Pub Date : 2024-07-02DOI: 10.1016/j.clim.2024.110304
Mastura Monif , Richard P. Sequeira , Andrea Muscat , Sian Stuckey , Paul G. Sanfilippo , Viet Minh , Naomi Loftus , Veronica Voo , Katherine Fazzolari , Melinda Moss , Vicki E. Maltby , Ai-Lan Nguyen , Robb Wesselingh , Nabil Seery , Cassie Nesbitt , Josephine Baker , Chris Dwyer , Lisa Taylor , Louise Rath , Anneke Van der Walt , Helmut Butzkueven
Cladribine (Mavenclad®) is an oral treatment for relapsing remitting MS (RRMS), but its mechanism of action and its effects on innate immune responses in unknown. This study is a prospective Phase IV study of 41 patients with RRMS, and aims to investigate the mechanism of action of cladribine on peripheral monocytes, and its impact on the P2X7 receptor. There was a significant reduction in monocyte count in vivo at week 1 post cladribine administration, and the subset of cells being most impacted were the CD14lo CD16+ ‘non-classical’ monocytes. Of the 14 cytokines measured in serum, CCL2 levels increased at week 1. In vitro, cladrabine induced a reduction in P2X7R pore as well as channel activity. This study demonstrates a novel mechanism of action for cladribine. It calls for studying potential benefits of cladribine in progressive forms of MS and other neurodegenerative diseases where innate immune related inflammation is implicated in disease pathogenesis.
{"title":"CLADIN- CLADribine and INnate immune response in multiple sclerosis – A phase IV prospective study","authors":"Mastura Monif , Richard P. Sequeira , Andrea Muscat , Sian Stuckey , Paul G. Sanfilippo , Viet Minh , Naomi Loftus , Veronica Voo , Katherine Fazzolari , Melinda Moss , Vicki E. Maltby , Ai-Lan Nguyen , Robb Wesselingh , Nabil Seery , Cassie Nesbitt , Josephine Baker , Chris Dwyer , Lisa Taylor , Louise Rath , Anneke Van der Walt , Helmut Butzkueven","doi":"10.1016/j.clim.2024.110304","DOIUrl":"10.1016/j.clim.2024.110304","url":null,"abstract":"<div><p>Cladribine (Mavenclad®) is an oral treatment for relapsing remitting MS (RRMS), but its mechanism of action and its effects on innate immune responses in unknown. This study is a prospective Phase IV study of 41 patients with RRMS, and aims to investigate the mechanism of action of cladribine on peripheral monocytes, and its impact on the P2X7 receptor. There was a significant reduction in monocyte count <em>in vivo</em> at week 1 post cladribine administration, and the subset of cells being most impacted were the CD14lo CD16+ ‘non-classical’ monocytes. Of the 14 cytokines measured in serum, CCL2 levels increased at week 1. <em>In vitro</em>, cladrabine induced a reduction in P2X7R pore as well as channel activity. This study demonstrates a novel mechanism of action for cladribine. It calls for studying potential benefits of cladribine in progressive forms of MS and other neurodegenerative diseases where innate immune related inflammation is implicated in disease pathogenesis.</p></div>","PeriodicalId":10392,"journal":{"name":"Clinical immunology","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2024-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141533852","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 : 2024-06-29DOI: 10.1016/j.clim.2024.110288
Interleukin-2 (IL-2) holds promise for the treatment of cancer and autoimmune diseases, but its high-dose usage is associated with systemic immunotoxicity. Differential IL-2 receptor (IL-2R) regulation might impact function of cells upon IL-2 stimulation, possibly inducing cellular changes similar to patients with hypomorphic IL2RB mutations, presenting with multiorgan autoimmunity. Here, we show that sustained high-dose IL-2 stimulation of human lymphocytes drastically reduces IL-2Rβ surface expression especially on T cells, resulting in impaired IL-2R signaling which correlates with high IL-2Rα baseline expression. IL-2R signaling in NK cells is maintained. CD4+ T cells, especially regulatory T cells are more broadly affected than CD8+ T cells, consistent with lineage-specific differences in IL-2 responsiveness. Given the resemblance of cellular characteristics of high-dose IL-2-stimulated cells and cells from patients with IL-2Rβ defects, impact of continuous IL-2 stimulation on IL-2R signaling should be considered in the onset of clinical adverse events during IL-2 therapy.
