G. Serena, G. Serena, Shu Yan, Stephanie Camhi, S. Patel, Rosiane Lima, A. Sapone, A. Sapone, M. Leonard, R. Mukherjee, B. Nath, K. Lammers, A. Fasano
Coeliac disease (CD) is an autoimmune enteropathy triggered by gluten and characterized by a strong T helper type 1 (Th1)/Th17 immune response in the small intestine. Regulatory T cells (Treg) are CD4+CD25++forkhead box protein 3 (FoxP3+) cells that regulate the immune response. Conversely to its counterpart, FoxP3 full length (FL), the alternatively spliced isoform FoxP3 Δ2, cannot properly down‐regulate the Th17‐driven immune response. As the active state of CD has been associated with impairments in Treg cell function, we aimed at determining whether imbalances between FoxP3 isoforms may be associated with the disease. Intestinal biopsies from patients with active CD showed increased expression of FOXP3 Δ2 isoform over FL, while both isoforms were expressed similarly in non‐coeliac control subjects (HC). Conversely to what we saw in the intestine, peripheral blood mononuclear cells (PBMC) from HC subjects did not show the same balance between isoforms. We therefore hypothesized that the intestinal microenvironment may play a role in modulating alternative splicing. The proinflammatory intestinal microenvironment of active patients has been reported to be enriched in butyrate‐producing bacteria, while high concentrations of lactate have been shown to characterize the preclinical stage of the disease. We show that the combination of interferon (IFN)‐γ and butyrate triggers the balance between FoxP3 isoforms in HC subjects, while the same does not occur in CD patients. Furthermore, we report that lactate increases both isoforms in CD patients. Collectively, these findings highlight the importance of the ratio between FoxP3 isoforms in CD and, for the first time, associate the alternative splicing process mechanistically with microbial‐derived metabolites.
{"title":"Proinflammatory cytokine interferon‐γ and microbiome‐derived metabolites dictate epigenetic switch between forkhead box protein 3 isoforms in coeliac disease","authors":"G. Serena, G. Serena, Shu Yan, Stephanie Camhi, S. Patel, Rosiane Lima, A. Sapone, A. Sapone, M. Leonard, R. Mukherjee, B. Nath, K. Lammers, A. Fasano","doi":"10.1111/cei.12911","DOIUrl":"https://doi.org/10.1111/cei.12911","url":null,"abstract":"Coeliac disease (CD) is an autoimmune enteropathy triggered by gluten and characterized by a strong T helper type 1 (Th1)/Th17 immune response in the small intestine. Regulatory T cells (Treg) are CD4+CD25++forkhead box protein 3 (FoxP3+) cells that regulate the immune response. Conversely to its counterpart, FoxP3 full length (FL), the alternatively spliced isoform FoxP3 Δ2, cannot properly down‐regulate the Th17‐driven immune response. As the active state of CD has been associated with impairments in Treg cell function, we aimed at determining whether imbalances between FoxP3 isoforms may be associated with the disease. Intestinal biopsies from patients with active CD showed increased expression of FOXP3 Δ2 isoform over FL, while both isoforms were expressed similarly in non‐coeliac control subjects (HC). Conversely to what we saw in the intestine, peripheral blood mononuclear cells (PBMC) from HC subjects did not show the same balance between isoforms. We therefore hypothesized that the intestinal microenvironment may play a role in modulating alternative splicing. The proinflammatory intestinal microenvironment of active patients has been reported to be enriched in butyrate‐producing bacteria, while high concentrations of lactate have been shown to characterize the preclinical stage of the disease. We show that the combination of interferon (IFN)‐γ and butyrate triggers the balance between FoxP3 isoforms in HC subjects, while the same does not occur in CD patients. Furthermore, we report that lactate increases both isoforms in CD patients. Collectively, these findings highlight the importance of the ratio between FoxP3 isoforms in CD and, for the first time, associate the alternative splicing process mechanistically with microbial‐derived metabolites.","PeriodicalId":10179,"journal":{"name":"Clinical & Experimental Immunology","volume":"36 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2016-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"84643923","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
J. Wang, X. Cao, J. Zhao, H. Zhao, J. Wei, Q. Li, X. Qi, Z. Yang, L. Wang, H. Zhang, L. Bai, Z. Wu, L. Zhao, Z. Hong, Z. Yin
Dendritic cells (DCs) play critical roles in initiating and regulating innate immunity as well as adaptive immune responses. However, the role of conventional dendritic cells (cDCs) in concanavalin A (ConA)‐induced fulminant hepatitis is unknown. In this study, we demonstrated that depletion of cDCs using either CD11c‐diphtheria toxin receptor transgenic mice (DTR Tg) mice or anti‐CD11c antibody reduced the severity of liver injury significantly, indicating a detrimental role of cDCs in ConA‐induced hepatitis. We elucidated further the pathological role of cDCs as being the critical source of interleukin (IL)‐12, which induced the secretion of interferon (IFN)‐γ by natural killer (NK) T cells. Reconstitution of cDCs‐depleted mice with IL‐12 restored ConA‐induced hepatitis significantly. Furthermore, we determined that NK T cells were the target of DC‐derived IL‐12, and NK T cells contributed to liver inflammation and injury through production of IFN‐γ. In summary, our study demonstrated a novel function of cDCs in mediating ConA‐induced hepatitis through regulating IFN‐γ secretion of NK T cells in an IL‐12‐dependent fashion. Targeting cDCs might provide potentially therapeutic applications in treating autoimmune related liver diseases.
