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":"265 ","pages":"Article 110278"},"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":"265 ","pages":"Article 110270"},"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":"265 ","pages":"Article 110266"},"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":"265 ","pages":"Article 110269"},"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":"265 ","pages":"Article 110268"},"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}
Pub Date : 2024-05-31DOI: 10.1016/j.clim.2024.110267
Pedro Martínez-Fleta , María Celeste Marcos , Daniel Jimenez-Carretero , José María Galván-Román , Rosa María Girón-Moreno , Ana Adela Calero-García , Ana Arcos-García , Enrique Martín-Gayo , Hortensia de la Fuente , Laura Esparcia-Pinedo , Javier Aspa , Julio Ancochea , Arantzazu Alfranca , Francisco Sánchez-Madrid
Long-COVID (LC) is characterised by persistent symptoms for at least 3 months after acute infection. A dysregulation of the immune system and a persistent hyperinflammatory state may cause LC. LC patients present differences in activation and exhaustion states of innate and adaptive compartments. Different T CD4+ cell subsets can be identified by differential expression of chemokine receptors (CCR). However, changes in T cells with expression of CCRs such as CCR6 and CXCR3 and their relationship with CD8+ T cells remains unexplored in LC. Here, we performed unsupervised analysis and found CCR6+ CD4+ subpopulations enriched in COVID-19 convalescent individuals upon activation with SARS-CoV-2 peptides. SARS-CoV-2 specific CCR6+ CD4+ are decreased in LC patients, whereas CXCR3+ CCR6- and CCR4+ CCR6- CD4+ T cells are increased. LC patients showed lower IFN-γ-secreting CD8+ T cells after stimulation with SARS-CoV-2 Spike protein. This work underscores the role of CCR6 in the pathophysiology of LC.
{"title":"Imbalance of SARS-CoV-2-specific CCR6+ and CXCR3+ CD4+ T cells and IFN-γ + CD8+ T cells in patients with Long-COVID","authors":"Pedro Martínez-Fleta , María Celeste Marcos , Daniel Jimenez-Carretero , José María Galván-Román , Rosa María Girón-Moreno , Ana Adela Calero-García , Ana Arcos-García , Enrique Martín-Gayo , Hortensia de la Fuente , Laura Esparcia-Pinedo , Javier Aspa , Julio Ancochea , Arantzazu Alfranca , Francisco Sánchez-Madrid","doi":"10.1016/j.clim.2024.110267","DOIUrl":"10.1016/j.clim.2024.110267","url":null,"abstract":"<div><p>Long-COVID (LC) is characterised by persistent symptoms for at least 3 months after acute infection. A dysregulation of the immune system and a persistent hyperinflammatory state may cause LC. LC patients present differences in activation and exhaustion states of innate and adaptive compartments. Different T CD4<sup>+</sup> cell subsets can be identified by differential expression of chemokine receptors (CCR). However, changes in T cells with expression of CCRs such as CCR6 and CXCR3 and their relationship with CD8<sup>+</sup> T cells remains unexplored in LC. Here, we performed unsupervised analysis and found CCR6<sup>+</sup> CD4<sup>+</sup> subpopulations enriched in COVID-19 convalescent individuals upon activation with SARS-CoV-2 peptides. SARS-CoV-2 specific CCR6<sup>+</sup> CD4<sup>+</sup> are decreased in LC patients, whereas CXCR3<sup>+</sup> CCR6<sup>-</sup> and CCR4<sup>+</sup> CCR6<sup>-</sup> CD4<sup>+</sup> T cells are increased. LC patients showed lower IFN-γ-secreting CD8<sup>+</sup> T cells after stimulation with SARS-CoV-2 Spike protein. This work underscores the role of CCR6 in the pathophysiology of LC.</p></div>","PeriodicalId":10392,"journal":{"name":"Clinical immunology","volume":"264 ","pages":"Article 110267"},"PeriodicalIF":8.6,"publicationDate":"2024-05-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141199517","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}
