Pub Date : 2024-06-15DOI: 10.1016/j.clim.2024.110283
J. Soul , E. Carlsson , S.R. Hofmann , S. Russ , J. Hawkes , F. Schulze , M. Sergon , J. Pablik , S. Abraham , C.M. Hedrich
Overlapping clinical and pathomechanistic features can complicate the diagnosis and treatment of inflammatory skin diseases, including psoriasis and atopic dermatitis (AD). Spatial transcriptomics allows the identification of disease- and cell-specific molecular signatures that may advance biomarker development and future treatments.
This study identified transcriptional signatures in keratinocytes and sub-basal CD4+ and CD8+ T lymphocytes from patients with psoriasis and AD. In silico prediction of ligand:receptor interactions delivered key signalling pathways (interferon, effector T cells, stroma cell and matrix biology, neuronal development, etc.). Targeted validation of selected transcripts, including CCL22, RELB, and JUND, in peripheral blood T cells suggests the chosen approach as a promising tool also in other inflammatory diseases.
Psoriasis and AD are characterized by transcriptional dysregulation in T cells and keratinocytes that may be targeted therapeutically. Spatial transcriptomics is a valuable tool in the search for molecular signatures that can be used as biomarkers and/or therapeutic targets.
临床和病理机制特征的重叠会使包括银屑病和特应性皮炎(AD)在内的炎症性皮肤病的诊断和治疗复杂化。空间转录组学可以识别疾病和细胞特异性分子特征,从而推动生物标记物的开发和未来的治疗。这项研究确定了银屑病和 AD 患者的角朊细胞和基底下 CD4+ 和 CD8+ T 淋巴细胞的转录特征。对配体与受体之间的相互作用进行硅学预测,提供关键信号通路(干扰素、效应 T 细胞、基质细胞和基质生物学、神经元发育等)。在外周血 T 细胞中对包括 CCL22、RELB 和 JUND 在内的选定转录本进行的靶向验证表明,所选方法在其他炎症性疾病中也是一种很有前途的工具。牛皮癣和注意力缺失症的特点是 T 细胞和角质形成细胞的转录失调,这些都可能成为治疗的目标。空间转录组学是寻找可用作生物标记和/或治疗目标的分子特征的重要工具。
{"title":"Tissue gene expression profiles and communication networks inform candidate blood biomarker identification in psoriasis and atopic dermatitis","authors":"J. Soul , E. Carlsson , S.R. Hofmann , S. Russ , J. Hawkes , F. Schulze , M. Sergon , J. Pablik , S. Abraham , C.M. Hedrich","doi":"10.1016/j.clim.2024.110283","DOIUrl":"10.1016/j.clim.2024.110283","url":null,"abstract":"<div><p>Overlapping clinical and pathomechanistic features can complicate the diagnosis and treatment of inflammatory skin diseases, including psoriasis and atopic dermatitis (AD). Spatial transcriptomics allows the identification of disease- and cell-specific molecular signatures that may advance biomarker development and future treatments.</p><p>This study identified transcriptional signatures in keratinocytes and sub-basal CD4<sup>+</sup> and CD8<sup>+</sup> T lymphocytes from patients with psoriasis and AD. <em>In silico</em> prediction of ligand:receptor interactions delivered key signalling pathways (interferon, effector T cells, stroma cell and matrix biology, neuronal development, <em>etc.</em>). Targeted validation of selected transcripts, including CCL22, RELB, and JUND, in peripheral blood T cells suggests the chosen approach as a promising tool also in other inflammatory diseases.</p><p>Psoriasis and AD are characterized by transcriptional dysregulation in T cells and keratinocytes that may be targeted therapeutically. Spatial transcriptomics is a valuable tool in the search for molecular signatures that can be used as biomarkers and/or therapeutic targets.</p></div>","PeriodicalId":10392,"journal":{"name":"Clinical immunology","volume":null,"pages":null},"PeriodicalIF":8.6,"publicationDate":"2024-06-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1521661624003929/pdfft?md5=cd23fd33b393b9c213d5242c41baf828&pid=1-s2.0-S1521661624003929-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141330521","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-06-14DOI: 10.1016/j.clim.2024.110285
Jenn-Haung Lai , De-Wei Wu , Chuan-Yueh Huang , Li-Feng Hung , Chien-Hsiang Wu , Ling-Jun Ho
