S. Phatak, S. Chaurasia, S. Mishra, R. Gupta, V. Agrawal, A. Aggarwal, R. Misra
B cell activating factor (BAFF) and a proliferation‐inducing ligand (APRIL) help in B cell activation, maintenance and plasma cell survival. B cell infiltration has been demonstrated in kidneys of patients with lupus nephritis (LN). Serum levels of BAFF and APRIL have shown inconsistent relationships with lupus disease activity. We evaluated urinary levels of BAFF and APRIL as biomarker for LN. Thirty‐six patients with proliferative lupus nephritis (AN), 10 with active lupus without nephritis (AL) and 15 healthy controls (HC) were studied. APRIL and BAFF levels were measured in both serum and urine using enzyme‐linked immunosorbent assay (ELISA). Urine levels were normalized for urinary creatinine excretion. Urine levels were correlated with conventional disease activity markers and histology. Levels were reassessed in 20 AN patients at 6 months after treatment with cyclophosphamide. Urinary APRIL (uAPRIL) and BAFF (uBAFF) levels were raised significantly in AN. uAPRIL, but not uBAFF, correlated moderately with renal Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) in AN (r = 0·36, P < 0·05). On receiver operator curve (ROC) analysis, uBAFF and uAPRIL showed an area under the curve (AUC) of 0·825 and 0·781, respectively, in differentiating between nephritis and non‐nephritis, which performed better than low C3, C4 and raised anti‐dsDNA antibodies. There was no correlation of serum levels with uBAFF (r = 0·187, P = 0·261) and uAPRIL (r = 0·114, P = 0·494). uAPRIL levels reduced after treatment (mean 125 pg/mg to 36 pg/mg, P < 0·05). uBAFF levels reduced in 16 responders while two of four non‐responders had increase in levels. Thus, uBAFF and uAPRIL are potential biomarkers of proliferative lupus nephritis.
B细胞活化因子(BAFF)和增殖诱导配体(APRIL)有助于B细胞的活化、维持和浆细胞的存活。狼疮性肾炎(LN)患者肾脏中已发现B细胞浸润。血清BAFF和APRIL水平与狼疮疾病活动的关系不一致。我们评估了尿液BAFF和APRIL水平作为LN的生物标志物。本文对36例增殖性狼疮肾炎(AN)患者、10例活动性狼疮无肾炎(AL)患者和15例健康对照(HC)患者进行了研究。采用酶联免疫吸附试验(ELISA)测定血清和尿液中的APRIL和BAFF水平。尿肌酐排泄水平正常。尿水平与常规疾病活动标志物和组织学相关。在环磷酰胺治疗6个月后，对20例AN患者的水平进行重新评估。尿APRIL (uAPRIL)和BAFF (uBAFF)水平在AN组显著升高。uAPRIL与肾脏系统性红斑狼疮疾病活动指数(SLEDAI)中度相关(r = 0.36, P < 0.05)，而uBAFF与肾系统性红斑狼疮疾病活动指数(SLEDAI)不相关。在受试者操作曲线(ROC)分析中，uBAFF和u四月在鉴别肾炎和非肾炎的曲线下面积(AUC)分别为0.825和0.781，优于低C3、C4和高抗dsDNA抗体。血清水平与uBAFF (r = 0.187, P = 0.261)、uAPRIL (r = 0.114, P = 0.494)无相关性。治疗后uAPRIL水平降低(平均125 pg/mg至36 pg/mg, P < 0.05)。16名应答者的uBAFF水平降低，而4名无应答者中的2名水平升高。因此，uBAFF和uAPRIL是增殖性狼疮性肾炎的潜在生物标志物。
{"title":"Urinary B cell activating factor (BAFF) and a proliferation‐inducing ligand (APRIL): potential biomarkers of active lupus nephritis","authors":"S. Phatak, S. Chaurasia, S. Mishra, R. Gupta, V. Agrawal, A. Aggarwal, R. Misra","doi":"10.1111/cei.12894","DOIUrl":"https://doi.org/10.1111/cei.12894","url":null,"abstract":"B cell activating factor (BAFF) and a proliferation‐inducing ligand (APRIL) help in B cell activation, maintenance and plasma cell survival. B cell infiltration has been demonstrated in kidneys of patients with lupus nephritis (LN). Serum levels of BAFF and APRIL have shown inconsistent relationships with lupus disease activity. We evaluated urinary levels of BAFF and APRIL as biomarker for LN. Thirty‐six patients with proliferative lupus nephritis (AN), 10 with active lupus without nephritis (AL) and 15 healthy controls (HC) were studied. APRIL and BAFF levels were measured in both serum and urine using enzyme‐linked immunosorbent assay (ELISA). Urine levels were normalized for urinary creatinine excretion. Urine levels were correlated with conventional disease activity markers and histology. Levels were reassessed in 20 AN patients at 6 months after treatment with cyclophosphamide. Urinary APRIL (uAPRIL) and BAFF (uBAFF) levels were raised significantly in AN. uAPRIL, but not uBAFF, correlated moderately with renal Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) in AN (r = 0·36, P < 0·05). On receiver operator curve (ROC) analysis, uBAFF and uAPRIL showed an area under the curve (AUC) of 0·825 and 0·781, respectively, in differentiating between nephritis and non‐nephritis, which performed better than low C3, C4 and raised anti‐dsDNA antibodies. There was no correlation of serum levels with uBAFF (r = 0·187, P = 0·261) and uAPRIL (r = 0·114, P = 0·494). uAPRIL levels reduced after treatment (mean 125 pg/mg to 36 pg/mg, P < 0·05). uBAFF levels reduced in 16 responders while two of four non‐responders had increase in levels. Thus, uBAFF and uAPRIL are potential biomarkers of proliferative lupus nephritis.","PeriodicalId":10179,"journal":{"name":"Clinical & Experimental Immunology","volume":"15 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2017-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"88790530","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. Elkuch, Victor Greiff, Christoph Berger, M. Bouchenaki, T. Daikeler, A. Bircher, Alexander A. Navarini, I. Heijnen, M. Recher