白细胞介素-2(IL-2)有望用于治疗癌症和自身免疫性疾病,但其高剂量使用与全身免疫毒性有关。IL-2受体(IL-2R)调控的差异可能会影响细胞在IL-2刺激下的功能,从而可能诱发类似于IL2RB低位突变患者的细胞变化,表现为多器官自身免疫。在这里,我们发现持续高剂量的IL-2刺激人类淋巴细胞会大幅降低IL-2Rβ的表面表达,尤其是在T细胞上,从而导致IL-2R信号受损,这与IL-2Rα的高基线表达相关。NK 细胞中的 IL-2R 信号保持不变。与 CD8+ T 细胞相比,CD4+ T 细胞,尤其是调节性 T 细胞受到的影响更广泛,这与 IL-2 反应性的品系特异性差异是一致的。鉴于高剂量IL-2刺激的细胞和IL-2Rβ缺陷患者的细胞特征相似,在IL-2治疗期间出现临床不良反应时应考虑持续IL-2刺激对IL-2R信号的影响。
{"title":"Bridging therapy-induced phenotypes and genetic immune dysregulation to study interleukin-2-induced immunotoxicology","authors":"","doi":"10.1016/j.clim.2024.110288","DOIUrl":"10.1016/j.clim.2024.110288","url":null,"abstract":"<div><p>Interleukin-2 (IL-2) holds promise for the treatment of cancer and autoimmune diseases, but its high-dose usage is associated with systemic immunotoxicity. Differential IL-2 receptor (IL-2R) regulation might impact function of cells upon IL-2 stimulation, possibly inducing cellular changes similar to patients with hypomorphic <em>IL2RB</em> mutations, presenting with multiorgan autoimmunity. Here, we show that sustained high-dose IL-2 stimulation of human lymphocytes drastically reduces IL-2Rβ surface expression especially on T cells, resulting in impaired IL-2R signaling which correlates with high IL-2Rα baseline expression. IL-2R signaling in NK cells is maintained. CD4+ T cells, especially regulatory T cells are more broadly affected than CD8+ T cells, consistent with lineage-specific differences in IL-2 responsiveness. Given the resemblance of cellular characteristics of high-dose IL-2-stimulated cells and cells from patients with IL-2Rβ defects, impact of continuous IL-2 stimulation on IL-2R signaling should be considered in the onset of clinical adverse events during IL-2 therapy.</p></div>","PeriodicalId":10392,"journal":{"name":"Clinical immunology","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2024-06-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1521661624003978/pdfft?md5=163cd96bd24b7212bfec316b96897c81&pid=1-s2.0-S1521661624003978-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141476098","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}
A comprehensive analysis of spatial transcriptomics was carried out to better understand the progress of halo nevus. We found that halo nevus was characterized by overactive immune responses, triggered by chemokines and dendritic cells (DCs), T cells, and macrophages. Consequently, we observed abnormal cell death, such as apoptosis and disulfidptosis in halo nevus, some were closely related to immunity. Interestingly, we identified aberrant metabolites such as uridine diphosphate glucose (UDP-G) within the halo nevus. UDP-G, accompanied by the infiltration of DCs and T cells, exhibited correlations with certain forms of cell death. Subsequent experiments confirmed that UDP-G was increased in vitiligo serum and could activate DCs. We also confirmed that oxidative response is an inducer of UDP-G. In summary, the immune response in halo nevus, including DC activation, was accompanied by abnormal cell death and metabolites. Especially, melanocyte-derived UDP-G may play a crucial role in DC activation.