{"title":"Critical roles of conventional dendritic cells in promoting T cell‐dependent hepatitis through regulating natural killer T cells","authors":"J. Wang, X. Cao, J. Zhao, H. Zhao, J. Wei, Q. Li, X. Qi, Z. Yang, L. Wang, H. Zhang, L. Bai, Z. Wu, L. Zhao, Z. Hong, Z. Yin","doi":"10.1111/cei.12907","DOIUrl":"https://doi.org/10.1111/cei.12907","url":null,"abstract":"Dendritic cells (DCs) play critical roles in initiating and regulating innate immunity as well as adaptive immune responses. However, the role of conventional dendritic cells (cDCs) in concanavalin A (ConA)‐induced fulminant hepatitis is unknown. In this study, we demonstrated that depletion of cDCs using either CD11c‐diphtheria toxin receptor transgenic mice (DTR Tg) mice or anti‐CD11c antibody reduced the severity of liver injury significantly, indicating a detrimental role of cDCs in ConA‐induced hepatitis. We elucidated further the pathological role of cDCs as being the critical source of interleukin (IL)‐12, which induced the secretion of interferon (IFN)‐γ by natural killer (NK) T cells. Reconstitution of cDCs‐depleted mice with IL‐12 restored ConA‐induced hepatitis significantly. Furthermore, we determined that NK T cells were the target of DC‐derived IL‐12, and NK T cells contributed to liver inflammation and injury through production of IFN‐γ. In summary, our study demonstrated a novel function of cDCs in mediating ConA‐induced hepatitis through regulating IFN‐γ secretion of NK T cells in an IL‐12‐dependent fashion. Targeting cDCs might provide potentially therapeutic applications in treating autoimmune related liver diseases.","PeriodicalId":10179,"journal":{"name":"Clinical & Experimental Immunology","volume":"1 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2016-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"82144675","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. Golding, S. Darko, W. Wylie, D. Douek, E. Shevach
Maintenance of peripheral tolerance requires a balance between autoreactive conventional T cells (Tconv) and thymically derived forkhead box protein 3 (FoxP3)+ regulatory T cells (tTregs). Considerable controversy exists regarding the similarities/differences in T cell receptor (TCR) repertoires expressed by Tconv and tTregs. We generated highly purified populations of human adult and cord blood Tconv and tTregs based on the differential expression of CD25 and CD127. The purity of the sorted populations was validated by intracellular staining for FoxP3 and Helios. We also purified an overlap group of CD4 T cells from adult donors to ensure that considerable numbers of shared clonotypes could be detected when present. We used deep sequencing of entire TCR‐β CDR3 sequences to analyse the TCR repertoire of Tconv and tTregs. Our studies suggest that both neonatal and adult human Tconv and tTreg cells are, in fact, entirely distinct CD4 T cell lineages.