During the last two decades, hyper‐immunoglobulin (Ig)E syndromes have been characterized clinically and molecularly in patients with genetically determined primary immunodeficiencies. However, the detection of low IgE levels, defined here as below detection limit in the routine clinical immunology laboratory, has received little attention. We analysed the association of serum IgA, IgM and IgG levels (including IgG subclasses) with low, normal or high serum IgE levels in patients evaluated in a single‐centre out‐patient immunodeficiency and allergy clinic. The correlation of serum IgE levels with IgG subclasses depended on the clinical phenotype. In patients with immunodeficiencies, IgE correlated with IgG2 and IgG4 but not with IgG3. In contrast, in patients referred for signs of allergy, IgE correlated with IgG3 but not with IgG2. A low IgE result was associated with low IgG3 and IgG4 in allergy referrals, while immunodeficiency referrals with a low IgE result had significantly lower IgG1, IgG2 and IgG4 levels. Hierarchical clustering of non‐IgE immunoglobulin profiles (IgM, IgA, IgG, IgG1–4) validated that non‐IgE immunoglobulin levels predict the clinic referral, i.e. phenotype, of low‐IgE patients. These results suggesto guide the clinical management of patients with low serum IgE levels.
{"title":"Low immunoglobulin E flags two distinct types of immune dysregulation","authors":"M. Elkuch, Victor Greiff, Christoph Berger, M. Bouchenaki, T. Daikeler, A. Bircher, Alexander A. Navarini, I. Heijnen, M. Recher","doi":"10.1111/cei.12885","DOIUrl":"https://doi.org/10.1111/cei.12885","url":null,"abstract":"During the last two decades, hyper‐immunoglobulin (Ig)E syndromes have been characterized clinically and molecularly in patients with genetically determined primary immunodeficiencies. However, the detection of low IgE levels, defined here as below detection limit in the routine clinical immunology laboratory, has received little attention. We analysed the association of serum IgA, IgM and IgG levels (including IgG subclasses) with low, normal or high serum IgE levels in patients evaluated in a single‐centre out‐patient immunodeficiency and allergy clinic. The correlation of serum IgE levels with IgG subclasses depended on the clinical phenotype. In patients with immunodeficiencies, IgE correlated with IgG2 and IgG4 but not with IgG3. In contrast, in patients referred for signs of allergy, IgE correlated with IgG3 but not with IgG2. A low IgE result was associated with low IgG3 and IgG4 in allergy referrals, while immunodeficiency referrals with a low IgE result had significantly lower IgG1, IgG2 and IgG4 levels. Hierarchical clustering of non‐IgE immunoglobulin profiles (IgM, IgA, IgG, IgG1–4) validated that non‐IgE immunoglobulin levels predict the clinic referral, i.e. phenotype, of low‐IgE patients. These results suggesto guide the clinical management of patients with low serum IgE levels.","PeriodicalId":10179,"journal":{"name":"Clinical & Experimental Immunology","volume":"113 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2017-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"82433741","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. Radenkovic, K. Uvebrant, Oskar Skog, Luis Sarmiento, J. Avartsson, Petter Storm, P. Vickman, P. Bertilsson, Malin Fex, O. Korgsgren, C. M. Cilio
The current view of type 1 diabetes (T1D) is that it is an immune‐mediated disease where lymphocytes infiltrate the pancreatic islets, promote killing of beta cells and cause overt diabetes. Although tissue resident immune cells have been demonstrated in several organs, the composition of lymphocytes in human healthy pancreatic islets have been scarcely studied. Here we aimed to investigate the phenotype of immune cells associated with human islets of non‐diabetic organ donors. A flow cytometry analysis of isolated islets from perfused pancreases (n = 38) was employed to identify alpha, beta, T, natural killer (NK) and B cells. Moreover, the expression of insulin and glucagon transcripts was evaluated by RNA sequencing. Up to 80% of the lymphocytes were CD3+ T cells with a remarkable bias towards CD8+ cells. Central memory and effector memory phenotypes dominated within the CD8+ and CD4+ T cells and most CD8+ T cells were positive for CD69 and up to 50–70% for CD103, both markers of resident memory cells. The frequency of B and NK cells was low in most islet preparations (12 and 3% of CD45+ cells, respectively), and the frequency of alpha and beta cells varied between donors and correlated clearly with insulin and glucagon mRNA expression. In conclusion, we demonstrated the predominance of canonical tissue resident memory CD8+ T cells associated with human islets. We believe that these results are important to understand more clearly the immunobiology of human islets and the disease‐related phenotypes observed in diabetes.