Rheumatoid arthritis (RA) is a systemic chronic autoimmune disease that primarily affects the joints and surrounding soft tissues, characterized by chronic inflammation and proliferation of the synovium. Various immune cells are involved in the pathophysiology of RA. The complex interplay of factors such as chronic inflammation, genetic susceptibility, dysregulation of serum antibody levels, among others, contribute to the complexity of the disease mechanism, disease activity, and treatment of RA. Recently, the cytokine storm leading to increased disease activity in RA has gained significant attention. Interleukin-33 (IL-33), a member of the IL-1 family, plays a crucial role in inflammation and immune regulation. ST2 (suppression of tumorigenicity 2 receptor), the receptor for IL-33, is widely expressed on the surface of various immune cells. When IL-33 binds to its receptor ST2, it activates downstream signaling pathways to exert immunoregulatory effects. In RA, IL-33 regulates the progression of the disease by modulating immune cells such as circulating monocytes, tissue-resident macrophages, synovial fibroblasts, mast cells, dendritic cells, neutrophils, T cells, B cells, endothelial cells, and others. We have summarized and analyzed these findings to elucidate the pathways through which IL-33 regulates RA. Furthermore, IL-33 has been detected in the synovium, serum, and synovial fluid of RA patients. Due to inconsistent research results, we conducted a meta-analysis on the association between serum IL-33, synovial fluid IL-33, and the risk of developing RA in patients. The pooled SMD was 1.29 (95% CI: 1.15–1.44), indicating that IL-33 promotes the onset and pathophysiological progression of RA. Therefore, IL-33 may serve as a biomarker for predicting the risk of developing RA and treatment outcomes. As existing drugs for RA still cannot address drug resistance in some patients, new therapeutic approaches are needed to alleviate the significant burden on RA patients and healthcare systems. In light of this, we analyzed the potential of targeting the IL-33/ST2-related signaling pathway to modulate immune cells associated with RA and alleviate inflammation. We also reviewed IL-33 and RA susceptibility-related single nucleotide polymorphisms, suggesting potential involvement of IL-33 and macrophage-related drug-resistant genes in RA resistance therapy. Our review elucidates the role of IL-33 in the pathophysiology of RA, offering new insights for the treatment of RA.
类风湿性关节炎(RA)是一种全身性慢性自身免疫性疾病,主要影响关节和周围软组织,以滑膜的慢性炎症和增生为特征。各种免疫细胞参与了 RA 的病理生理学过程。慢性炎症、遗传易感性、血清抗体水平失调等因素的复杂相互作用,导致了 RA 的发病机制、疾病活动和治疗的复杂性。最近,导致 RA 疾病活动性增加的细胞因子风暴引起了广泛关注。白细胞介素-33(IL-33)是 IL-1 家族的成员之一,在炎症和免疫调节中发挥着至关重要的作用。IL-33的受体ST2(抑制肿瘤生成2受体)广泛表达于各种免疫细胞表面。当 IL-33 与其受体 ST2 结合时,会激活下游信号通路,从而发挥免疫调节作用。在 RA 中,IL-33 通过调节循环单核细胞、组织驻留巨噬细胞、滑膜成纤维细胞、肥大细胞、树突状细胞、中性粒细胞、T 细胞、B 细胞、内皮细胞等免疫细胞来调节疾病的进展。我们对这些发现进行了总结和分析,以阐明IL-33调节RA的途径。此外,在 RA 患者的滑膜、血清和滑液中也检测到了 IL-33。由于研究结果不一致,我们对血清IL-33、滑膜液IL-33与患者罹患RA风险之间的关系进行了荟萃分析。汇总的SMD为1.29(95% CI:1.15-1.44),表明IL-33会促进RA的发病和病理生理进展。因此,IL-33 可作为预测 RA 发病风险和治疗效果的生物标志物。由于现有的 RA 药物仍无法解决部分患者的耐药性问题,因此需要新的治疗方法来减轻 RA 患者和医疗系统的沉重负担。有鉴于此,我们分析了靶向 IL-33/ST2 相关信号通路以调节与 RA 相关的免疫细胞并缓解炎症的潜力。我们还回顾了IL-33和RA易感性相关的单核苷酸多态性,表明IL-33和巨噬细胞相关耐药基因可能参与RA耐药治疗。我们的综述阐明了IL-33在RA病理生理学中的作用,为RA的治疗提供了新的见解。