{"title":"Deep sequencing of the TCR‐β repertoire of human forkhead box protein 3 (FoxP3)+ and FoxP3– T cells suggests that they are completely distinct and non‐overlapping","authors":"A. Golding, S. Darko, W. Wylie, D. Douek, E. Shevach","doi":"10.1111/cei.12904","DOIUrl":"https://doi.org/10.1111/cei.12904","url":null,"abstract":"Maintenance of peripheral tolerance requires a balance between autoreactive conventional T cells (Tconv) and thymically derived forkhead box protein 3 (FoxP3)+ regulatory T cells (tTregs). Considerable controversy exists regarding the similarities/differences in T cell receptor (TCR) repertoires expressed by Tconv and tTregs. We generated highly purified populations of human adult and cord blood Tconv and tTregs based on the differential expression of CD25 and CD127. The purity of the sorted populations was validated by intracellular staining for FoxP3 and Helios. We also purified an overlap group of CD4 T cells from adult donors to ensure that considerable numbers of shared clonotypes could be detected when present. We used deep sequencing of entire TCR‐β CDR3 sequences to analyse the TCR repertoire of Tconv and tTregs. Our studies suggest that both neonatal and adult human Tconv and tTreg cells are, in fact, entirely distinct CD4 T cell lineages.","PeriodicalId":10179,"journal":{"name":"Clinical & Experimental Immunology","volume":"44 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2016-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"83022583","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}
Soo-Young Kim, M. Hur, B. Choi, Min Jung Kim, Yang Won Lee, Y. Choe, Kyu Joong Ahn
Psoriasis is a polygenic and multi‐factorial disease showing ethnic differences in terms of its severity and frequency. Therapies targeting interleukin (IL)−17A, IL‐17 receptor (IL‐17R) and Janus kinases (JAKs) are in clinical development for the treatment of psoriasis, and their success suggests the essential role of these molecules in psoriasis. To investigate the genetic susceptibility in T helper type 17 (Th17) cell signal transduction pathways for promoting psoriasis, we performed candidate gene and linkage disequilibrium analysis. In 208 patients and 266 normal controls, we analysed 31 single nucleotide polymorphisms in 12 genes (CAMP, IL17A, IL17F, IL17RA, IL22, JAK1, JAK2, JAK3, STAT3, TLR7, TLR9 and TYK2; abbreviations: CAMP, human cathelicidin antimicrobial peptide; STAT‐3, signal transducer and activator of transcription 3; TLR, Toll‐like receptor; TYK2, tyrosine kinase 2). Patients with psoriasis showed a strong association for IL17F rs763780 [odds ratio (OR) = 3·27, P = 0·04], which results in a histidine‐to‐arginine substitution, and JAK2 rs2274471 (OR = 2·66, P = 0·02). In addition, JAK2 rs7849191 showed a protective pattern, met the significance threshold (OR = 0·77, P = 0·05) and showed a tendency for an inverse association with the frequency of early‐onset psoriasis under age 40 years (P = 0·07). In haplotype analysis, JAK1 rs310241A/rs2780889T showed a protective effect (OR = 0·73, P = 0·03) in psoriasis. In conclusion, we report two new psoriasis‐susceptibility loci, in IL17F and JAK2, as well as a newly identified late‐onset associated protective JAK2 locus and a protective JAK1 haplotype in the Korean population.
银屑病是一种多基因、多因子的疾病，其严重程度和发病频率存在民族差异。针对白介素(IL) - 17A、IL - 17受体(IL - 17R)和Janus激酶(JAKs)的治疗方法正在临床开发中，它们的成功表明这些分子在牛皮癣中的重要作用。为了研究辅助性T型17 (Th17)细胞信号转导通路促进银屑病的遗传易感性，我们进行了候选基因和连锁不平衡分析。在208例患者和266例正常对照中，我们分析了12个基因(CAMP、IL17A、IL17F、IL17RA、IL22、JAK1、JAK2、JAK3、STAT3、TLR7、TLR9和TYK2)的31个单核苷酸多态性;缩写:CAMP，人抗菌肽;STAT‐3，信号转换器和转录激活器3;Toll样受体;银屑病患者与IL17F rs763780和JAK2 rs2274471有很强的相关性(OR = 2.66, P = 0.02)，这导致了组氨酸与精氨酸的替代(OR = 3.27, P = 0.04)。此外，JAK2 rs7849191表现出保护模式，达到显著性阈值(OR = 0.77, P = 0.05)，并与40岁以下早发性银屑病发病频率呈负相关(P = 0.07)。单倍型分析显示，JAK1 rs310241A/rs2780889T对银屑病具有保护作用(OR = 0.73, P = 0.03)。总之，我们在韩国人群中报告了两个新的银屑病易感位点，IL17F和JAK2，以及一个新发现的晚发性相关保护性JAK2位点和保护性JAK1单倍型。
{"title":"A preliminary study of new single polymorphisms in the T helper type 17 pathway for psoriasis in the Korean population","authors":"Soo-Young Kim, M. Hur, B. Choi, Min Jung Kim, Yang Won Lee, Y. Choe, Kyu Joong Ahn","doi":"10.1111/cei.12888","DOIUrl":"https://doi.org/10.1111/cei.12888","url":null,"abstract":"Psoriasis is a polygenic and multi‐factorial disease showing ethnic differences in terms of its severity and frequency. Therapies targeting interleukin (IL)−17A, IL‐17 receptor (IL‐17R) and Janus kinases (JAKs) are in clinical development for the treatment of psoriasis, and their success suggests the essential role of these molecules in psoriasis. To investigate the genetic susceptibility in T helper type 17 (Th17) cell signal transduction pathways for promoting psoriasis, we performed candidate gene and linkage disequilibrium analysis. In 208 patients and 266 normal controls, we analysed 31 single nucleotide polymorphisms in 12 genes (CAMP, IL17A, IL17F, IL17RA, IL22, JAK1, JAK2, JAK3, STAT3, TLR7, TLR9 and TYK2; abbreviations: CAMP, human cathelicidin antimicrobial peptide; STAT‐3, signal transducer and activator of transcription 3; TLR, Toll‐like receptor; TYK2, tyrosine kinase 2). Patients with psoriasis showed a strong association for IL17F rs763780 [odds ratio (OR) = 3·27, P = 0·04], which results in a histidine‐to‐arginine substitution, and JAK2 rs2274471 (OR = 2·66, P = 0·02). In addition, JAK2 rs7849191 showed a protective pattern, met the significance threshold (OR = 0·77, P = 0·05) and showed a tendency for an inverse association with the frequency of early‐onset psoriasis under age 40 years (P = 0·07). In haplotype analysis, JAK1 rs310241A/rs2780889T showed a protective effect (OR = 0·73, P = 0·03) in psoriasis. In conclusion, we report two new psoriasis‐susceptibility loci, in IL17F and JAK2, as well as a newly identified late‐onset associated protective JAK2 locus and a protective JAK1 haplotype in the Korean population.","PeriodicalId":10179,"journal":{"name":"Clinical & Experimental Immunology","volume":"98 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2016-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"85792249","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