{"title":"Characterization of resident lymphocytes in human pancreatic islets","authors":"M. Radenkovic, K. Uvebrant, Oskar Skog, Luis Sarmiento, J. Avartsson, Petter Storm, P. Vickman, P. Bertilsson, Malin Fex, O. Korgsgren, C. M. Cilio","doi":"10.1111/cei.12892","DOIUrl":"https://doi.org/10.1111/cei.12892","url":null,"abstract":"The current view of type 1 diabetes (T1D) is that it is an immune‐mediated disease where lymphocytes infiltrate the pancreatic islets, promote killing of beta cells and cause overt diabetes. Although tissue resident immune cells have been demonstrated in several organs, the composition of lymphocytes in human healthy pancreatic islets have been scarcely studied. Here we aimed to investigate the phenotype of immune cells associated with human islets of non‐diabetic organ donors. A flow cytometry analysis of isolated islets from perfused pancreases (n = 38) was employed to identify alpha, beta, T, natural killer (NK) and B cells. Moreover, the expression of insulin and glucagon transcripts was evaluated by RNA sequencing. Up to 80% of the lymphocytes were CD3+ T cells with a remarkable bias towards CD8+ cells. Central memory and effector memory phenotypes dominated within the CD8+ and CD4+ T cells and most CD8+ T cells were positive for CD69 and up to 50–70% for CD103, both markers of resident memory cells. The frequency of B and NK cells was low in most islet preparations (12 and 3% of CD45+ cells, respectively), and the frequency of alpha and beta cells varied between donors and correlated clearly with insulin and glucagon mRNA expression. In conclusion, we demonstrated the predominance of canonical tissue resident memory CD8+ T cells associated with human islets. We believe that these results are important to understand more clearly the immunobiology of human islets and the disease‐related phenotypes observed in diabetes.","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":"89302515","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. Mariaselvam, C. Mariaselvam, R. Tamouza, Rajagopal Krishnamoorthy, Dominique Charron, Durga Prasanna Misra, Vikramraj K Jain, V. S. Negi
NKG2D (KLRK1) is a C‐type lectin receptor present on natural killer (NK) cells, γδ, CD8+ and CD4+ T cells. Upon ligand binding, NKG2D mediates activatory and co‐stimulatory signals to NK cells and activated CD4+ T cells, respectively. Polymorphisms in NKG2D predispose to infectious diseases, cancer, transplantation and autoimmune disorders. We studied the influence of this NK receptor polymorphism on predisposition to and modification of the disease phenotype in patients with rheumatoid arthritis (RA). Eight different single nucleotide polymorphisms (SNP) in the NKG2 gene were genotyped in 236 patients with RA and 187 controls using Taqman 5' nuclease assays. NKG2D genotype/allele frequency did not differ between patients and controls. Subgroup analysis showed that the frequency of A allele of NKG2D9 and T allele of NKG2D10 was significantly higher in patients with deformities (a marker of severe disease) [11 versus 5%, Pc = 0·03, odds ratio (OR) = 2·44, 95% confidence interval (CI) = 1·09‐5·98 and 10 versus 4%, Pc = 0·04, OR = 2·45, 95% CI = 1·05‐6·39, respectively], while the frequency of alleles G of NKG2D9 and A of NKG2D10 was greater in patients without deformities (Pc = 0·03, OR = 0·41, 95% CI = 0·17‐0·91 and Pc = 0·04, OR = 0·41, 95% CI = 0·16‐0·96). Similar trends of association were observed with deforming phenotype of RA in female patients and deforming young onset RA subgroups. Haplotype analysis revealed that the frequency of haplotype G‐C‐A‐G‐A‐T‐C‐C was higher in patients than in controls (12 versus 8%, P = 0·04, OR = 1·61, 95% CI = 1·01‐2·55), suggesting that it may predispose to RA. Our study suggests that the NKG2D gene polymorphisms may modify the risk of development and severity of RA.