Effective treatment of systemic lupus erythematosus (SLE) remains an unmet need. Different subsets of macrophages play differential roles in SLE and the modulation of macrophage polarization away from M1 status is beneficial for SLE therapeutics. Given the pathogenic roles of type I interferons (IFN-I) in SLE, this study investigated the effects and mechanisms of a mitochondria localization molecule ubiquitin specific peptidase 18 (USP18) preserving anti-IFN effects and isopeptidase activity on macrophage polarization. After observing USP18 induction in monocytes from SLE patients, we studied mouse bone marrow-derived macrophages and showed that USP18 deficiency increased M1signal (LPS + IFN-γ treatment)-induced macrophage polarization, and the effects involved the induction of glycolysis and mitochondrial respiration and the expression of several glycolysis-associated enzymes and molecules, such as hypoxia-inducible factor-1α. Moreover, the effects on mitochondrial activities, such as mitochondrial DNA release and mitochondrial reactive oxygen species production were observed. In contrast, the overexpression of USP18 inhibited M1signal-mediated and enhanced interleukin-4 (IL-4)-mediated polarization of macrophages and the related cellular events. Moreover, the levels of USP18 mRNA expression showed tendency of correlation with the expression of metabolic enzymes in monocytes from patients with SLE. We thus concluded that by preserving anti-IFN effect and downregulating M1 signaling, promoting USP18 activity may serve as a useful approach for SLE therapeutics.
{"title":"USP18 induction regulates immunometabolism to attenuate M1 signal-polarized macrophages and enhance IL-4-polarized macrophages in systemic lupus erythematosus","authors":"Jenn-Haung Lai , De-Wei Wu , Chuan-Yueh Huang , Li-Feng Hung , Chien-Hsiang Wu , Ling-Jun Ho","doi":"10.1016/j.clim.2024.110285","DOIUrl":"10.1016/j.clim.2024.110285","url":null,"abstract":"<div><p>Effective treatment of systemic lupus erythematosus (SLE) remains an unmet need. Different subsets of macrophages play differential roles in SLE and the modulation of macrophage polarization away from M1 status is beneficial for SLE therapeutics. Given the pathogenic roles of type I interferons (IFN-I) in SLE, this study investigated the effects and mechanisms of a mitochondria localization molecule ubiquitin specific peptidase 18 (USP18) preserving anti-IFN effects and isopeptidase activity on macrophage polarization. After observing USP18 induction in monocytes from SLE patients, we studied mouse bone marrow-derived macrophages and showed that USP18 deficiency increased M1signal (LPS + IFN-γ treatment)-induced macrophage polarization, and the effects involved the induction of glycolysis and mitochondrial respiration and the expression of several glycolysis-associated enzymes and molecules, such as hypoxia-inducible factor-1α. Moreover, the effects on mitochondrial activities, such as mitochondrial DNA release and mitochondrial reactive oxygen species production were observed. In contrast, the overexpression of USP18 inhibited M1signal-mediated and enhanced interleukin-4 (IL-4)-mediated polarization of macrophages and the related cellular events. Moreover, the levels of <em>USP18</em> mRNA expression showed tendency of correlation with the expression of metabolic enzymes in monocytes from patients with SLE. We thus concluded that by preserving anti-IFN effect and downregulating M1 signaling, promoting USP18 activity may serve as a useful approach for SLE therapeutics.</p></div>","PeriodicalId":10392,"journal":{"name":"Clinical immunology","volume":null,"pages":null},"PeriodicalIF":8.6,"publicationDate":"2024-06-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141330522","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-06-13DOI: 10.1016/j.clim.2024.110279
Alexandru Tatomir , Sonia Vlaicu , Vinh Nguyen , Irina G. Luzina , Sergei P. Atamas , Cinthia Drachenberg , John Papadimitriou , Tudor C. Badea , Horea G. Rus , Violeta Rus
Systemic lupus erythematosus is an autoimmune disease that results in immune-mediated damage to kidneys and other organs. We investigated the role of response gene to complement-32 (RGC-32), a proinflammatory and profibrotic mediator induced by TGFβ and C5b-9, in nephrotoxic nephritis (NTN), an experimental model that mimics human lupus nephritis. Proteinuria, loss of renal function and kidney histopathology were attenuated in RGC-32 KO NTN mice. RGC-32 KO NTN mice displayed downregulation of the CCL20/CCR6 and CXCL9/CXCR3 ligand/receptor pairs resulting in decreased renal recruitment of IL-17+ and IFNγ+ cells and subsequent decrease in the influx of innate immune cells. RGC-32 deficiency attenuated renal fibrosis as demonstrated by decreased deposition of collagen I, III and fibronectin. Thus, RGC-32 is a unique mediator shared by the Th17 and Th1 dependent proinflammatory and profibrotic pathways and a potential novel therapeutic target in the treatment of immune complex mediated glomerulonephritis such as lupus nephritis.