E. Balada, L. Felip, J. Ordi‐Ros, M. Vilardell‐Tarrés
We evaluated the transcriptional expression of dual‐specificity protein phosphatase 23 (DUSP23) in CD4+ T cells from 30 systemic lupus erythematosus (SLE) patients and 30 healthy controls. DUSP23 mRNA levels were considerably higher in the patient group: 1490 ± 1713 versus 294·1 ± 204·2. No association was found between DUSP23 mRNA expression and the presence of typical serological and clinical parameters associated with SLE. Meaningful statistical values were obtained in the patient group between the levels of DUSP23 and integrin subunit alpha L (ITGAL), perforin 1 (PRF1) and CD40L. Similarly, transcript levels of different DNA methylation‐related enzymes [DNA methylation‐related enzymes (DNMT1, DNMT3A, DNMT3B, MBD2, and MBD4)] were also correlated positively with the expression of DUSP23. In an attempt to counteract the hypomethylation status of the promoters of certain genes known to be over‐expressed in SLE, it is possible that DUSP23 acts as a negative regulatory mechanism which ultimately silences the transcription of these epigenetically regulated genes by triggering an increase in the expression of different DNMTs.
我们评估了30例系统性红斑狼疮(SLE)患者和30例健康对照者的CD4+ T细胞中双特异性蛋白磷酸酶23 (DUSP23)的转录表达。患者组DUSP23 mRNA水平明显较高，分别为1490±1713和294·1±204·2。未发现DUSP23 mRNA表达与SLE相关的典型血清学和临床参数存在关联。患者组DUSP23与整合素亚单位α L (ITGAL)、穿孔素1 (PRF1)、CD40L水平比较，差异有统计学意义。同样，不同DNA甲基化相关酶[DNA甲基化相关酶(DNMT1、DNMT3A、DNMT3B、MBD2和MBD4)]的转录水平也与DUSP23的表达呈正相关。为了抵消已知在SLE中过度表达的某些基因启动子的低甲基化状态，DUSP23可能作为一种负调控机制，通过触发不同dnmt表达的增加，最终使这些表观遗传调控基因的转录沉默。
{"title":"DUSP23 is over‐expressed and linked to the expression of DNMTs in CD4+ T cells from systemic lupus erythematosus patients","authors":"E. Balada, L. Felip, J. Ordi‐Ros, M. Vilardell‐Tarrés","doi":"10.1111/cei.12883","DOIUrl":"https://doi.org/10.1111/cei.12883","url":null,"abstract":"We evaluated the transcriptional expression of dual‐specificity protein phosphatase 23 (DUSP23) in CD4+ T cells from 30 systemic lupus erythematosus (SLE) patients and 30 healthy controls. DUSP23 mRNA levels were considerably higher in the patient group: 1490 ± 1713 versus 294·1 ± 204·2. No association was found between DUSP23 mRNA expression and the presence of typical serological and clinical parameters associated with SLE. Meaningful statistical values were obtained in the patient group between the levels of DUSP23 and integrin subunit alpha L (ITGAL), perforin 1 (PRF1) and CD40L. Similarly, transcript levels of different DNA methylation‐related enzymes [DNA methylation‐related enzymes (DNMT1, DNMT3A, DNMT3B, MBD2, and MBD4)] were also correlated positively with the expression of DUSP23. In an attempt to counteract the hypomethylation status of the promoters of certain genes known to be over‐expressed in SLE, it is possible that DUSP23 acts as a negative regulatory mechanism which ultimately silences the transcription of these epigenetically regulated genes by triggering an increase in the expression of different DNMTs.","PeriodicalId":10179,"journal":{"name":"Clinical & Experimental Immunology","volume":"1 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2016-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"89745434","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}
Devin M Boe, Lisbeth A. Boulé, Elizabeth J. Kovacs
The world is undergoing an unprecedented shift in demographics, with the number of individuals over the age of 60 years projected to reach 2 billion or more by 2050, representing 22% of the global population. Elderly people are at a higher risk for chronic disease and more susceptible to infection, due in part to age‐related dysfunction of the immune system resulting from low‐grade chronic inflammation known as ‘inflamm‐ageing’. The innate immune system of older individuals exhibits a diminished ability to respond to microbial threats and clear infections, resulting in a greater occurrence of many infectious diseases in elderly people. In particular, the incidence of and mortality from lung infections increase sharply with age, with such infections often leading to worse outcomes, prolonged hospital stays and life‐threatening complications, such as sepsis or acute respiratory distress syndrome. In this review, we highlight research on bacterial pneumonias and pulmonary viral infections and discuss age‐related changes in innate immunity that contribute to the higher rate of these infections in older populations. By understanding more clearly the innate immune defects in elderly individuals, we can design age‐specific therapies to address lung infections in such a vulnerable population.