NKG2D (KLRK1)是一种C型凝集素受体，存在于自然杀伤细胞(NK)、γδ、CD8+和CD4+ T细胞上。在配体结合后，NKG2D分别介导NK细胞和活化CD4+ T细胞的激活和共刺激信号。NKG2D的多态性易导致传染病、癌症、移植和自身免疫性疾病。我们研究了这种NK受体多态性对类风湿关节炎(RA)患者的易感性和疾病表型改变的影响。采用Taqman 5′核酸酶测定方法，对236例RA患者和187例对照患者的NKG2基因进行了8种不同的单核苷酸多态性(SNP)分型。NKG2D基因型/等位基因频率在患者和对照组之间没有差异。亚组分析显示,一个等位基因的频率NKG2D10 NKG2D9和T等位基因的患者明显高于畸形(严重疾病的一个标志)(11 5%,电脑= 0·03,比值比(或)= 2·44岁的95%可信区间(CI) = 1·09年5·98和10 4%,个人电脑= 0·04或45 = 2·95% CI = 1·05年还是6·39岁,分别),而G等位基因的频率NKG2D9和NKG2D10更大的患者没有畸形(电脑= 0·03,或= 0·41岁,95% CI = 0·17 0·91和Pc = 0·04,Or = 0.41, 95% ci = 0.16‐0.96)。在女性患者和年轻发病的变形型RA亚组中，观察到类似的关联趋势。单倍型分析显示，患者中G‐C‐A‐G‐A‐T‐C‐C的单倍型频率高于对照组(12%比8%，P = 0.04, OR = 1.61, 95% CI = 1.01‐2.55)，提示其可能易患RA。我们的研究提示NKG2D基因多态性可能改变RA的发展风险和严重程度。
{"title":"Association of NKG2D gene variants with susceptibility and severity of rheumatoid arthritis","authors":"C. Mariaselvam, C. Mariaselvam, R. Tamouza, Rajagopal Krishnamoorthy, Dominique Charron, Durga Prasanna Misra, Vikramraj K Jain, V. S. Negi","doi":"10.1111/cei.12891","DOIUrl":"https://doi.org/10.1111/cei.12891","url":null,"abstract":"NKG2D (KLRK1) is a C‐type lectin receptor present on natural killer (NK) cells, γδ, CD8+ and CD4+ T cells. Upon ligand binding, NKG2D mediates activatory and co‐stimulatory signals to NK cells and activated CD4+ T cells, respectively. Polymorphisms in NKG2D predispose to infectious diseases, cancer, transplantation and autoimmune disorders. We studied the influence of this NK receptor polymorphism on predisposition to and modification of the disease phenotype in patients with rheumatoid arthritis (RA). Eight different single nucleotide polymorphisms (SNP) in the NKG2 gene were genotyped in 236 patients with RA and 187 controls using Taqman 5' nuclease assays. NKG2D genotype/allele frequency did not differ between patients and controls. Subgroup analysis showed that the frequency of A allele of NKG2D9 and T allele of NKG2D10 was significantly higher in patients with deformities (a marker of severe disease) [11 versus 5%, Pc = 0·03, odds ratio (OR) = 2·44, 95% confidence interval (CI) = 1·09‐5·98 and 10 versus 4%, Pc = 0·04, OR = 2·45, 95% CI = 1·05‐6·39, respectively], while the frequency of alleles G of NKG2D9 and A of NKG2D10 was greater in patients without deformities (Pc = 0·03, OR = 0·41, 95% CI = 0·17‐0·91 and Pc = 0·04, OR = 0·41, 95% CI = 0·16‐0·96). Similar trends of association were observed with deforming phenotype of RA in female patients and deforming young onset RA subgroups. Haplotype analysis revealed that the frequency of haplotype G‐C‐A‐G‐A‐T‐C‐C was higher in patients than in controls (12 versus 8%, P = 0·04, OR = 1·61, 95% CI = 1·01‐2·55), suggesting that it may predispose to RA. Our study suggests that the NKG2D gene polymorphisms may modify the risk of development and severity of RA.","PeriodicalId":10179,"journal":{"name":"Clinical & Experimental Immunology","volume":"11 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2017-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"88820670","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}
Non‐coding RNAs (ncRNAs), including microRNAs (miRNAs) and long non‐coding RNAs (lncRNAs), are RNA molecules that do not translate into protein. Both miRNAs and lncRNAs are known to regulate gene expression and to play an essential role in T cell differentiation and function. Both systemic lupus erythematosus (SLE), a prototypic systemic autoimmune disease, and rheumatoid arthritis (RA), a representative disease of inflammatory arthritis, are characterized by a complex dysfunction in the innate and adaptive immunity. T cells play a central role in cell‐mediated immune response and multiple defects in T cells from patients with SLE and RA have been observed. Abnormality in T cell signalling, cytokine and chemokine production, T cell activation and apoptosis, T cell differentiation and DNA methylation that are associated closely with the aberrant expression of a number of miRNAs and lncRNAs have been implicated in the immunopathogenesis of SLE and RA. This review aims to provide an overview of the current state of research on the abnormal expression of miRNAs and lncRNAs in T cells and their roles in the immunopathogenesis of SLE and RA. In addition, by comparing the differences in aberrant expression of miRNAs and lncRNAs in T cells between patients with SLE and RA, controversial areas are highlighted that warrant further investigation.