为了更好地了解晕痣的发展过程,我们对空间转录组学进行了全面分析。我们发现,晕痣的特点是过度活跃的免疫反应,由趋化因子和树突状细胞(DC)、T 细胞和巨噬细胞引发。因此,我们在晕痣中观察到细胞异常死亡,如凋亡和二硫化钼,其中一些与免疫密切相关。有趣的是,我们在晕痣中发现了尿苷二磷酸葡萄糖(UDP-G)等异常代谢物。伴随着直流电和 T 细胞的浸润,UDP-G 与某些形式的细胞死亡相关。随后的实验证实,UDP-G 在白癜风血清中增加,并能激活 DCs。我们还证实,氧化反应是 UDP-G 的诱导剂。总之,晕痣的免疫反应(包括 DC 激活)伴随着异常的细胞死亡和代谢产物。尤其是黑色素细胞衍生的UDP-G可能在DC活化过程中起着至关重要的作用。
{"title":"Abnormal metabolism in melanocytes participates in the activation of dendritic cell in halo nevus","authors":"Ling Jiang , Yibo Hu , Yushan Zhang , Yuanyuan Zhao , Lijuan Gao , Yumeng Dong , Yixuan Liang , Haoran Guo , Songjiang Wu , Yuanmin Zhang , Jing Chen , Qinghai Zeng","doi":"10.1016/j.clim.2024.110300","DOIUrl":"10.1016/j.clim.2024.110300","url":null,"abstract":"<div><p>A comprehensive analysis of spatial transcriptomics was carried out to better understand the progress of halo nevus. We found that halo nevus was characterized by overactive immune responses, triggered by chemokines and dendritic cells (DCs), T cells, and macrophages. Consequently, we observed abnormal cell death, such as apoptosis and disulfidptosis in halo nevus, some were closely related to immunity. Interestingly, we identified aberrant metabolites such as uridine diphosphate glucose (UDP-G) within the halo nevus. UDP-G, accompanied by the infiltration of DCs and T cells, exhibited correlations with certain forms of cell death. Subsequent experiments confirmed that UDP-G was increased in vitiligo serum and could activate DCs. We also confirmed that oxidative response is an inducer of UDP-G. In summary, the immune response in halo nevus, including DC activation, was accompanied by abnormal cell death and metabolites. Especially, melanocyte-derived UDP-G may play a crucial role in DC activation.</p></div>","PeriodicalId":10392,"journal":{"name":"Clinical immunology","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2024-06-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141476097","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 : 2024-06-27DOI: 10.1016/j.clim.2024.110301
Xuelian Li , Shijiu Jiang , Boyuan Wang , Shaolin He , Xiaopeng Guo , Jibin Lin , Yumiao Wei
Septic cardiomyopathy (SCM) is characterized by an abnormal inflammatory response and increased mortality. The role of efferocytosis in SCM is not well understood. We used integrated multi-omics analysis to explore the clinical and genetic roles of efferocytosis in SCM. We identified six module genes (ATP11C, CD36, CEBPB, MAPK3, MAPKAPK2, PECAM1) strongly associated with SCM, leading to an accurate predictive model. Subgroups defined by EFFscore exhibited distinct clinical features and immune infiltration levels. Survival analysis showed that the C1 subtype with a lower EFFscore had better survival outcomes. scRNA-seq analysis of peripheral blood mononuclear cells (PBMCs) from sepsis patients identified four genes (CEBPB, CD36, PECAM1, MAPKAPK2) associated with high EFFscores, highlighting their role in SCM. Molecular docking confirmed interactions between diagnostic genes and tamibarotene. Experimental validation supported our computational results. In conclusion, our study identifies a novel efferocytosis-related SCM subtype and diagnostic biomarkers, offering new insights for clinical diagnosis and therapy.