{"title":"Innate immune responses in the ageing lung","authors":"Devin M Boe, Lisbeth A. Boulé, Elizabeth J. Kovacs","doi":"10.1111/cei.12881","DOIUrl":"https://doi.org/10.1111/cei.12881","url":null,"abstract":"The world is undergoing an unprecedented shift in demographics, with the number of individuals over the age of 60 years projected to reach 2 billion or more by 2050, representing 22% of the global population. Elderly people are at a higher risk for chronic disease and more susceptible to infection, due in part to age‐related dysfunction of the immune system resulting from low‐grade chronic inflammation known as ‘inflamm‐ageing’. The innate immune system of older individuals exhibits a diminished ability to respond to microbial threats and clear infections, resulting in a greater occurrence of many infectious diseases in elderly people. In particular, the incidence of and mortality from lung infections increase sharply with age, with such infections often leading to worse outcomes, prolonged hospital stays and life‐threatening complications, such as sepsis or acute respiratory distress syndrome. In this review, we highlight research on bacterial pneumonias and pulmonary viral infections and discuss age‐related changes in innate immunity that contribute to the higher rate of these infections in older populations. By understanding more clearly the innate immune defects in elderly individuals, we can design age‐specific therapies to address lung infections in such a vulnerable population.","PeriodicalId":10179,"journal":{"name":"Clinical & Experimental Immunology","volume":"12 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2016-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"89201862","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. Singh, A. Mohan, Aprajit B Dey, Dipendra K. Mitra
Optimal T cell activation is vital for the successful resolution of microbial infections. Programmed death‐1 (PD‐1) is a key immune check‐point receptor expressed by activated T cells. Aberrant/excessive inhibition mediated by PD‐1 may impair host immunity to Mycobacterium tuberculosis infection, leading to disseminated disease such as miliary tuberculosis (MTB). PD‐1 mediated inhibition of T cells in pulmonary tuberculosis and TB pleurisy is reported. However, their role in MTB, particularly at the pathological site, remains to be addressed. The objective of this study was to investigate the role of PD‐1–PD‐ligand 1 (PD‐L1) in T cell responses at the pathological site from patients of TB pleurisy and MTB as clinical models of contained and disseminated forms of tuberculosis, respectively. We examined the expression and function of PD‐1 and its ligands (PD‐L1–PD‐L2) on host immune cells among tuberculosis patients. Bronchoalveolar lavage‐derived CD3 T cells in MTB expressed PD‐1 (54·2 ± 27·4%, P ≥ 0·0009) with significantly higher PD‐1 ligand‐positive T cells (PD‐L1: 19·8 ± 11·8%; P ≥ 0·019, PD‐L2: 12·6 ± 6·2%; P ≥ 0·023), CD19+ B cells (PD‐L1: 14·4 ± 10·4%; P ≥ 0·042, PD‐L2: 2·6 ± 1·43%; not significant) and CD14+ monocytes (PD‐L1: 40·2 ± 20·1%; P ≥ 0·047, PD‐L2: 22·4 ± 15·6%; P ≥ 0·032) compared with peripheral blood (PB) of MTB and healthy controls. The expression of PD‐1 was associated with a diminished number of cells producing effector cytokines interferon (IFN)‐γ, tumour necrosis factor (TNF)‐α, interleukin (IL)−2 and elevated apoptosis. Locally accumulated T cells were predominantly PD‐1+–PD‐L1+, and blocking this pathway restores the protective T cell response. We conclude that M. tuberculosis exploits the PD‐1 pathway to evade the host immune response by altering the T helper type 1 (Th1) and Th2 balance at the pathological site of MTB, thereby favouring disease dissemination.