{"title":"The immunomodulatory of interleukin-33 in rheumatoid arthritis: A systematic review","authors":"Renli Liu, Fangfang Wang, Xing Luo, Fengfan Yang, Jie Gao, Haomiao Shen, Zhaohui Zheng","doi":"10.1016/j.clim.2024.110264","DOIUrl":"10.1016/j.clim.2024.110264","url":null,"abstract":"<div><p>Rheumatoid arthritis (RA) is a systemic chronic autoimmune disease that primarily affects the joints and surrounding soft tissues, characterized by chronic inflammation and proliferation of the synovium. Various immune cells are involved in the pathophysiology of RA. The complex interplay of factors such as chronic inflammation, genetic susceptibility, dysregulation of serum antibody levels, among others, contribute to the complexity of the disease mechanism, disease activity, and treatment of RA. Recently, the cytokine storm leading to increased disease activity in RA has gained significant attention. Interleukin-33 (IL-33), a member of the IL-1 family, plays a crucial role in inflammation and immune regulation. ST2 (suppression of tumorigenicity 2 receptor), the receptor for IL-33, is widely expressed on the surface of various immune cells. When IL-33 binds to its receptor ST2, it activates downstream signaling pathways to exert immunoregulatory effects. In RA, IL-33 regulates the progression of the disease by modulating immune cells such as circulating monocytes, tissue-resident macrophages, synovial fibroblasts, mast cells, dendritic cells, neutrophils, T cells, B cells, endothelial cells, and others. We have summarized and analyzed these findings to elucidate the pathways through which IL-33 regulates RA. Furthermore, IL-33 has been detected in the synovium, serum, and synovial fluid of RA patients. Due to inconsistent research results, we conducted a meta-analysis on the association between serum IL-33, synovial fluid IL-33, and the risk of developing RA in patients. The pooled SMD was 1.29 (95% CI: 1.15–1.44), indicating that IL-33 promotes the onset and pathophysiological progression of RA. Therefore, IL-33 may serve as a biomarker for predicting the risk of developing RA and treatment outcomes. As existing drugs for RA still cannot address drug resistance in some patients, new therapeutic approaches are needed to alleviate the significant burden on RA patients and healthcare systems. In light of this, we analyzed the potential of targeting the IL-33/ST2-related signaling pathway to modulate immune cells associated with RA and alleviate inflammation. We also reviewed IL-33 and RA susceptibility-related single nucleotide polymorphisms, suggesting potential involvement of IL-33 and macrophage-related drug-resistant genes in RA resistance therapy. Our review elucidates the role of IL-33 in the pathophysiology of RA, offering new insights for the treatment of RA.</p></div>","PeriodicalId":10392,"journal":{"name":"Clinical immunology","volume":"265 ","pages":"Article 110264"},"PeriodicalIF":8.6,"publicationDate":"2024-05-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141199519","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}
Allergic bronchopulmonary aspergillosis (ABPA) is a complex hypersensitivity reaction to Aspergillus spp. ABPA diagnosis may be challenging due to its non-specific presentation. Standard ABPA treatment consists of systemic corticosteroids and antifungal agents. Mepolizumab, a monoclonal antibody against interleukin-5 seems to be a promising treatment for ABPA. Data about ABPA following lung transplantation (LuTx) are scarce. LuTx recipients are at higher risk for adverse effects of ABPA treatment compared to the general population.
Here we present a case of a LuTx recipient who was successfully treated with mepolizumab for ABPA following LuTx. Prolonged administration of high dose prednisone was thus avoided. To our knowledge, this is the first case describing mepolizumab administration following LuTx. Mepolizumab seems particularly attractive as a corticosteroid-sparing agent or as an alternative option to antifungal treatments, because of its excellent safety profile and low risk of drug interactions.