系统性红斑狼疮是一种自身免疫性疾病,会导致免疫介导的肾脏和其他器官损伤。我们研究了补体32反应基因(RGC-32)在肾毒性肾炎(NTN)中的作用,肾毒性肾炎是一种模拟人类狼疮肾炎的实验模型。RGC-32 KO NTN 小鼠的蛋白尿、肾功能丧失和肾组织病理学均有所减轻。RGC-32 KO NTN小鼠的CCL20/CCR6和CXCL9/CXCR3配体/受体对出现下调,导致IL-17+和IFNγ+细胞的肾脏招募减少,先天性免疫细胞的流入也随之减少。RGC-32 缺乏会减轻肾脏纤维化,这表现在胶原蛋白 I、III 和纤维连接蛋白的沉积减少。因此,RGC-32 是 Th17 和 Th1 依赖性促炎和促纤维化途径共有的一种独特介质,是治疗免疫复合物介导的肾小球肾炎(如狼疮性肾炎)的潜在新治疗靶点。
{"title":"RGC-32 mediates proinflammatory and profibrotic pathways in immune-mediated kidney disease","authors":"Alexandru Tatomir , Sonia Vlaicu , Vinh Nguyen , Irina G. Luzina , Sergei P. Atamas , Cinthia Drachenberg , John Papadimitriou , Tudor C. Badea , Horea G. Rus , Violeta Rus","doi":"10.1016/j.clim.2024.110279","DOIUrl":"10.1016/j.clim.2024.110279","url":null,"abstract":"<div><p>Systemic lupus erythematosus is an autoimmune disease that results in immune-mediated damage to kidneys and other organs. We investigated the role of response gene to complement-32 (RGC-32), a proinflammatory and profibrotic mediator induced by TGFβ and C5b-9, in nephrotoxic nephritis (NTN), an experimental model that mimics human lupus nephritis. Proteinuria, loss of renal function and kidney histopathology were attenuated in RGC-32 KO NTN mice. RGC-32 KO NTN mice displayed downregulation of the CCL20/CCR6 and CXCL9/CXCR3 ligand/receptor pairs resulting in decreased renal recruitment of IL-17<sup>+</sup> and IFNγ<sup>+</sup> cells and subsequent decrease in the influx of innate immune cells. RGC-32 deficiency attenuated renal fibrosis as demonstrated by decreased deposition of collagen I, III and fibronectin. Thus, RGC-32 is a unique mediator shared by the Th17 and Th1 dependent proinflammatory and profibrotic pathways and a potential novel therapeutic target in the treatment of immune complex mediated glomerulonephritis such as lupus nephritis.</p></div>","PeriodicalId":10392,"journal":{"name":"Clinical immunology","volume":null,"pages":null},"PeriodicalIF":8.6,"publicationDate":"2024-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141327296","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-06-13DOI: 10.1016/j.clim.2024.110284
Litong Zhu , Yick Hei Wong , Sunny S.H. Wong , Simon C.Y. Cheung , Jason K.H. Sher , Irene Y.L. Yam , Susan Yung , Tak Mao Chan , Desmond Y.H. Yap
Introduction
B cell exhaustion is a functional abnormality of B lymphocytes observed in chronic infections and shows association with autoreactivity. The role of exhausted and classical memory B cells in maintaining disease stability of lupus nephritis (LN) remains unclear.