{"title":"Immunopathogenesis of systemic lupus erythematosus and rheumatoid arthritis: the role of aberrant expression of non‐coding RNAs in T cells","authors":"N. Lai, Malcolm Koo, Chia-Li Yu, Ming-Chi Lu","doi":"10.1111/cei.12903","DOIUrl":"https://doi.org/10.1111/cei.12903","url":null,"abstract":"Non‐coding RNAs (ncRNAs), including microRNAs (miRNAs) and long non‐coding RNAs (lncRNAs), are RNA molecules that do not translate into protein. Both miRNAs and lncRNAs are known to regulate gene expression and to play an essential role in T cell differentiation and function. Both systemic lupus erythematosus (SLE), a prototypic systemic autoimmune disease, and rheumatoid arthritis (RA), a representative disease of inflammatory arthritis, are characterized by a complex dysfunction in the innate and adaptive immunity. T cells play a central role in cell‐mediated immune response and multiple defects in T cells from patients with SLE and RA have been observed. Abnormality in T cell signalling, cytokine and chemokine production, T cell activation and apoptosis, T cell differentiation and DNA methylation that are associated closely with the aberrant expression of a number of miRNAs and lncRNAs have been implicated in the immunopathogenesis of SLE and RA. This review aims to provide an overview of the current state of research on the abnormal expression of miRNAs and lncRNAs in T cells and their roles in the immunopathogenesis of SLE and RA. In addition, by comparing the differences in aberrant expression of miRNAs and lncRNAs in T cells between patients with SLE and RA, controversial areas are highlighted that warrant further investigation.","PeriodicalId":10179,"journal":{"name":"Clinical & Experimental Immunology","volume":"15 6","pages":""},"PeriodicalIF":0.0,"publicationDate":"2017-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"91512220","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}
William Egner, Matthew Helbert, R. Sargur, K. Swallow, N. Harper, T. Garcez, Sinisa Savic, L. Savic, Eren Effren
We describe an observational survey of diagnostic pathways in 104 patients attending four specialist allergy clinics in the United Kingdom following perioperative hypersensitivity reactions to chlorhexidine reactions. The majority were life‐threatening. Men undergoing urological or cardiothoracic surgery predominated. Skin prick testing and specific immunoglobulin (sIg)E testing were the most common tests used for diagnosis. Fifty‐three per cent of diagnoses were made on the basis of a single positive test. Where multiple tests were performed the sensitivity of intradermal, basophil activation and skin prick testing was 68% (50–86%), 50% (10–90%) and 35% (17–55%), respectively. Seven per cent were negative on screening tests initially, and 12 cases were only positive for a single test despite multiple testing. Intradermal tests appeared most sensitive in this context. Additional sensitization to other substances used perioperatively, particularly neuromuscular blocking agents (NMBA), was found in 28 patients, emphasizing the need to test for possible allergy to all drugs to which the patient was exposed even where chlorhexidine is positive.
{"title":"Chlorhexidine allergy in four specialist allergy centres in the United Kingdom, 2009–13: clinical features and diagnostic tests","authors":"William Egner, Matthew Helbert, R. Sargur, K. Swallow, N. Harper, T. Garcez, Sinisa Savic, L. Savic, Eren Effren","doi":"10.1111/cei.12944","DOIUrl":"https://doi.org/10.1111/cei.12944","url":null,"abstract":"We describe an observational survey of diagnostic pathways in 104 patients attending four specialist allergy clinics in the United Kingdom following perioperative hypersensitivity reactions to chlorhexidine reactions. The majority were life‐threatening. Men undergoing urological or cardiothoracic surgery predominated. Skin prick testing and specific immunoglobulin (sIg)E testing were the most common tests used for diagnosis. Fifty‐three per cent of diagnoses were made on the basis of a single positive test. Where multiple tests were performed the sensitivity of intradermal, basophil activation and skin prick testing was 68% (50–86%), 50% (10–90%) and 35% (17–55%), respectively. Seven per cent were negative on screening tests initially, and 12 cases were only positive for a single test despite multiple testing. Intradermal tests appeared most sensitive in this context. Additional sensitization to other substances used perioperatively, particularly neuromuscular blocking agents (NMBA), was found in 28 patients, emphasizing the need to test for possible allergy to all drugs to which the patient was exposed even where chlorhexidine is positive.","PeriodicalId":10179,"journal":{"name":"Clinical & Experimental Immunology","volume":"37 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2017-02-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"91092025","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}
Microarray of peripheral blood (PB) and synovial fluid mononuclear cells (PBMC, SFMC) of patients with juvenile idiopathic arthritis–enthesitis‐related arthritis (JIA‐ERA) has shown the involvement of monocytes. On the basis of CD14 and CD16 expression, monocytes are classified as classical, intermediate and non‐classical. In response to Toll‐like receptor (TLR) stimulation, intermediate monocytes produce proinflammatory cytokines and play a role in inflammatory diseases. Therefore, we have studied the microarray profile of monocytes, the frequency of their subsets and cytokine production. Monocyte‐specific microarray analysis was performed in six healthy controls' PBMC and six patients' PBMC and SFMC using Illumina chips WG12. Monocyte subsets were assessed in 46 patients with JIA‐ERA and 17 healthy controls and 17 disease controls by flow cytometry. Interleukin (IL)−23 and tumour necrosis factor (TNF) levels were measured in culture supernatants of eight controls and seven patients' PBMC/SFMC with/without lipopolysaccharide (LPS) stimulation. Cytokine‐producing intermediate monocytes were assessed by flow cytometry. Genes related to antigen presentation, cytokine signalling and TLR pathway were regulated differentially in PB and synovial monocytes of patients with JIA‐ERA. Key genes of intermediate monocytes, such as CLEC10A and MARCO, were expressed three‐ to fourfold more in JIA‐ERA. In PB, the frequency of intermediate monocytes was significantly higher in JIA‐ERA (4·90% ± 3·5) compared to controls (1·8% ± 1·06; P < 0·001). Patients' synovial cells also had more intermediate monocytes compared to PB (11·25% ± 11·32, 5·9% ± 4·8; P = 0.004). Intermediate monocytes are the major producers of IL‐23. Thus, intermediate monocytes may play an important role in JIA‐ERA, possibly by producing cytokines, and contribute to joint inflammation.