{"title":"Integrated multi-omics analysis and machine learning developed diagnostic markers and prognostic model based on Efferocytosis-associated signatures for septic cardiomyopathy","authors":"Xuelian Li , Shijiu Jiang , Boyuan Wang , Shaolin He , Xiaopeng Guo , Jibin Lin , Yumiao Wei","doi":"10.1016/j.clim.2024.110301","DOIUrl":"10.1016/j.clim.2024.110301","url":null,"abstract":"<div><p>Septic cardiomyopathy (SCM) is characterized by an abnormal inflammatory response and increased mortality. The role of efferocytosis in SCM is not well understood. We used integrated multi-omics analysis to explore the clinical and genetic roles of efferocytosis in SCM. We identified six module genes (ATP11C, CD36, CEBPB, MAPK3, MAPKAPK2, PECAM1) strongly associated with SCM, leading to an accurate predictive model. Subgroups defined by EFFscore exhibited distinct clinical features and immune infiltration levels. Survival analysis showed that the C1 subtype with a lower EFFscore had better survival outcomes. scRNA-seq analysis of peripheral blood mononuclear cells (PBMCs) from sepsis patients identified four genes (CEBPB, CD36, PECAM1, MAPKAPK2) associated with high EFFscores, highlighting their role in SCM. Molecular docking confirmed interactions between diagnostic genes and tamibarotene. Experimental validation supported our computational results. In conclusion, our study identifies a novel efferocytosis-related SCM subtype and diagnostic biomarkers, offering new insights for clinical diagnosis and therapy.</p></div>","PeriodicalId":10392,"journal":{"name":"Clinical immunology","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2024-06-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141466662","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 : 2024-06-27DOI: 10.1016/j.clim.2024.110290
Tingyan He , Linlin Wang , Xiaomei Huang, Ruohang Weng, Jun Yang
Objective
Juvenile arthritis caused by loss-of-function LACC1 mutations is characterized by early onset of symmetric and chronic arthritis, associated with an elevation of inflammatory markers. We aimed to describe serum cytokine levels, explore the type I interferon pathway, and evaluate the efficacy of treatment in a patient presenting with polyarthritis and anemia caused by novel compound heterozygous variations in LACC1.
Methods
Clinical data of a patient with compound heterozygous variations in LACC1 was collected. Serum cytokine levels and IFN-stimulated cytokine genes were analyzed at diagnosis, at disease flare, and after treatment. Full-length cDNA of LACC1 was checked by RNA analysis. Single-cell RNA sequencing was performed in PBMCs.
Results
Two novel variants in the LACC1 gene were identified in a patient presenting with polyarthritis and anemia. LACC1-cDNA was normally expressed in the healthy control, the target production at 1384 bp was not observed in the patient. Compared to nine patient controls with non-systemic juvenile idiopathic arthritis, serum interleukin(IL)-6 level was significantly elevated in the affected patient. The median IFN score for the patient, her mother, and controls were 118, 8, and 4.9, respectively. The combined treatment of JAK inhibitors with prednisone or tocilizumab led to a complete response, including remission of joint symptoms, resolution of anemia, reduced expression of IFN-stimulated cytokine genes, and normalized levels of inflammatory markers, including CRP, ESR, SAA, and serum IL-6.
Conclusion
LACC1 may play a crucial role in multiple inflammatory signaling pathways. The combination therapy of JAK inhibitors and tocilizumab may be effective for a subset of refractory patients.
{"title":"LACC1 deficiency leading to juvenile arthritis and anemia","authors":"Tingyan He , Linlin Wang , Xiaomei Huang, Ruohang Weng, Jun Yang","doi":"10.1016/j.clim.2024.110290","DOIUrl":"10.1016/j.clim.2024.110290","url":null,"abstract":"<div><h3>Objective</h3><p>Juvenile arthritis caused by loss-of-function <em>LACC1</em> mutations is characterized by early onset of symmetric and chronic arthritis, associated with an elevation of inflammatory markers. We aimed to describe serum cytokine levels, explore the type I interferon pathway, and evaluate the efficacy of treatment in a patient presenting with polyarthritis and anemia caused by novel compound heterozygous variations in <em>LACC1</em>.</p></div><div><h3>Methods</h3><p>Clinical data of a patient with compound heterozygous variations in <em>LACC1</em> was collected. Serum cytokine levels and IFN-stimulated cytokine genes were analyzed at diagnosis, at disease flare, and after treatment. Full-length cDNA of <em>LACC1</em> was checked by RNA analysis. Single-cell RNA sequencing was performed in PBMCs.</p></div><div><h3>Results</h3><p>Two novel variants in the <em>LACC1</em> gene were identified in a patient presenting with polyarthritis and anemia. <em>LACC1</em>-cDNA was normally expressed in the healthy control, the target production at 1384 bp was not observed in the patient. Compared to nine patient controls with non-systemic juvenile idiopathic arthritis, serum interleukin(IL)-6 level was significantly elevated in the affected patient. The median IFN score for the patient, her mother, and controls were 118, 8, and 4.9, respectively. The combined treatment of JAK inhibitors with prednisone or tocilizumab led to a complete response, including remission of joint symptoms, resolution of anemia, reduced expression of IFN-stimulated cytokine genes, and normalized levels of inflammatory markers, including CRP, ESR, SAA, and serum IL-6.</p></div><div><h3>Conclusion</h3><p>LACC1 may play a crucial role in multiple inflammatory signaling pathways. The combination therapy of JAK inhibitors and tocilizumab may be effective for a subset of refractory patients.</p></div>","PeriodicalId":10392,"journal":{"name":"Clinical immunology","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2024-06-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141466659","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 : 2024-06-26DOI: 10.1016/j.clim.2024.110302
Katrine Kielsen , Dina Leth Møller , Anders Elm Pedersen , Claus Henrik Nielsen , Marianne Ifversen , Lars Peter Ryder , Klaus Müller
Pediatric hematopoietic stem cell transplantation (HSCT) is challenged by chronic graft-versus-host disease (cGvHD) significantly affecting survival and long-term morbidity, but underlying mechanisms including the impact of post-HSCT CMV infection are sparsely studied.