Methods
We measured classical memory (CD19+CD21+CD27+), exhausted B cells (CD19+CD21−CD27−), and related cytokines in LN patients with multiple relapses (MR) (n = 15) and no relapse (NR) (n = 15) during disease remission. The expression of inhibitory/adhesion molecules, cell proliferation and calcium mobilization in classical memory and exhausted B cells were also assessed.
Results
The MR group had higher proportion of circulating exhausted and classical memory B cells compared to the NR group and healthy controls (HC) (p all <0.05 for MR vs. NR or HC). Blood levels of IL-6, BAFF, IL-21, CD62L, CXCR3 and Siglec-6 were all higher in the MR group (p < 0.05, for all). Exhausted B cells from the MR group showed higher FcRL4, CD22, CD85j and CD183 but lower CD62L expression than NR and HC groups. Exhausted B cells from MR patients exhibited reduced proliferation compared to NR patients and HC, while classical memory B cell proliferation in MR group was higher than the other two groups. Exhausted B cells from both MR and NR patients showed impaired calcium mobilization.
Conclusion
Alterations in exhausted and classical memory B cells are related to disease relapse in LN. These findings may help devise new strategies for monitoring disease activity and preventing relapse in LN.
引言B细胞衰竭是慢性感染时观察到的一种B淋巴细胞功能异常,与自身反应性有关。衰竭B细胞和经典记忆B细胞在维持狼疮性肾炎(LN)疾病稳定性方面的作用仍不清楚:我们测量了疾病缓解期间多次复发(MR)(15 人)和未复发(NR)(15 人)的狼疮肾炎患者的经典记忆 B 细胞(CD19+CD21+CD27+)、衰竭 B 细胞(CD19+CD21-CD27-)和相关细胞因子。此外,还评估了经典记忆B细胞和衰竭B细胞中抑制/粘附分子的表达、细胞增殖和钙动员情况:结果:与 NR 组和健康对照组(HC)相比,MR 组的循环衰竭和经典记忆 B 细胞比例较高(P 均为结论:衰竭和经典记忆 B 细胞的变化与 LN 疾病复发有关。这些发现可能有助于制定监测 LN 疾病活动和预防复发的新策略。
{"title":"Alterations in exhausted and classical memory B cells in lupus nephritis – Relationship with disease relapse","authors":"Litong Zhu , Yick Hei Wong , Sunny S.H. Wong , Simon C.Y. Cheung , Jason K.H. Sher , Irene Y.L. Yam , Susan Yung , Tak Mao Chan , Desmond Y.H. Yap","doi":"10.1016/j.clim.2024.110284","DOIUrl":"10.1016/j.clim.2024.110284","url":null,"abstract":"<div><h3>Introduction</h3><p>B cell exhaustion is a functional abnormality of B lymphocytes observed in chronic infections and shows association with autoreactivity. The role of exhausted and classical memory B cells in maintaining disease stability of lupus nephritis (LN) remains unclear.</p></div><div><h3>Methods</h3><p>We measured classical memory (CD19<sup>+</sup>CD21<sup>+</sup>CD27<sup>+</sup>), exhausted B cells (CD19<sup>+</sup>CD21<sup>−</sup>CD27<sup>−</sup>), and related cytokines in LN patients with multiple relapses (MR) (<em>n</em> = 15) and no relapse (NR) (n = 15) during disease remission. The expression of inhibitory/adhesion molecules, cell proliferation and calcium mobilization in classical memory and exhausted B cells were also assessed.</p></div><div><h3>Results</h3><p>The MR group had higher proportion of circulating exhausted and classical memory B cells compared to the NR group and healthy controls (HC) (p all <0.05 for MR vs. NR or HC). Blood levels of IL-6, BAFF, IL-21, CD62L, CXCR3 and Siglec-6 were all higher in the MR group (<em>p</em> < 0.05, for all). Exhausted B cells from the MR group showed higher FcRL4, CD22, CD85j and CD183 but lower CD62L expression than NR and HC groups. Exhausted B cells from MR patients exhibited reduced proliferation compared to NR patients and HC, while classical memory B cell proliferation in MR group was higher than the other two groups. Exhausted B cells from both MR and NR patients showed impaired calcium mobilization.</p></div><div><h3>Conclusion</h3><p>Alterations in exhausted and classical memory B cells are related to disease relapse in LN. These findings may help devise new strategies for monitoring disease activity and preventing relapse in LN.</p></div>","PeriodicalId":10392,"journal":{"name":"Clinical immunology","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2024-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1521661624003930/pdfft?md5=11b0e15f4ee4915608200ebb30e145ec&pid=1-s2.0-S1521661624003930-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141327295","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-06-13DOI: 10.1016/j.clim.2024.110278