{"title":"Intermediate monocytes are increased in enthesitis‐related arthritis, a category of juvenile idiopathic arthritis","authors":"Priyanka Gaur, A. Myles, R. Misra, A. Aggarwal","doi":"10.1111/cei.12880","DOIUrl":"https://doi.org/10.1111/cei.12880","url":null,"abstract":"Microarray of peripheral blood (PB) and synovial fluid mononuclear cells (PBMC, SFMC) of patients with juvenile idiopathic arthritis–enthesitis‐related arthritis (JIA‐ERA) has shown the involvement of monocytes. On the basis of CD14 and CD16 expression, monocytes are classified as classical, intermediate and non‐classical. In response to Toll‐like receptor (TLR) stimulation, intermediate monocytes produce proinflammatory cytokines and play a role in inflammatory diseases. Therefore, we have studied the microarray profile of monocytes, the frequency of their subsets and cytokine production. Monocyte‐specific microarray analysis was performed in six healthy controls' PBMC and six patients' PBMC and SFMC using Illumina chips WG12. Monocyte subsets were assessed in 46 patients with JIA‐ERA and 17 healthy controls and 17 disease controls by flow cytometry. Interleukin (IL)−23 and tumour necrosis factor (TNF) levels were measured in culture supernatants of eight controls and seven patients' PBMC/SFMC with/without lipopolysaccharide (LPS) stimulation. Cytokine‐producing intermediate monocytes were assessed by flow cytometry. Genes related to antigen presentation, cytokine signalling and TLR pathway were regulated differentially in PB and synovial monocytes of patients with JIA‐ERA. Key genes of intermediate monocytes, such as CLEC10A and MARCO, were expressed three‐ to fourfold more in JIA‐ERA. In PB, the frequency of intermediate monocytes was significantly higher in JIA‐ERA (4·90% ± 3·5) compared to controls (1·8% ± 1·06; P < 0·001). Patients' synovial cells also had more intermediate monocytes compared to PB (11·25% ± 11·32, 5·9% ± 4·8; P = 0.004). Intermediate monocytes are the major producers of IL‐23. Thus, intermediate monocytes may play an important role in JIA‐ERA, possibly by producing cytokines, and contribute to joint inflammation.","PeriodicalId":10179,"journal":{"name":"Clinical & Experimental Immunology","volume":"85 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2017-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"74321239","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 interleukin (IL)‐21/IL‐21 receptor (R) is a promising system to be exploited for the development of therapeutic strategies. Although the biological activities of IL‐21 and its cell signalling events have been largely studied in immunocytes, its interaction with human monocytes and macrophages have been neglected. Previously, we reported that IL‐21 enhances Fc gamma receptor (FcRγ)‐mediated phagocytosis in human monocytes and in human monocyte‐derived macrophages (HMDM) and identified Syk as a novel molecular target of IL‐21. Here, we elucidate further how IL‐21 promotes phagocytosis in these cells. Unlike its ability to enhance phagocytosis of opsonized sheep red blood cells (SRBCs), IL‐21 did not promote phagocytosis of Escherichia coli and zymosan by monocytes and did not alter the cell surface expression of CD16, CD32 and CD64. In HMDM, IL‐21 was found to enhance phagocytosis of zymosan. In addition, we found that IL‐21 activates p38, protein kinase B (Akt), signal transducer and activator of transcription (STAT)‐1 and STAT‐3 in monocytes and HMDM. Using a pharmacological approach, we demonstrate that IL‐21 enhances phagocytosis by activating some mitogen‐activated protein kinases (MAPKs) and phosphoinositide 3‐kinase (PI3K)–Akt and Janus kinase (JAK)–STAT pathways. These results obtained in human monocytes and macrophages have to be considered for a better exploitation of the IL‐21/IL‐21R system for therapeutic purposes.