{"title":"Programmed death‐1+ T cells inhibit effector T cells at the pathological site of miliary tuberculosis","authors":"A. Singh, A. Mohan, Aprajit B Dey, Dipendra K. Mitra","doi":"10.1111/cei.12871","DOIUrl":"https://doi.org/10.1111/cei.12871","url":null,"abstract":"Optimal T cell activation is vital for the successful resolution of microbial infections. Programmed death‐1 (PD‐1) is a key immune check‐point receptor expressed by activated T cells. Aberrant/excessive inhibition mediated by PD‐1 may impair host immunity to Mycobacterium tuberculosis infection, leading to disseminated disease such as miliary tuberculosis (MTB). PD‐1 mediated inhibition of T cells in pulmonary tuberculosis and TB pleurisy is reported. However, their role in MTB, particularly at the pathological site, remains to be addressed. The objective of this study was to investigate the role of PD‐1–PD‐ligand 1 (PD‐L1) in T cell responses at the pathological site from patients of TB pleurisy and MTB as clinical models of contained and disseminated forms of tuberculosis, respectively. We examined the expression and function of PD‐1 and its ligands (PD‐L1–PD‐L2) on host immune cells among tuberculosis patients. Bronchoalveolar lavage‐derived CD3 T cells in MTB expressed PD‐1 (54·2 ± 27·4%, P ≥ 0·0009) with significantly higher PD‐1 ligand‐positive T cells (PD‐L1: 19·8 ± 11·8%; P ≥ 0·019, PD‐L2: 12·6 ± 6·2%; P ≥ 0·023), CD19+ B cells (PD‐L1: 14·4 ± 10·4%; P ≥ 0·042, PD‐L2: 2·6 ± 1·43%; not significant) and CD14+ monocytes (PD‐L1: 40·2 ± 20·1%; P ≥ 0·047, PD‐L2: 22·4 ± 15·6%; P ≥ 0·032) compared with peripheral blood (PB) of MTB and healthy controls. The expression of PD‐1 was associated with a diminished number of cells producing effector cytokines interferon (IFN)‐γ, tumour necrosis factor (TNF)‐α, interleukin (IL)−2 and elevated apoptosis. Locally accumulated T cells were predominantly PD‐1+–PD‐L1+, and blocking this pathway restores the protective T cell response. We conclude that M. tuberculosis exploits the PD‐1 pathway to evade the host immune response by altering the T helper type 1 (Th1) and Th2 balance at the pathological site of MTB, thereby favouring disease dissemination.","PeriodicalId":10179,"journal":{"name":"Clinical & Experimental Immunology","volume":"79 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2016-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"90493463","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. Anderson, D. Swan, O. Y. Wong, Matthew Buck, O. Eltherington, R. Harry, A. Patterson, A. Pratt, G. Reynolds, J. Doran, J. Kirby, J. Isaacs, C. Hilkens
Tolerogenic dendritic cells (tolDC) are a new immunotherapeutic tool for the treatment of rheumatoid arthritis (RA) and other autoimmune disorders. We have established a method to generate stable tolDC by pharmacological modulation of human monocyte‐derived DC. These tolDC exert potent pro‐tolerogenic actions on CD4+ T cells. Lack of interleukin (IL)−12p70 production is a key immunoregulatory attribute of tolDC but does not explain their action fully. Here we show that tolDC express transforming growth factor (TGF)‐β1 at both mRNA and protein levels, and that expression of this immunoregulatory cytokine is significantly higher in tolDC than in mature monocyte‐derived DC. By inhibiting TGF‐β1 signalling we demonstrate that tolDC regulate CD4+ T cell responses in a manner that is at least partly dependent upon this cytokine. Crucially, we also show that while there is no significant difference in expression of TGF‐βRII on CD4+ T cells from RA patients and healthy controls, RA patient CD4+ T cells are measurably less responsive to TGF‐β1 than healthy control CD4+ T cells [reduced TGF‐β‐induced mothers against decapentaplegic homologue (Smad)2/3 phosphorylation, forkhead box protein 3 (FoxP3) expression and suppression of (IFN)‐γ secretion]. However, CD4+ T cells from RA patients can, nonetheless, be regulated efficiently by tolDC in a TGF‐β1‐dependent manner. This work is important for the design and development of future studies investigating the potential use of tolDC as a novel immunotherapy for the treatment of RA.