We first investigated the impact of CMV infection for development of cGvHD in 322 children undergoing standard myeloablative HSCT between 2000 and 2018. Clinically significant CMV infection (n = 61) was an independent risk factor for chronic GvHD in a multivariable Cox regression analysis (HR = 2.17, 95% CI = 1.18–3.97, P = 0.013). We next explored the underlying mechanisms in a subcohort of 39 children. CMV infection was followed by reduced concentration of recent thymic emigrants (17.5 vs. 51.9 × 106/L, P = 0.048) and naïve CD4+ and CD8+ T cells at 6 months post-HSCT (all P < 0.05). Furthermore, CD25highFOXP3+ Tregs tended to be lower in patients with CMV infection (2.9 vs. 9.6 × 106/L, P = 0.055), including Tregs expressing the naivety markers CD45RA and Helios. CD8+ T-cell numbers rose after CMV infection and was dominated by exhausted PD1-expressing cells (66% vs. 39%, P = 0.023).
These findings indicate that post-HSCT CMV infection is a main risk factor for development of chronic GvHD after pediatric HSCT and suggest that this effect is caused by reduced thymic function with a persistently impaired production of naïve and regulatory T cells in combination with increased peripheral T-cell exhaustion.
小儿造血干细胞移植(HSCT)面临着慢性移植物抗宿主疾病(cGvHD)的挑战,严重影响了存活率和长期发病率,但包括HSCT后CMV感染影响在内的潜在机制却鲜有研究。我们首先调查了2000年至2018年期间接受标准髓鞘脱落造血干细胞移植的322名儿童中CMV感染对cGvHD发生的影响。在一项多变量 Cox 回归分析中,临床上明显的 CMV 感染(n = 61)是慢性 GvHD 的独立风险因素(HR = 2.17,95% CI = 1.18-3.97,P = 0.013)。接下来,我们在 39 名儿童的子队列中探讨了其潜在机制。CMV感染后,近期胸腺移出者(17.5 vs. 51.9 × 106/L,P = 0.048)以及HSCT后6个月的幼稚CD4+和CD8+ T细胞浓度降低(所有P高),包括表达幼稚标记物CD45RA和Helios的Tregs,在CMV感染患者中往往较低(2.9 vs. 9.6 × 106/L,P = 0.055)。CD8+ T细胞数量在CMV感染后上升,并以表达PD1的衰竭细胞为主(66% vs. 39%,P = 0.023)。这些研究结果表明,造血干细胞移植后CMV感染是小儿造血干细胞移植后发生慢性GvHD的主要风险因素,并提示这种影响是由于胸腺功能降低、幼稚T细胞和调节性T细胞的生成持续受损以及外周T细胞衰竭增加造成的。
{"title":"Cytomegalovirus infection is associated with thymic dysfunction and chronic graft-versus-host disease after pediatric hematopoietic stem cell transplantation","authors":"Katrine Kielsen , Dina Leth Møller , Anders Elm Pedersen , Claus Henrik Nielsen , Marianne Ifversen , Lars Peter Ryder , Klaus Müller","doi":"10.1016/j.clim.2024.110302","DOIUrl":"10.1016/j.clim.2024.110302","url":null,"abstract":"<div><p>Pediatric hematopoietic stem cell transplantation (HSCT) is challenged by chronic graft-versus-host disease (cGvHD) significantly affecting survival and long-term morbidity, but underlying mechanisms including the impact of post-HSCT CMV infection are sparsely studied.</p><p>We first investigated the impact of CMV infection for development of cGvHD in 322 children undergoing standard myeloablative HSCT between 2000 and 2018. Clinically significant CMV infection (<em>n</em> = 61) was an independent risk factor for chronic GvHD in a multivariable Cox regression analysis (HR = 2.17, 95% CI = 1.18–3.97, <em>P</em> = 0.013). We next explored the underlying mechanisms in a subcohort of 39 children. CMV infection was followed by reduced concentration of recent thymic emigrants (17.5 vs. 51.9 × 10<sup>6</sup>/L, <em>P</em> = 0.048) and naïve CD4+ and CD8+ T cells at 6 months post-HSCT (all <em>P</em> < 0.05). Furthermore, CD25<sup>high</sup>FOXP3+ Tregs tended to be lower in patients with CMV infection (2.9 vs. 9.6 × 10<sup>6</sup>/L, <em>P</em> = 0.055), including Tregs expressing the naivety markers CD45RA and Helios. CD8+ T-cell numbers rose after CMV infection and was dominated by exhausted PD1-expressing cells (66% vs. 39%, <em>P</em> = 0.023).</p><p>These findings indicate that post-HSCT CMV infection is a main risk factor for development of chronic GvHD after pediatric HSCT and suggest that this effect is caused by reduced thymic function with a persistently impaired production of naïve and regulatory T cells in combination with increased peripheral T-cell exhaustion.</p></div>","PeriodicalId":10392,"journal":{"name":"Clinical immunology","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2024-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141466660","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}