{"title":"Mechanism involved in interleukin‐21‐induced phagocytosis in human monocytes and macrophages","authors":"F. Vallières, D. Girard","doi":"10.1111/cei.12886","DOIUrl":"https://doi.org/10.1111/cei.12886","url":null,"abstract":"The interleukin (IL)‐21/IL‐21 receptor (R) is a promising system to be exploited for the development of therapeutic strategies. Although the biological activities of IL‐21 and its cell signalling events have been largely studied in immunocytes, its interaction with human monocytes and macrophages have been neglected. Previously, we reported that IL‐21 enhances Fc gamma receptor (FcRγ)‐mediated phagocytosis in human monocytes and in human monocyte‐derived macrophages (HMDM) and identified Syk as a novel molecular target of IL‐21. Here, we elucidate further how IL‐21 promotes phagocytosis in these cells. Unlike its ability to enhance phagocytosis of opsonized sheep red blood cells (SRBCs), IL‐21 did not promote phagocytosis of Escherichia coli and zymosan by monocytes and did not alter the cell surface expression of CD16, CD32 and CD64. In HMDM, IL‐21 was found to enhance phagocytosis of zymosan. In addition, we found that IL‐21 activates p38, protein kinase B (Akt), signal transducer and activator of transcription (STAT)‐1 and STAT‐3 in monocytes and HMDM. Using a pharmacological approach, we demonstrate that IL‐21 enhances phagocytosis by activating some mitogen‐activated protein kinases (MAPKs) and phosphoinositide 3‐kinase (PI3K)–Akt and Janus kinase (JAK)–STAT pathways. These results obtained in human monocytes and macrophages have to be considered for a better exploitation of the IL‐21/IL‐21R system for therapeutic purposes.","PeriodicalId":10179,"journal":{"name":"Clinical & Experimental Immunology","volume":"50 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2017-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"75785673","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}
Masahiro Tahara, H. Tsuboi, S. Segawa, H. Asashima, Mana Iizuka-Koga, T. Hirota, Hiroyuki Takahashi, Y. Kondo, Minoru Matsui, I. Matsumoto, Takayuki Sumida
We showed recently that M3 muscarinic acetylcholine receptor (M3R)‐reactive CD3+ T cells play a pathogenic role in the development of murine autoimmune sialadenitis (MIS), which mimics Sjögren's syndrome (SS). The aim of this study was to determine the effectiveness and mechanism of action of retinoic acid‐related orphan receptor‐gamma t (RORγt) antagonist (A213) in MIS. Splenocytes from M3R knockout (M3R–/–) mice immunized with murine M3R peptide mixture were inoculated into recombination‐activating gene 1 knockout (Rag‐1–/–) mice (M3R–/–→Rag‐1–/–) with MIS. Immunized M3R–/– mice (pretransfer treatment) and M3R–/–→Rag‐1–/– mice (post‐transfer treatment) were treated with A213 every 3 days. Salivary volume, severity of sialadenitis and cytokine production from M3R peptide‐stimulated splenocytes and lymph node cells were examined. Effects of A213 on cytokine production were analysed by enzyme‐linked immunosorbent assay (ELISA) and on T helper type 1 (Th1), Th17 and Th2 differentiation from CD4+ T cells by flow cytometry. Pretransfer A213 treatment maintained salivary volume, improved MIS and reduced interferon (IFN)‐γ and interleukin (IL)‐17 production significantly compared with phosphate‐buffered saline (PBS) (P < 0·05). These suppressive effects involved CD4+ T cells rather than CD11c+ cells. Post‐transfer treatment with A213 increased salivary volume (P < 0·05), suppressed MIS (P < 0·005) and reduced IFN‐γ and IL‐17 production (P < 0·05). In vitro, A213 suppressed IFN‐γ and IL‐17 production from M3R‐stimulated splenocytes and CD4+ T cells of immunized M3R–/– mice (P < 0·05). In contrast with M3R specific responses, A213 suppressed only IL‐17 production from Th17 differentiated CD4+ T cells without any effect on Th1 and Th2 differentiation in vitro. Our findings suggested that RORγt antagonism is potentially suitable treatment strategy for SS‐like sialadenitis through suppression of IL‐17 and IFN‐γ production by M3R‐specific T cells.
