Clinical immunology最新文献_第5页

JAK inhibitor ameliorates inflammatory bowel disease in a patient with IKZF1 haploinsufficiency JAK抑制剂改善IKZF1单倍不全患者的炎症性肠病

IF 4.5 3区医学

Clinical immunology Pub Date : 2025-03-02 DOI: 10.1016/j.clim.2025.110470

Shota Inoue , Masaatsu Ikai , Ryusuke Nambu , Kunihiko Moriya , Ryo Kojima , Yuji Tagami , Yuki Hoshino , Masashi Kyushiki , Kayoko Ichimura , Atsuko Nakazawa , Akihiro Hoshino , Takeshi Isoda , Hirokazu Kanegane , Kohsuke Imai

{"title":"JAK inhibitor ameliorates inflammatory bowel disease in a patient with IKZF1 haploinsufficiency","authors":"Shota Inoue , Masaatsu Ikai , Ryusuke Nambu , Kunihiko Moriya , Ryo Kojima , Yuji Tagami , Yuki Hoshino , Masashi Kyushiki , Kayoko Ichimura , Atsuko Nakazawa , Akihiro Hoshino , Takeshi Isoda , Hirokazu Kanegane , Kohsuke Imai","doi":"10.1016/j.clim.2025.110470","DOIUrl":"10.1016/j.clim.2025.110470","url":null,"abstract":"<div><div>IKAROS, encoded by <em>IKZF1</em>, is a crucial transcription factor regulating hematopoiesis and B cell development. While <em>IKZF1</em> haploinsufficiency variants are associated with various immunological disorders, inflammatory bowel disease (IBD) has been rarely reported. We report a case of <em>IKZF1</em> haploinsufficiency presenting with an atypical IBD phenotype and its response to filgotinib. The patient was previously diagnosed with <em>IKZF</em>1 haploinsufficiency and presented with chronic diarrhea, fatigue and anemia. Laboratory findings indicated folate deficiency-induced megaloblastic anemia and malabsorption syndrome. Endoscopic examination showed inflammation with erythema in the colon and extensive villous blunting of the small intestine. Immunohistochemical analysis revealed increased pSTAT3/5 in the colon. Considering the clinical features and increased JAK-STAT cascade, treatment with filgotinib was initiated. At 10 weeks post-treatment, we observed improvement in endoscopic findings and suppression of pSTAT3/5. This case extends the clinical spectrum of <em>IKZF1</em> haploinsufficiency. A JAK1 inhibitor is considered to be useful for <em>IKZF1</em> haploinsufficiency-associated IBD.</div></div>","PeriodicalId":10392,"journal":{"name":"Clinical immunology","volume":"274 ","pages":"Article 110470"},"PeriodicalIF":4.5,"publicationDate":"2025-03-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143548330","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}

引用次数: 0

IKAROS protein stability is regulated by its early N-terminal region and C-terminal dimerization domain IKAROS蛋白的稳定性受其早期n端和c端二聚化结构域的调控。

IF 4.5 3区医学

Clinical immunology Pub Date : 2025-02-28 DOI: 10.1016/j.clim.2025.110469

Natchanun Klangkalya , Ana Esteve-Sole , Agustin A. Gil Silva , Jennifer L. Stoddard , Julie E. Niemela , Seraina Prader , Gregor Dueckers , Lina Igel , Tim Niehues , Benjamin C. Stewart-Bates , Talal Mousallem , Thomas A. Fleisher , Sergio D. Rosenzweig , Hye Sun Kuehn

{"title":"IKAROS protein stability is regulated by its early N-terminal region and C-terminal dimerization domain","authors":"Natchanun Klangkalya , Ana Esteve-Sole , Agustin A. Gil Silva , Jennifer L. Stoddard , Julie E. Niemela , Seraina Prader , Gregor Dueckers , Lina Igel , Tim Niehues , Benjamin C. Stewart-Bates , Talal Mousallem , Thomas A. Fleisher , Sergio D. Rosenzweig , Hye Sun Kuehn","doi":"10.1016/j.clim.2025.110469","DOIUrl":"10.1016/j.clim.2025.110469","url":null,"abstract":"<div><div>IKAROS, encoded by <em>IKZF1</em>, is a six zinc-finger (ZF) transcription factor integral to lymphocyte development and function. <em>IKZF1</em> mutations affecting DNA-binding (ZF1–4) and dimerization (ZF5–6) have been extensively reported and result in human disease. Herein, we investigated <em>IKZF1</em> mutations affecting protein stability.</div><div>We identified ten individuals in three families carrying <em>IKZF1</em> mutations mapping either to the pre-ZF1 area (D22N), or the dimerization domain (M494Vfs*86, Y503*) presenting with infections, immune dysregulation and/or lymphoproliferation with incomplete clinical penetrance. IKAROS expression was reduced in all mutation-carrier evaluated. Protein stability was decreased for D22N, V52L (another pre-ZF1 variant reported in COSMIC), Y503* and Del1–116, a laboratory-designed mutant encompassing the pre-ZF1 area. Mutants Y503* and Del1–116 also exhibited other impaired functions. IKAROS N-terminal pre-ZF1 area, encompassing a previously uncharacterized protein stability-associated region (PSAR), is crucial for IKAROS stability. Variants in the IKAROS PSAR leading to decreased protein stability and IKAROS haploinsufficiency seem sufficient to result in immune defects and IKAROS-associated diseases.</div></div>","PeriodicalId":10392,"journal":{"name":"Clinical immunology","volume":"274 ","pages":"Article 110469"},"PeriodicalIF":4.5,"publicationDate":"2025-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143536832","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}