{"title":"Tolerogenic dendritic cells generated with dexamethasone and vitamin D3 regulate rheumatoid arthritis CD4+ T cells partly via transforming growth factor‐β1","authors":"A. Anderson, D. Swan, O. Y. Wong, Matthew Buck, O. Eltherington, R. Harry, A. Patterson, A. Pratt, G. Reynolds, J. Doran, J. Kirby, J. Isaacs, C. Hilkens","doi":"10.1111/cei.12870","DOIUrl":"https://doi.org/10.1111/cei.12870","url":null,"abstract":"Tolerogenic dendritic cells (tolDC) are a new immunotherapeutic tool for the treatment of rheumatoid arthritis (RA) and other autoimmune disorders. We have established a method to generate stable tolDC by pharmacological modulation of human monocyte‐derived DC. These tolDC exert potent pro‐tolerogenic actions on CD4+ T cells. Lack of interleukin (IL)−12p70 production is a key immunoregulatory attribute of tolDC but does not explain their action fully. Here we show that tolDC express transforming growth factor (TGF)‐β1 at both mRNA and protein levels, and that expression of this immunoregulatory cytokine is significantly higher in tolDC than in mature monocyte‐derived DC. By inhibiting TGF‐β1 signalling we demonstrate that tolDC regulate CD4+ T cell responses in a manner that is at least partly dependent upon this cytokine. Crucially, we also show that while there is no significant difference in expression of TGF‐βRII on CD4+ T cells from RA patients and healthy controls, RA patient CD4+ T cells are measurably less responsive to TGF‐β1 than healthy control CD4+ T cells [reduced TGF‐β‐induced mothers against decapentaplegic homologue (Smad)2/3 phosphorylation, forkhead box protein 3 (FoxP3) expression and suppression of (IFN)‐γ secretion]. However, CD4+ T cells from RA patients can, nonetheless, be regulated efficiently by tolDC in a TGF‐β1‐dependent manner. This work is important for the design and development of future studies investigating the potential use of tolDC as a novel immunotherapy for the treatment of RA.","PeriodicalId":10179,"journal":{"name":"Clinical & Experimental Immunology","volume":"62 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2016-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"77583237","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}
Fane F. K. Mensah, Amolak S. Bansal, S. Berkovitz, Arti Sharma, Venkat Reddy, M. Leandro, G. Cambridge
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a heterogeneous condition of unknown aetiology characterized by multiple symptoms including fatigue, post‐exertional malaise and cognitive impairment, lasting for at least 6 months. Recently, two clinical trials of B cell depletion therapy with rituximab (anti‐CD20) reported convincing improvement in symptoms. A possible but undefined role for B cells has therefore been proposed. Studies of the relative percentages of B cell subsets in patients with ME/CFS have not revealed any reproducible differences from healthy controls (HC). In order to explore whether more subtle alterations in B cell subsets related to B cell differentiation exist in ME/CFS patients we used flow cytometry to immunophenotype CD19+ B cells. The panel utilized immunoglobulin (Ig)D, CD27 and CD38 (classical B cell subsets) together with additional markers. A total of 38 patients fulfilling Canadian, Centre for Disease Control and Fukuda ME/CFS criteria and 32 age‐ and sex‐matched HC were included. We found no difference in percentages of classical subsets between ME/CFS patients and HC. However, we observed an increase in frequency (P < 0·01) and expression (MFI; P = 0·03) of CD24 on total B cells, confined to IgD+ subsets. Within memory subsets, a higher frequency of CD21+CD38– B cells (>20%) was associated with the presence of ME/CFS [odds ratio: 3·47 (1·15–10·46); P = 0·03] compared with HC, and there was a negative correlation with disease duration. In conclusion, we identified possible changes in B cell phenotype in patients with ME/CFS. These may reflect altered B cell function and, if confirmed in other patient cohorts, could provide a platform for studies based on clinical course or responsiveness to rituximab therapy.