Zhonghua Li , Qi Zhi , Jiahuang Li , Bo Zhu
Nucleotide-binding leucine-rich repeat-containing receptor 12-associated autoinflammatory disease (NLRP12-AID) is a rare autosomal dominant disorder. In this study, we reported a case of this rare disease with a novel NLRP12 mutation (A218V, rs749659859). The patient displayed typical symptoms, including recurrent fever, arthralgia, and skin allergies. Elevated serum IgE, decreased apolipoprotein A1, high-density lipoprotein cholesterol, and fluctuating levels of various leukocyte subtypes, procalcitonin, IL6, creatine kinase, and 25-hydroxyvitamin D were also detected. Inflammatory lesions were observed in multiple organs using 18F-FDG PET/CT. By mining single-cell transcriptome data, we identified relatively high expression of NLRP12 in monocytes compared to other human peripheral blood mononuclear cells. NLRP12-positive monocytes exhibited reduced expression of IL18, CCL3, and TNFA compared to NLRP12-negative monocytes. Structural analyses suggested that the A218V mutation, along with A218T and F402L, may reduce the ATP-binding affinity of the NLRP12 protein. These findings may provide new insights into the mechanisms of NLRP12-AID, and suggest the potential ATP-based therapy for further investigation.
{"title":"NLRP12-associated autoinflammatory disease: A novel causal mutation and bioinformatics analyses","authors":"Zhonghua Li , Qi Zhi , Jiahuang Li , Bo Zhu","doi":"10.1016/j.clim.2024.110278","DOIUrl":"https://doi.org/10.1016/j.clim.2024.110278","url":null,"abstract":"<div><p>Nucleotide-binding leucine-rich repeat-containing receptor 12-associated autoinflammatory disease (<em>NLRP12</em>-AID) is a rare autosomal dominant disorder. In this study, we reported a case of this rare disease with a novel <em>NLRP12</em> mutation (A218V, rs749659859). The patient displayed typical symptoms, including recurrent fever, arthralgia, and skin allergies. Elevated serum IgE, decreased apolipoprotein A1, high-density lipoprotein cholesterol, and fluctuating levels of various leukocyte subtypes, procalcitonin, IL6, creatine kinase, and 25-hydroxyvitamin D were also detected. Inflammatory lesions were observed in multiple organs using <sup>18</sup>F-FDG PET/CT. By mining single-cell transcriptome data, we identified relatively high expression of <em><em>NLRP12</em></em> in monocytes compared to other human peripheral blood mononuclear cells. <em>NLRP12</em>-positive monocytes exhibited reduced expression of <em>IL18</em>, <em>CCL3</em>, and <em>TNFA</em> compared to <em>NLRP12</em>-negative monocytes. Structural analyses suggested that the A218V mutation, along with A218T and F402L, may reduce the ATP-binding affinity of the NLRP12 protein. These findings may provide new insights into the mechanisms of <em>NLRP12</em>-AID, and suggest the potential ATP-based therapy for further investigation.</p></div>","PeriodicalId":10392,"journal":{"name":"Clinical immunology","volume":null,"pages":null},"PeriodicalIF":8.6,"publicationDate":"2024-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141325179","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-06-07DOI: 10.1016/j.clim.2024.110270
Solmaz Yazdani , Anikó Lovik , Christina Seitz , Caroline Ingre , Fang Fang , John Andersson
Inflammation is a hallmark of amyotrophic lateral sclerosis (ALS) and is often assessed through biological samples. Due to the easier access, peripheral blood is more commonly phenotyped instead of cerebrospinal fluid (CSF) or affected tissues in ALS. Here, using flow cytometry, we compared the composition of T cell subsets in blood and CSF in ALS patients. We found consistent but weak correlations between blood and CSF for all T cell subsets examined. This finding implies that blood and CSF offer complementary information when characterizing T cell immunity in ALS and blood may not be used as a surrogate for CSF.