引用次数: 0

New biomarkers in IgA nephropathy IgA 肾病的新生物标记物

IF 4.5 3区医学

Clinical immunology Pub Date : 2025-02-27 DOI: 10.1016/j.clim.2025.110468

Zhixin Xu , Haoting Zhan , Jingdi Zhang, Zhan Li, Linlin Cheng, Qian Chen, Ye Guo, Yongzhe Li

引用次数: 0

Spatial transcriptomics of Glomerulo-centric antibody mediated rejection in renal transplants 肾小球中心抗体介导的肾移植排斥反应的空间转录组学研究

IF 4.5 3区医学

Clinical immunology Pub Date : 2025-02-22 DOI: 10.1016/j.clim.2025.110460

Dajana Margeta , Hirotsugu Noguchi , Sepideh Khazaie , Leal C. Herlitz , Joshua J. Augustine , Peter S. Heeger , Anat R. Tambur , Robert L. Fairchild , William M. Baldwin III

{"title":"Spatial transcriptomics of Glomerulo-centric antibody mediated rejection in renal transplants","authors":"Dajana Margeta , Hirotsugu Noguchi , Sepideh Khazaie , Leal C. Herlitz , Joshua J. Augustine , Peter S. Heeger , Anat R. Tambur , Robert L. Fairchild , William M. Baldwin III","doi":"10.1016/j.clim.2025.110460","DOIUrl":"10.1016/j.clim.2025.110460","url":null,"abstract":"<div><div>In this case study, we used Digital Spatial Profiling to localize transcripts in a series of 4 biopsies from a single patient before, during and after treatment for acute antibody-mediated rejection that was characterized by strong C4d staining of the glomeruli. Spatial resolution demonstrated that molecular signatures of innate immune cells including NK cells and macrophages are located in glomeruli during AMR, and transcripts for HLA class II antigens were upregulated in the glomeruli. In contrast, transcripts of signature genes for podocytes were decreased during rejection. Treatment with IVIg resolved histological evidence of glomerulitis but did not restore expression of podocyte transcripts. These data demonstrate a vulnerability of podocytes in acute AMR with persistent glomerulitis. Additionally, by using a protocol biopsy from the same patient as a baseline, transcript changes for an informative set of genes were uncovered to test for podocyte dysfunction in future patients.</div></div>","PeriodicalId":10392,"journal":{"name":"Clinical immunology","volume":"274 ","pages":"Article 110460"},"PeriodicalIF":4.5,"publicationDate":"2025-02-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143487986","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}

引用次数: 0

The efficacy and safety between efgartigimod and intravenous immunoglobulin in elderly generalized myasthenia gravis patients 依加替莫德与静脉注射免疫球蛋白治疗老年广泛性重症肌无力的疗效及安全性比较。

IF 4.5 3区医学

Clinical immunology Pub Date : 2025-02-21 DOI: 10.1016/j.clim.2025.110457

Chaoyue Zhang , Xiang Li , Yufei Deng , Haocheng Luo , Shuangshuang Wang , Xianni Yan , Xiaojun Yang , Qilong Jiang

引用次数: 0

Complement C5a and C5a receptor 1 mediates glomerular damage in focal segmental glomerulosclerosis 补体C5a和C5a受体1介导局灶节段性肾小球硬化的肾小球损伤

IF 4.5 3区医学

Clinical immunology Pub Date : 2025-02-19 DOI: 10.1016/j.clim.2025.110459

Xiao-jie Gong , Jing Huang , Yue Shu , Miao Wang , Jing Ji , Li Yang , Ming-hui Zhao , Zhao Cui