{"title":"Allergic bronchopulmonary aspergillosis in a lung transplant recipient treated with mepolizumab","authors":"Foteini Ioakeim , Christophe Abellan , Alessio Casutt , Benoit Lechartier , Leslie Noirez , Catherine Beigelman-Aubry , John-David Aubert , Zisis Balmpouzis , Angela Koutsokera","doi":"10.1016/j.clim.2024.110265","DOIUrl":"10.1016/j.clim.2024.110265","url":null,"abstract":"<div><p>Allergic bronchopulmonary aspergillosis (ABPA) is a complex hypersensitivity reaction to <em>Aspergillus</em> spp. ABPA diagnosis may be challenging due to its non-specific presentation. Standard ABPA treatment consists of systemic corticosteroids and antifungal agents. Mepolizumab, a monoclonal antibody against interleukin-5 seems to be a promising treatment for ABPA. Data about ABPA following lung transplantation (LuTx) are scarce. LuTx recipients are at higher risk for adverse effects of ABPA treatment compared to the general population.</p><p>Here we present a case of a LuTx recipient who was successfully treated with mepolizumab for ABPA following LuTx. Prolonged administration of high dose prednisone was thus avoided. To our knowledge, this is the first case describing mepolizumab administration following LuTx. Mepolizumab seems particularly attractive as a corticosteroid-sparing agent or as an alternative option to antifungal treatments, because of its excellent safety profile and low risk of drug interactions.</p></div>","PeriodicalId":10392,"journal":{"name":"Clinical immunology","volume":"264 ","pages":"Article 110265"},"PeriodicalIF":8.6,"publicationDate":"2024-05-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141157536","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 : 2024-05-23DOI: 10.1016/j.clim.2024.110263
Salem Al-Tamemi , Abdulhakim Al-Rawas , Murtadha Al-Khabori , Khalil Al-Farsi , Mohammed Al-Huneini , Amr Abdalla , Salam Al-Kindi , David Dennison
Background
Hematopoietic stem cell transplantation (HSCT) is a curative treatment for certain inborn errors of immunity.
Methods
A 17-year retrospective cohort study was conducted on 40 immunodeficient patients who underwent HSCT.
Results
The median age at transplant was 11.0 months (4.6–61.0). Donors were primarily matched sibling donors (60%). 90% and 85% of patients received conditioning and graft-versus-host disease (GVHD) prophylaxis, respectively. The mean donor chimerism at the last follow-up was 88.6% ± 17.9% (40–100). Median serum immunoglobulin (Ig) G level, CD4+ T-cell count, and CD19+ B-cell count were 11.7 g/L (9.2–13.6), 0.9 × 109/L 0.6–1.2), and 0.5 × 109/L (0.2–0.7), respectively. 29 patients (72.5%) received intravenous immunoglobulins (IVIG) therapy, with a median duration of 10.0 months (4.0–14.0). The median post-transplant follow-up was 6.5 years (IQR:1.4–11.5). The 10-year overall probability of survival is 84.3%.
Conclusion
Monitoring IRC is important in ensuring adequate disease-free survival.
{"title":"Immune reconstitution and survival, following hematopoietic stem cell transplantation in Omani patients with inborn errors of immunity","authors":"Salem Al-Tamemi , Abdulhakim Al-Rawas , Murtadha Al-Khabori , Khalil Al-Farsi , Mohammed Al-Huneini , Amr Abdalla , Salam Al-Kindi , David Dennison","doi":"10.1016/j.clim.2024.110263","DOIUrl":"10.1016/j.clim.2024.110263","url":null,"abstract":"<div><h3>Background</h3><p>Hematopoietic stem cell transplantation (HSCT) is a curative treatment for certain inborn errors of immunity.</p></div><div><h3>Methods</h3><p>A 17-year retrospective cohort study was conducted on 40 immunodeficient patients who underwent HSCT.</p></div><div><h3>Results</h3><p>The median age at transplant was 11.0 months (4.6–61.0). Donors were primarily matched sibling donors (60%). 