炎症是肌萎缩性脊髓侧索硬化症(ALS)的标志,通常通过生物样本进行评估。由于更容易获得,外周血而不是脑脊液(CSF)或 ALS 患者的受累组织更常被进行表型分析。在这里,我们使用流式细胞术比较了 ALS 患者血液和 CSF 中 T 细胞亚群的组成。我们发现血液和脑脊液中的所有 T 细胞亚群之间存在一致但微弱的相关性。这一发现意味着,在描述 ALS 的 T 细胞免疫特征时,血液和 CSF 可提供互补信息,而血液不可用作 CSF 的替代物。
{"title":"T cell subset composition differs between blood and cerebrospinal fluid in amyotrophic lateral sclerosis","authors":"Solmaz Yazdani , Anikó Lovik , Christina Seitz , Caroline Ingre , Fang Fang , John Andersson","doi":"10.1016/j.clim.2024.110270","DOIUrl":"10.1016/j.clim.2024.110270","url":null,"abstract":"<div><p>Inflammation is a hallmark of amyotrophic lateral sclerosis (ALS) and is often assessed through biological samples. Due to the easier access, peripheral blood is more commonly phenotyped instead of cerebrospinal fluid (CSF) or affected tissues in ALS. Here, using flow cytometry, we compared the composition of T cell subsets in blood and CSF in ALS patients. We found consistent but weak correlations between blood and CSF for all T cell subsets examined. This finding implies that blood and CSF offer complementary information when characterizing T cell immunity in ALS and blood may not be used as a surrogate for CSF.</p></div>","PeriodicalId":10392,"journal":{"name":"Clinical immunology","volume":null,"pages":null},"PeriodicalIF":8.6,"publicationDate":"2024-06-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141295700","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-06-06DOI: 10.1016/j.clim.2024.110266
Silvia Sartoris , Giovanna Del Pozzo
The genes mapping at the HLA region show high density, strong linkage disequilibrium and high polymorphism, which affect the association of HLA class I and class II genes with autoimmunity. We focused on the HLA haplotypes, genomic structures consisting of an array of specific alleles showing some degrees of genetic association with different autoimmune disorders. GWASs in many pathologies have identified variants in either the coding loci or the flanking regulatory regions, both in linkage disequilibrium in haplotypes, that are frequently associated with increased risk and may influence gene expression. We discuss the relevance of the HLA gene expression because the level of surface heterodimers determines the number of complexes presenting self-antigen and, thus, the strength of pathogenic autoreactive T cells immune response.