Patients with caspase-associated recruitment domain-9 (CARD9) deficiency are more likely to develop invasive fungal disease that affect CNS. However, the understanding of how Candida invades and persists in CNS is still limited. We here reported a 24-year-old woman who were previously immunocompetent and diagnosed with CNS candidiasis. A novel autosomal recessive homozygous CARD9 mutation (c.184 + 5G > T) from this patient was identified using whole genomic sequencing. Furthermore, we extensively characterized the impact of this CARD9 mutation on the host immune response in monocytes, neutrophils and CD4 + T cells, using single cell sequencing and in vitro experiments. Decreased pro-inflammatory cytokine productions of CD14 + monocyte, impaired Th17 cell differentiation, and defective neutrophil accumulation in CNS were found in this patient. In conclusion, this study proposed a novel mechanism of CNS candidiasis development. Patients with CNS candidiasis in absence of known immunodeficiencies should be analyzed for CARD9 gene mutation as the cause of invasive fungal infection predisposition.
{"title":"A novel inherited CARD9 deficiency in an otherwise healthy woman with CNS candidiasis","authors":"Ling-Hong Zhou , Wen-Jia Qiu , Chun-Xing Que , Jia-Hui Cheng , Rong-Sheng Zhu , Jun-Tian Huang , Ying-Kui Jiang , Hua-Zhen Zhao , Xuan Wang , Xun-Jia Cheng , Li-Ping Zhu","doi":"10.1016/j.clim.2024.110293","DOIUrl":"10.1016/j.clim.2024.110293","url":null,"abstract":"<div><p>Patients with caspase-associated recruitment domain-9 (<em>CARD9</em>) deficiency are more likely to develop invasive fungal disease that affect CNS. However, the understanding of how <em>Candida</em> invades and persists in CNS is still limited. We here reported a 24-year-old woman who were previously immunocompetent and diagnosed with CNS candidiasis. A novel autosomal recessive homozygous <em>CARD9</em> mutation (c.184 + 5G > T) from this patient was identified using whole genomic sequencing. Furthermore, we extensively characterized the impact of this <em>CARD9</em> mutation on the host immune response in monocytes, neutrophils and CD4 + T cells, using single cell sequencing and in vitro experiments. Decreased pro-inflammatory cytokine productions of CD14 + monocyte, impaired Th17 cell differentiation, and defective neutrophil accumulation in CNS were found in this patient. In conclusion, this study proposed a novel mechanism of CNS candidiasis development. Patients with CNS candidiasis in absence of known immunodeficiencies should be analyzed for <em>CARD9</em> gene mutation as the cause of invasive fungal infection predisposition.</p></div>","PeriodicalId":10392,"journal":{"name":"Clinical immunology","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2024-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141466658","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 : 2024-06-25DOI: 10.1016/j.clim.2024.110299
S.E. Detiger , D. Paridaens , P.G. Kemps , A.G.S. van Halteren , P.M. van Hagen , J.A.M. van Laar , R.M. Verdijk
Adult orbital xanthogranulomatous disease (AOXGD) is a spectrum of histiocytoses with four subtypes. Mitogen-activated protein kinase (MAPK) pathway mutations have been detected in various histiocytic neoplasms, little is known about this in AOXGD. Targeted regions of cancer- and histiocytosis-related genes were analyzed and immunohistochemical staining of phosphorylated ERK (pERK), cyclin D1 and PU.1 was performed in 28 AOXGD and 10 control xanthelasma biopsies to assess MAPK pathway activation.