{"title":"Extended B cell phenotype in patients with myalgic encephalomyelitis/chronic fatigue syndrome: a cross‐sectional study","authors":"Fane F. K. Mensah, Amolak S. Bansal, S. Berkovitz, Arti Sharma, Venkat Reddy, M. Leandro, G. Cambridge","doi":"10.1111/cei.12749","DOIUrl":"https://doi.org/10.1111/cei.12749","url":null,"abstract":"Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a heterogeneous condition of unknown aetiology characterized by multiple symptoms including fatigue, post‐exertional malaise and cognitive impairment, lasting for at least 6 months. Recently, two clinical trials of B cell depletion therapy with rituximab (anti‐CD20) reported convincing improvement in symptoms. A possible but undefined role for B cells has therefore been proposed. Studies of the relative percentages of B cell subsets in patients with ME/CFS have not revealed any reproducible differences from healthy controls (HC). In order to explore whether more subtle alterations in B cell subsets related to B cell differentiation exist in ME/CFS patients we used flow cytometry to immunophenotype CD19+ B cells. The panel utilized immunoglobulin (Ig)D, CD27 and CD38 (classical B cell subsets) together with additional markers. A total of 38 patients fulfilling Canadian, Centre for Disease Control and Fukuda ME/CFS criteria and 32 age‐ and sex‐matched HC were included. We found no difference in percentages of classical subsets between ME/CFS patients and HC. However, we observed an increase in frequency (P < 0·01) and expression (MFI; P = 0·03) of CD24 on total B cells, confined to IgD+ subsets. Within memory subsets, a higher frequency of CD21+CD38– B cells (>20%) was associated with the presence of ME/CFS [odds ratio: 3·47 (1·15–10·46); P = 0·03] compared with HC, and there was a negative correlation with disease duration. In conclusion, we identified possible changes in B cell phenotype in patients with ME/CFS. These may reflect altered B cell function and, if confirmed in other patient cohorts, could provide a platform for studies based on clinical course or responsiveness to rituximab therapy.","PeriodicalId":10179,"journal":{"name":"Clinical & Experimental Immunology","volume":"14 6","pages":""},"PeriodicalIF":0.0,"publicationDate":"2016-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"91424114","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. Sandin, P. Eriksson, M. Segelmark, T. Skogh, A. Kastbom
Circulating immunoglobulin (Ig)A class anti‐neutrophil cytoplasm antibodies (ANCA) directed against proteinase 3 (PR3) have been reported in ANCA‐associated vasculitis (AAV) with mucosal involvement. However, secretory IgA (SIgA) PR3‐ANCA has not been reported previously. In this study we compared serum levels of SIgA PR3‐ANCA and IgA PR3‐ANCA with IgG PR3‐ANCA in relation to disease characteristics. Among 73 patients with AAV and PR3‐ANCA at diagnosis, 84% tested positive for IgG PR3‐ANCA, 47% for IgA‐ANCA and 36% for SIgA PR3‐ANCA at the time of sampling for the present study. IgA and IgG PR3‐ANCA were represented similarly among patients with different organ manifestations, i.e. upper airway, lung or kidney at time of sampling. However, SIgA PR3‐ANCA was significantly less represented among patients with upper airway involvement. During active disease, the proportions of IgA PR3‐ANCA and SIgA PR3‐ANCA‐positive patients were significantly higher compared to inactive disease. Eight patients were sampled prospectively during 24 months from onset of active disease. In these patients, IgA PR3‐ANCA and SIgA PR3‐ANCA turned negative more often after remission induction compared to IgG PR3‐ANCA. Our findings suggest that serum IgA PR3‐ANCA and SIgA PR3‐ANCA are related more closely to disease activity in AAV compared to IgG PR3‐ANCA. Further studies are required to reveal if this has implications for disease activity monitoring. The mean number of PR3‐ANCA isotypes increased along with disease activity, suggesting a global B cell activation during active disease.
{"title":"IgA‐ and SIgA anti‐PR3 antibodies in serum versus organ involvement and disease activity in PR3‐ANCA‐associated vasculitis","authors":"C. Sandin, P. Eriksson, M. Segelmark, T. Skogh, A. Kastbom","doi":"10.1111/cei.12769","DOIUrl":"https://doi.org/10.1111/cei.12769","url":null,"abstract":"Circulating immunoglobulin (Ig)A class anti‐neutrophil cytoplasm antibodies (ANCA) directed against proteinase 3 (PR3) have been reported in ANCA‐associated vasculitis (AAV) with mucosal involvement. However, secretory IgA (SIgA) PR3‐ANCA has not been reported previously. In this study we compared serum levels of SIgA PR3‐ANCA and IgA PR3‐ANCA with IgG PR3‐ANCA in relation to disease characteristics. Among 73 patients with AAV and PR3‐ANCA at diagnosis, 84% tested positive for IgG PR3‐ANCA, 47% for IgA‐ANCA and 36% for SIgA PR3‐ANCA at the time of sampling for the present study. IgA and IgG PR3‐ANCA were represented similarly among patients with different organ manifestations, i.e. upper airway, lung or kidney at time of sampling. However, SIgA PR3‐ANCA was significantly less represented among patients with upper airway involvement. During active disease, the proportions of IgA PR3‐ANCA and SIgA PR3‐ANCA‐positive patients were significantly higher compared to inactive disease. Eight patients were sampled prospectively during 24 months from onset of active disease. In these patients, IgA PR3‐ANCA and SIgA PR3‐ANCA turned negative more often after remission induction compared to IgG PR3‐ANCA. Our findings suggest that serum IgA PR3‐ANCA and SIgA PR3‐ANCA are related more closely to disease activity in AAV compared to IgG PR3‐ANCA. Further studies are required to reveal if this has implications for disease activity monitoring. The mean number of PR3‐ANCA isotypes increased along with disease activity, suggesting a global B cell activation during active disease.","PeriodicalId":10179,"journal":{"name":"Clinical & Experimental Immunology","volume":"86 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2016-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"75292161","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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