映射在 HLA 区域的基因显示出高密度、强连锁不平衡和高多态性,这影响了 HLA I 类和 II 类基因与自身免疫的关联。我们的研究重点是 HLA 单倍型,它是由一系列特定等位基因组成的基因组结构,与不同的自身免疫性疾病有一定程度的遗传关联。对许多病症进行的全球基因组研究发现,编码基因位点或侧翼调控区域的变异(两者在单倍型中处于连锁不平衡状态)经常与风险增加有关,并可能影响基因表达。我们讨论了 HLA 基因表达的相关性,因为表面异质二聚体的水平决定了呈现自身抗原的复合物的数量,从而决定了致病性自反应 T 细胞免疫反应的强度。
{"title":"Exploring the HLA complex in autoimmunity: From the risk haplotypes to the modulation of expression","authors":"Silvia Sartoris , Giovanna Del Pozzo","doi":"10.1016/j.clim.2024.110266","DOIUrl":"10.1016/j.clim.2024.110266","url":null,"abstract":"<div><p>The genes mapping at the HLA region show high density, strong linkage disequilibrium and high polymorphism, which affect the association of HLA class I and class II genes with autoimmunity. We focused on the HLA haplotypes, genomic structures consisting of an array of specific alleles showing some degrees of genetic association with different autoimmune disorders. GWASs in many pathologies have identified variants in either the coding loci or the flanking regulatory regions, both in linkage disequilibrium in haplotypes, that are frequently associated with increased risk and may influence gene expression. We discuss the relevance of the HLA gene expression because the level of surface heterodimers determines the number of complexes presenting self-antigen and, thus, the strength of pathogenic autoreactive T cells immune response.</p></div>","PeriodicalId":10392,"journal":{"name":"Clinical immunology","volume":null,"pages":null},"PeriodicalIF":8.6,"publicationDate":"2024-06-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1521661624003759/pdfft?md5=7cd06c6f943cee63d821e9d1f86f0600&pid=1-s2.0-S1521661624003759-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141293224","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-06-04DOI: 10.1016/j.clim.2024.110269
Wen-I Lee , Jing-Long Huang , Meng-Ying Hsieh , Li-Chen Chen , Kuo-Wei Yeh , Liang-Shiou Ou , Tsung-Chieh Yao , Chao-Yi Wu , Syh-Jae Lin , Shih-Hsiang Chen , Tang-Her Jaing , Chi-Jou Liang , Chen-Chen Kang
Lymphoproliferative disorders (LPD) comprise a heterogeneous group and are originally classified into the “Disease of immune dysregulation” category. Of 96 Taiwanese patients during 2003–2022, 31 (median 66, range 0.03–675 months) developed LPD, mainly including palpable lymphadenopathy (in 10 patients), intestinal lymphadenopathy associated with refractory inflammatory bowel disease (IBD in 8) and hepatosplenomegaly (in 7) during long-term follow-up (median 144, range 3–252 months). They distributed in the categories of antibody deficiency (2 CVID, 2 TTC37, PIK3CD, PIK3R1 and AICDA each), phagocyte (4 CYBB, 1 STAT1 and 1 IFNRG1), immune dysregulation (2 FOXP3, 2 XIAP and 2 HLH), combined immunodeficiencies (2 IL2RG; CD40L, ZAP70 and unknown each), syndromic features (2 STAT3-LOF, 1 WAS and 1 ATM) and three with anti-IFN-γ autoantibodies. An increased senescent (CD8 + CD57+) and CD21-low, disturbed transitional B (CD38 + IgM++), plasmablast B (CD38++IgM-), memory B (CD19 + CD27+) and TEMRA (CD27-IgD-) components were often observed in cross-sectional immunophenotyping and trended to develop LPD.
{"title":"Clinical features and lymphocyte immunophenotyping analysis in primary immunodeficiency patients with non-transplant lymphoproliferative disorders","authors":"Wen-I Lee , Jing-Long Huang , Meng-Ying Hsieh , Li-Chen Chen , Kuo-Wei Yeh , Liang-Shiou Ou , Tsung-Chieh Yao , Chao-Yi Wu , Syh-Jae Lin , Shih-Hsiang Chen , Tang-Her Jaing , Chi-Jou Liang , Chen-Chen Kang","doi":"10.1016/j.clim.2024.110269","DOIUrl":"10.1016/j.clim.2024.110269","url":null,"abstract":"<div><p>Lymphoproliferative disorders (LPD) comprise a heterogeneous group and are originally classified into the “Disease of immune dysregulation” category. Of 96 Taiwanese patients during 2003–2022, 31 (median 66, range 0.03–675 months) developed LPD, mainly including palpable lymphadenopathy (in 10 patients), intestinal lymphadenopathy associated with refractory inflammatory bowel disease (IBD in 8) and hepatosplenomegaly (in 7) during long-term follow-up (median 144, range 3–252 months). They distributed in the categories of