Mutations were detected in 7/28 (25%) patients. Positive staining for pERK and/or cyclin D1 was found across all subtypes in 17/27 (63%) patients of whom 12/17 (71%) did not harbour a mutation. Xanthelasma tissue stained negative for pERK and cyclin D1. Relapse occurred in 5/7 (71%) patients with a MAPK pathway mutation compared to 8/21 (38%) patients in whom no mutation could be detected.
Molecular analysis and evaluation for systemic disease is warranted to identify patients at risk of recurrent xanthomatous disease.
{"title":"Histological evidence of MAPK pathway activation across subtypes of adult orbital xanthogranulomatous disease irrespective of the detection of oncogenic mutations","authors":"S.E. Detiger , D. Paridaens , P.G. Kemps , A.G.S. van Halteren , P.M. van Hagen , J.A.M. van Laar , R.M. Verdijk","doi":"10.1016/j.clim.2024.110299","DOIUrl":"10.1016/j.clim.2024.110299","url":null,"abstract":"<div><p>Adult orbital xanthogranulomatous disease (AOXGD) is a spectrum of histiocytoses with four subtypes. Mitogen-activated protein kinase (MAPK) pathway mutations have been detected in various histiocytic neoplasms, little is known about this in AOXGD. Targeted regions of cancer- and histiocytosis-related genes were analyzed and immunohistochemical staining of phosphorylated ERK (pERK), cyclin D1 and PU.1 was performed in 28 AOXGD and 10 control xanthelasma biopsies to assess MAPK pathway activation.</p><p>Mutations were detected in 7/28 (25%) patients. Positive staining for pERK and/or cyclin D1 was found across all subtypes in 17/27 (63%) patients of whom 12/17 (71%) did not harbour a mutation. Xanthelasma tissue stained negative for pERK and cyclin D1. Relapse occurred in 5/7 (71%) patients with a MAPK pathway mutation compared to 8/21 (38%) patients in whom no mutation could be detected.</p><p>Molecular analysis and evaluation for systemic disease is warranted to identify patients at risk of recurrent xanthomatous disease.</p></div>","PeriodicalId":10392,"journal":{"name":"Clinical immunology","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2024-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141466661","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 : 2024-06-23DOI: 10.1016/j.clim.2024.110282
Bill Giannakopoulos , Steven A. Krilis
Beta 2 glycoprotein I (β2GPI) is the major autoantigen in the antiphospholipid syndrome, an autoimmune disorder characterized by thrombotic and obstetric complications. The autoantibodies that target beta 2 glycoprotein I are pathogenic and contribute to disease pathogenesis. The β2GPI molecule is composed of 5 domains that are numbered 1 through to 5. Autoantibodies bind mainly to domain 1 whereas the majority of the biological functions of the β2GPI molecule in diverse processes such as apoptotic cell clearance, complement regulation, lipopolysaccharide clearance and anticoagulation have been localised to domain 5 and its unique biochemistry, reviewed in this article. The role of purified domain 5 peptide as a potential therapeutic agent in APS and ischemia reperfusion injury is discussed.