{"title":"RORγt antagonist suppresses M3 muscarinic acetylcholine receptor‐induced Sjögren's syndrome‐like sialadenitis","authors":"Masahiro Tahara, H. Tsuboi, S. Segawa, H. Asashima, Mana Iizuka-Koga, T. Hirota, Hiroyuki Takahashi, Y. Kondo, Minoru Matsui, I. Matsumoto, Takayuki Sumida","doi":"10.1111/cei.12868","DOIUrl":"https://doi.org/10.1111/cei.12868","url":null,"abstract":"We showed recently that M3 muscarinic acetylcholine receptor (M3R)‐reactive CD3+ T cells play a pathogenic role in the development of murine autoimmune sialadenitis (MIS), which mimics Sjögren's syndrome (SS). The aim of this study was to determine the effectiveness and mechanism of action of retinoic acid‐related orphan receptor‐gamma t (RORγt) antagonist (A213) in MIS. Splenocytes from M3R knockout (M3R–/–) mice immunized with murine M3R peptide mixture were inoculated into recombination‐activating gene 1 knockout (Rag‐1–/–) mice (M3R–/–→Rag‐1–/–) with MIS. Immunized M3R–/– mice (pretransfer treatment) and M3R–/–→Rag‐1–/– mice (post‐transfer treatment) were treated with A213 every 3 days. Salivary volume, severity of sialadenitis and cytokine production from M3R peptide‐stimulated splenocytes and lymph node cells were examined. Effects of A213 on cytokine production were analysed by enzyme‐linked immunosorbent assay (ELISA) and on T helper type 1 (Th1), Th17 and Th2 differentiation from CD4+ T cells by flow cytometry. Pretransfer A213 treatment maintained salivary volume, improved MIS and reduced interferon (IFN)‐γ and interleukin (IL)‐17 production significantly compared with phosphate‐buffered saline (PBS) (P < 0·05). These suppressive effects involved CD4+ T cells rather than CD11c+ cells. Post‐transfer treatment with A213 increased salivary volume (P < 0·05), suppressed MIS (P < 0·005) and reduced IFN‐γ and IL‐17 production (P < 0·05). In vitro, A213 suppressed IFN‐γ and IL‐17 production from M3R‐stimulated splenocytes and CD4+ T cells of immunized M3R–/– mice (P < 0·05). In contrast with M3R specific responses, A213 suppressed only IL‐17 production from Th17 differentiated CD4+ T cells without any effect on Th1 and Th2 differentiation in vitro. Our findings suggested that RORγt antagonism is potentially suitable treatment strategy for SS‐like sialadenitis through suppression of IL‐17 and IFN‐γ production by M3R‐specific T cells.","PeriodicalId":10179,"journal":{"name":"Clinical & Experimental Immunology","volume":"8 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2017-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"74617820","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. Theil, C. Wilhelm, M. Kuhn, A. Petzold, S. Tuve, U. Oelschlägel, A. Dahl, M. Bornhäuser, E. Bonifacio, A. Eugster
Regulatory T cell (Treg) therapy has been exploited in autoimmune disease, solid organ transplantation and in efforts to prevent or treat graft‐versus‐host disease (GVHD). However, our knowledge on the in‐vivo persistence of transfused Treg is limited. Whether Treg transfusion leads to notable changes in the overall Treg repertoire or whether longevity of Treg in the periphery is restricted to certain clones is unknown. Here we use T cell receptor alpha chain sequencing (TCR‐α‐NGS) to monitor changes in the repertoire of Treg upon polyclonal expansion and after subsequent adoptive transfer. We applied TCR‐α‐NGS to samples from two patients with chronic GVHD who received comparable doses of stem cell donor derived expanded Treg. We found that in‐vitro polyclonal expansion led to notable repertoire changes in vitro and that Treg cell therapy altered the peripheral Treg repertoire considerably towards that of the infused cell product, to different degrees, in each patient. Clonal changes in the peripheral blood were transient and correlated well with the clinical parameters. We suggest that T cell clonotype analyses using TCR sequencing should be considered as a means to monitor longevity and fate of adoptively transferred T cells.
{"title":"T cell receptor repertoires after adoptive transfer of expanded allogeneic regulatory T cells","authors":"A. Theil, C. Wilhelm, M. Kuhn, A. Petzold, S. Tuve, U. Oelschlägel, A. Dahl, M. Bornhäuser, E. Bonifacio, A. Eugster","doi":"10.1111/cei.12887","DOIUrl":"https://doi.org/10.1111/cei.12887","url":null,"abstract":"Regulatory T cell (Treg) therapy has been exploited in autoimmune disease, solid organ transplantation and in efforts to prevent or treat graft‐versus‐host disease (GVHD). However, our knowledge on the in‐vivo persistence of transfused Treg is limited. Whether Treg transfusion leads to notable changes in the overall Treg repertoire or whether longevity of Treg in the periphery is restricted to certain clones is unknown. Here we use T cell receptor alpha chain sequencing (TCR‐α‐NGS) to monitor changes in the repertoire of Treg upon polyclonal expansion and after subsequent adoptive transfer. We applied TCR‐α‐NGS to samples from two patients with chronic GVHD who received comparable doses of stem cell donor derived expanded Treg. We found that in‐vitro polyclonal expansion led to notable repertoire changes in vitro and that Treg cell therapy altered the peripheral Treg repertoire considerably towards that of the infused cell product, to different degrees, in each patient. Clonal changes in the peripheral blood were transient and correlated well with the clinical parameters. We suggest that T cell clonotype analyses using TCR sequencing should be considered as a means to monitor longevity and fate of adoptively transferred T cells.","PeriodicalId":10179,"journal":{"name":"Clinical & Experimental Immunology","volume":"81 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2017-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"78511625","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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