antibody deficiency (2 CVID, 2 <em>TTC37</em>, <em>PIK3CD</em>, <em>PIK3R1</em> and <em>AICDA</em> each), phagocyte (4 <em>CYBB</em>, 1 <em>STAT1</em> and 1 <em>IFNRG1</em>), immune dysregulation (2 <em>FOXP3</em>, 2 <em>XIAP</em> and 2 HLH), combined immunodeficiencies (2 <em>IL2RG</em>; <em>CD40L</em>, <em>ZAP70</em> and unknown each), syndromic features (2 <em>STAT3</em>-LOF, 1 <em>WAS</em> and 1 <em>ATM</em>) and three with anti-IFN-γ autoantibodies. An increased senescent (CD8 + CD57+) and CD21-low, disturbed transitional B (CD38 + IgM++), plasmablast B (CD38++IgM-), memory B (CD19 + CD27+) and T<sub>EMRA</sub> (CD27-IgD-) components were often observed in cross-sectional immunophenotyping and trended to develop LPD.</p></div>","PeriodicalId":10392,"journal":{"name":"Clinical immunology","volume":null,"pages":null},"PeriodicalIF":8.6,"publicationDate":"2024-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141261210","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-06-03DOI: 10.1016/j.clim.2024.110268
Fang Zhang , Zhiwei Wang , Shuai Men, Jinglu Zhang, Leilei Wang
Purpose
To report a case of a five-month-old Chinese infant who died of interleukin-1 receptor-associated kinase-4 (IRAK-4) deficiency presenting with rapid and progressive Pseudomonas aeruginosa sepsis.
Methods
The genetic etiology of IRAK-4 deficiency was confirmed through trio-whole exome sequencing and Sanger sequencing. Functional consequences were invested using an in vitro minigene splicing assay.
Results
Trio-whole exome sequencing of genomic DNA identified two novel compound heterozygous mutations, IRAK-4 (NM_016123.3): c.942–1G > A and c.644_651+ 6delTTGCAGCAGTAAGT in the proband, which originated from his symptom-free parents. These mutations were predicted to cause frameshifts and generate three truncated proteins without enzyme activity.
Conclusions
Our findings expand the range of IRAK-4 mutations and provide functional support for the pathogenic effects of splice-site mutations. Additionally, this case highlights the importance of considering the underlying genetic defects of immunity when dealing with unusually overwhelming infections in previously healthy children and emphasizes the necessity for timely treatment with wide-spectrum antimicrobials.
{"title":"Two novel compound heterozygous loss-of-function mutations cause fetal IRAK-4 deficiency presenting with Pseudomonas Aeruginosa sepsis","authors":"Fang Zhang , Zhiwei Wang , Shuai Men, Jinglu Zhang, Leilei Wang","doi":"10.1016/j.clim.2024.110268","DOIUrl":"10.1016/j.clim.2024.110268","url":null,"abstract":"<div><h3>Purpose</h3><p>To report a case of a five-month-old Chinese infant who died of interleukin-1 receptor-associated kinase-4 (IRAK-4) deficiency presenting with rapid and progressive <em>Pseudomonas aeruginosa</em> sepsis.</p></div><div><h3>Methods</h3><p>The genetic etiology of IRAK-4 deficiency was confirmed through trio-whole exome sequencing and Sanger sequencing. Functional consequences were invested using an in vitro minigene splicing assay.</p></div><div><h3>Results</h3><p>Trio-whole exome sequencing of genomic DNA identified two novel compound heterozygous mutations, <em>IRAK-4</em> (NM_016123.3): c.942–1G > A and c.644_651+ 6delTTGCAGCAGTAAGT in the proband, which originated from his symptom-free parents. These mutations were predicted to cause frameshifts and generate three truncated proteins without enzyme activity.</p></div><div><h3>Conclusions</h3><p>Our findings expand the range of IRAK-4 mutations and provide functional support for the pathogenic effects of splice-site mutations. Additionally, this case highlights the importance of considering the underlying genetic defects of immunity when dealing with unusually overwhelming infections in previously healthy children and emphasizes the necessity for timely treatment with wide-spectrum antimicrobials.</p></div>","PeriodicalId":10392,"journal":{"name":"Clinical immunology","volume":null,"pages":null},"PeriodicalIF":8.6,"publicationDate":"2024-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141261220","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}