90% and 85% of patients received conditioning and graft-versus-host disease (GVHD) prophylaxis, respectively. The mean donor chimerism at the last follow-up was 88.6% ± 17.9% (40–100). Median serum immunoglobulin (Ig) G level, CD4+ T-cell count, and CD19+ B-cell count were 11.7 g/L (9.2–13.6), 0.9 × 10<sup>9</sup>/L 0.6–1.2), and 0.5 × 10<sup>9</sup>/L (0.2–0.7), respectively. 29 patients (72.5%) received intravenous immunoglobulins (IVIG) therapy, with a median duration of 10.0 months (4.0–14.0). The median post-transplant follow-up was 6.5 years (IQR:1.4–11.5). The 10-year overall probability of survival is 84.3%.</p></div><div><h3>Conclusion</h3><p>Monitoring IRC is important in ensuring adequate disease-free survival.</p></div>","PeriodicalId":10392,"journal":{"name":"Clinical immunology","volume":"264 ","pages":"Article 110263"},"PeriodicalIF":8.6,"publicationDate":"2024-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141141525","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 : 2024-05-23DOI: 10.1016/j.clim.2024.110262
Sahla El Mahdaoui , Marie Mathilde Hansen , Malene Bredahl Hansen , Victoria Hyslop Hvalkof , Helle Bach Søndergaard , Mie Reith Mahler , Jeppe Romme Christensen , Finn Sellebjerg , Marina Rode von Essen
Follicular helper T (Tfh) cells and their interplay with B cells likely contribute to the pathogenesis of relapsing-remitting multiple sclerosis (RRMS). Tfh cells are enriched in cerebrospinal fluid (CSF) in RRMS, but effects of anti-CD20 therapy are unknown. We investigated Tfh cells in controls, untreated and anti-CD20-treated patients with RRMS using flow cytometry. CSF Tfh cells were increased in untreated patients. Compared to paired blood samples, CD25− Tfh cells were enriched in CSF in RRMS, but not in controls. Contrast-enhancing brain MRI lesions and IgG index correlated with CSF CD25− Tfh cell frequency in untreated patients with RRMS. Anti-CD20 therapy reduced the numbers of circulating PD1+ Tfh cells and CD25− Tfh cells, and the frequency of CSF CD25− Tfh cells. The study suggests that CD25− Tfh cells are recruited to the CSF in RRMS, associated with focal inflammation, and are reduced by anti-CD20 therapy.
{"title":"Effects of anti-CD20 therapy on circulating and intrathecal follicular helper T cell subsets in multiple sclerosis","authors":"Sahla El Mahdaoui , Marie Mathilde Hansen , Malene Bredahl Hansen , Victoria Hyslop Hvalkof , Helle Bach Søndergaard , Mie Reith Mahler , Jeppe Romme Christensen , Finn Sellebjerg , Marina Rode von Essen","doi":"10.1016/j.clim.2024.110262","DOIUrl":"10.1016/j.clim.2024.110262","url":null,"abstract":"<div><p>Follicular helper T (Tfh) cells and their interplay with B cells likely contribute to the pathogenesis of relapsing-remitting multiple sclerosis (RRMS). Tfh cells are enriched in cerebrospinal fluid (CSF) in RRMS, but effects of anti-CD20 therapy are unknown. We investigated Tfh cells in controls, untreated and anti-CD20-treated patients with RRMS using flow cytometry. CSF Tfh cells were increased in untreated patients. Compared to paired blood samples, CD25<sup>−</sup> Tfh cells were enriched in CSF in RRMS, but not in controls. Contrast-enhancing brain MRI lesions and IgG index correlated with CSF CD25<sup>−</sup> Tfh cell frequency in untreated patients with RRMS. Anti-CD20 therapy reduced the numbers of circulating PD1<sup>+</sup> Tfh cells and CD25<sup>−</sup> Tfh cells, and the frequency of CSF CD25<sup>−</sup> Tfh cells. The study suggests that CD25<sup>−</sup> Tfh cells are recruited to the CSF in RRMS, associated with focal inflammation, and are reduced by anti-CD20 therapy.</p></div>","PeriodicalId":10392,"journal":{"name":"Clinical immunology","volume":"264 ","pages":"Article 110262"},"PeriodicalIF":8.6,"publicationDate":"2024-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1521661624003711/pdfft?md5=067c9241e5b14c9188b12b45b28eafd8&pid=1-s2.0-S1521661624003711-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141092672","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}