support to a model of intrinsic activation in salivary epithelia in SS, whereby these cells actively participate in the induction and maintenance of lymphocytic infiltrates of patients.
{"title":"CD40 on salivary gland epithelial cells: high constitutive expression by cultured cells from Sjögren’s syndrome patients indicating their intrinsic activation","authors":"Id Dimitriou, E. Kapsogeorgou, H. Moutsopoulos, M. Manoussakis","doi":"10.1046/j.1365-2249.2002.01752.x","DOIUrl":"https://doi.org/10.1046/j.1365-2249.2002.01752.x","url":null,"abstract":"CD40 has been identified in an expanding list of haematopoietic and non‐haematopoietic cells and has received an increased interest based on its role in a variety of cell‐mediated responses and its potential to participate in the pathogenesis of chronic inflammatory disorders. Sjögren’s syndrome (SS) is an autoimmune exocrinopathy, which is characterized by chronic lymphocytic infiltration of exocrine glands and aberrant activation of epithelial tissues. We studied the expression of CD40 protein in cultured non‐neoplastic salivary gland epithelial cell (SGEC) lines as well as in minor SG biopsies obtained from 17 SS patients and 12 controls. Immunocytochemical and flow cytometric analyses had revealed the occurrence of constitutively expressed CD40 molecules on the surface of long‐term cultured SGEC lines, which could be further induced by interferon‐gamma (IFN‐γ) and IL‐1β cytokines, but not tumour necrosis factor‐alpha (TNF‐α), IL‐4, IL‐6, granulocyte‐macrophage colony‐stimulating factor (GM‐CSF) or IFN‐α. Triggering of SGEC through CD40 enhanced the surface expression of the adhesion molecule intercellular adhesion molecule‐1 (ICAM‐1)/CD54, but not MHC class I and class II (HLA‐DR) molecules. Spontaneous CD40 expression was significantly higher in SGEC lines derived from SS patients, compared with controls (P < 0·001), which is suggestive of their intrinsically activated status. In SG biopsies, CD40 was constitutively expressed by lymphocytes, ductal epithelial cells and endothelial cells but not by other glandular cell types, such as acinar cells, myoepithelial cells and fibroblasts. In addition, CD40L staining was also detected in 30–50% of the infiltrating lymphocytes in the biopsies of SS patients. Our findings indicate the immunoregulatory potential of SGEC and lend further support to a model of intrinsic activation in salivary epithelia in SS, whereby these cells actively participate in the induction and maintenance of lymphocytic infiltrates of patients.","PeriodicalId":10179,"journal":{"name":"Clinical & Experimental Immunology","volume":"2 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2002-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"78338546","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}
京公网安备 11010802042870号
京ICP备2023020795号-1
扫码关注我们
求助内容：
应助结果提醒方式：