{"title":"Domain 5 of Beta 2 glycoprotein I: Friend or foe in health? Context matters","authors":"Bill Giannakopoulos , Steven A. Krilis","doi":"10.1016/j.clim.2024.110282","DOIUrl":"10.1016/j.clim.2024.110282","url":null,"abstract":"<div><p>Beta 2 glycoprotein I (β2GPI) is the major autoantigen in the antiphospholipid syndrome, an autoimmune disorder characterized by thrombotic and obstetric complications. The autoantibodies that target beta 2 glycoprotein I are pathogenic and contribute to disease pathogenesis. The β2GPI molecule is composed of 5 domains that are numbered 1 through to 5. Autoantibodies bind mainly to domain 1 whereas the majority of the biological functions of the β2GPI molecule in diverse processes such as apoptotic cell clearance, complement regulation, lipopolysaccharide clearance and anticoagulation have been localised to domain 5 and its unique biochemistry, reviewed in this article. The role of purified domain 5 peptide as a potential therapeutic agent in APS and ischemia reperfusion injury is discussed.</p></div>","PeriodicalId":10392,"journal":{"name":"Clinical immunology","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2024-06-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1521661624003917/pdfft?md5=e2e0f290e6fee9131019cbade220641e&pid=1-s2.0-S1521661624003917-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141449897","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 : 2024-06-22DOI: 10.1016/j.clim.2024.110295
Thomas B. Martins , Harry R. Hill , Lisa K. Peterson
Assessing T-cell independent antibody response to polysaccharide vaccines is crucial for diagnosing humoral immune deficiencies. However, immunocompetence criteria based on S. pneumoniae vaccination remain unclear. We evaluated IgG antibody vaccine response in healthy individuals to establish interpretive criteria. Pre- and 4-week post-vaccination sera were collected from 79 adults. Antibody concentrations to PNEUMOVAX 23 serotypes were measured using a multiplexed platform. Immunocompetence was determined by fold increase in post-vaccination response, percentage of serotypes achieving 4- or 2-fold antibody ratio, and post-vaccination concentration ≥ 1.3 μg/mL. Immunogenicity varied widely across the 23 serotypes (26.6% to 94.9% for ≥4-fold increase, 51.9% to 98.7% for ≥2-fold increase). Immunocompetence based on historic criteria of ≥4-fold increase in antibody ratio to ≥70% of serotypes was low (72.2%), but increased to 98.7% with criteria of at least a 2-fold increase and/or post-vaccination concentration ≥ 1.3 μg/mL. Current criteria for assessing immunocompetence may be overly stringent and require updating.
{"title":"Evaluating patient immunocompetence through antibody response to pneumococcal polysaccharide vaccine using a newly developed 23 serotype multiplexed assay","authors":"Thomas B. Martins , Harry R. Hill , Lisa K. Peterson","doi":"10.1016/j.clim.2024.110295","DOIUrl":"10.1016/j.clim.2024.110295","url":null,"abstract":"<div><p>Assessing T-cell independent antibody response to polysaccharide vaccines is crucial for diagnosing humoral immune deficiencies. However, immunocompetence criteria based on <em>S. pneumoniae</em> vaccination remain unclear. We evaluated IgG antibody vaccine response in healthy individuals to establish interpretive criteria. Pre- and 4-week post-vaccination sera were collected from 79 adults. Antibody concentrations to PNEUMOVAX 23 serotypes were measured using a multiplexed platform. Immunocompetence was determined by fold increase in post-vaccination response, percentage of serotypes achieving 4- or 2-fold antibody ratio, and post-vaccination concentration ≥ 1.3 μg/mL. Immunogenicity varied widely across the 23 serotypes (26.6% to 94.9% for ≥4-fold increase, 51.9% to 98.7% for ≥2-fold increase). Immunocompetence based on historic criteria of ≥4-fold increase in antibody ratio to ≥70% of serotypes was low (72.2%), but increased to 98.7% with criteria of at least a 2-fold increase and/or post-vaccination concentration ≥ 1.3 μg/mL. Current criteria for assessing immunocompetence may be overly stringent and require updating.</p></div>","PeriodicalId":10392,"journal":{"name":"Clinical immunology","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2024-06-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141445777","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}