{"title":"Complement C5a and C5a receptor 1 mediates glomerular damage in focal segmental glomerulosclerosis","authors":"Xiao-jie Gong , Jing Huang , Yue Shu , Miao Wang , Jing Ji , Li Yang , Ming-hui Zhao , Zhao Cui","doi":"10.1016/j.clim.2025.110459","DOIUrl":"10.1016/j.clim.2025.110459","url":null,"abstract":"<div><h3>Background</h3><div>Clinical data and animal models have provided compelling evidence supporting the pathogenic role of complement activation in the progression of focal segmental glomerulosclerosis (FSGS). However, the mechanisms underlying complement-induced podocyte injury and parietal epithelial cell (PEC) activation are not well understood.</div></div><div><h3>Methods</h3><div>We evaluated glomerular C5aR1 (CD88) expression in FSGS patients and tested the effects of the C5aR1 antagonist (PMX205) in Adriamycin nephropathy mice. The effects on PECs and podocytes were evaluated following exposure to recombinant C5a or FSGS plasma, with or without the C5aR1 antagonist.</div></div><div><h3>Results</h3><div>C5aR1 was overexpressed on PECs and podocytes in FSGS patients, with levels positively correlated with serum creatinine, the percentage of segmental glomerulosclerosis, and the prognosis of refractory nephrotic syndrome. In Adriamycin nephropathy mice, the C5aR1 antagonist significantly attenuated proteinuria, blood urea nitrogen levels, and the percentage of segmental and global glomerulosclerosis. It also alleviated PEC activation and proliferation, and mitigated podocyte loss. Moreover, glomerular IgM deposits were reduced, followed by decreased deposits of C3d and C5b-9. In vitro, PECs exposed to recombinant C5a exhibited upregulated expression of CD44 and Notch1, along with increased secretion of COL4A2. Podocytes exposed to FSGS plasma showed impaired cell viability and downregulation of synaptopodin, effects that were reversed by the C5aR1 antagonist.</div></div><div><h3>Conclusions</h3><div>These findings highlight the pathogenic role of the complement system in the development of FSGS through the C5a-C5aR1 axis on podocytes and PECs. The C5aR1 antagonist represents a promising therapeutic intervention for FSGS patients.</div></div>","PeriodicalId":10392,"journal":{"name":"Clinical immunology","volume":"273 ","pages":"Article 110459"},"PeriodicalIF":4.5,"publicationDate":"2025-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143454181","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}

引用次数: 0

Plasma extracellular vesicles promote follicular T helper cell expansion in primary Sjögren's syndrome 血浆细胞外囊泡促进滤泡T辅助细胞在原发性Sjögren综合征中的扩张

IF 4.5 3区医学

Clinical immunology Pub Date : 2025-02-18 DOI: 10.1016/j.clim.2025.110458

Suying Liu , Chaowen Luo , Chengmei He , Jinlei Sun , Zhilei Chen , Taibiao Lyu , Lin Qiao , Fengchun Zhang , Hua Chen

引用次数: 0

Ex vivo T-lymphopoiesis assays assisting corrective treatment choice for genetically undefined T-lymphocytopenia 体外t淋巴细胞生成分析有助于基因不明的t淋巴细胞减少症的纠正治疗选择。

IF 4.5 3区医学

Clinical immunology Pub Date : 2025-02-16 DOI: 10.1016/j.clim.2025.110453

Zainab M. Golwala , Helena Spiridou Goncalves , Ranjita Devi Moirangthem , Grace Evans , Sabrina Lizot , Coco de Koning , Alexandrine Garrigue , Marta Martin Corredera , Juan Moises Ocampo-Godinez , Evey Howley , Susanne Kricke , Arnold Awuah , Irene Obiri-Yeboa , Rajeev Rai , Neil Sebire , Fanette Bernard , Victoria Bordon Cueto De Braem , Kaan Boztug , Theresa Cole , Andrew R. Gennery , Alexandra Y. Kreins

{"title":"Ex vivo T-lymphopoiesis assays assisting corrective treatment choice for genetically undefined T-lymphocytopenia","authors":"Zainab M. Golwala , Helena Spiridou Goncalves , Ranjita Devi Moirangthem , Grace Evans , Sabrina Lizot , Coco de Koning , Alexandrine Garrigue , Marta Martin Corredera , Juan Moises Ocampo-Godinez , Evey Howley , Susanne Kricke , Arnold Awuah , Irene Obiri-Yeboa , Rajeev Rai , Neil Sebire , Fanette Bernard , Victoria Bordon Cueto De Braem , Kaan Boztug , Theresa Cole , Andrew R. Gennery , Alexandra Y. Kreins","doi":"10.1016/j.clim.2025.110453","DOIUrl":"10.1016/j.clim.2025.110453","url":null,"abstract":"<div><div>Persistent selective T-lymphocytopenia is found both in SCID and congenital athymia. Without molecular diagnosis, it is challenging to determine whether HCT or thymus transplantation ought to be performed. <em>Ex vivo</em> T-lymphopoiesis assays have been proposed to assist clinical decision-making for genetically undefined patients. We investigated 20 T-lymphocytopenic patients, including 13 patients awaiting first-line treatment and 7 patients with failed immune reconstitution after previous HCT or thymus transplantation. Whilst developmental blocks in <em>ex vivo</em> T-lymphopoiesis indicated hematopoietic cell-intrinsic defects, successful T-lymphocyte differentiation required careful interpretation, in conjunction with clinical status, immunophenotyping, and genetic investigations. Of the 20 patients, 13 proceeded to treatment, with successful immune reconstitution observed in 4 of the 6 patients post-HCT and 4 of the 7 patients after thymus transplantation, the latter including two patients who had previously undergone HCT. Whilst further validation and standardization are required, we conclude that assessing <em>ex vivo</em> T-lymphopoiesis during the diagnostic pathway for genetically undefined T-lymphocytopenia improves patient outcomes by facilitating corrective treatment choice.</div></div>","PeriodicalId":10392,"journal":{"name":"Clinical immunology","volume":"274 ","pages":"Article 110453"},"PeriodicalIF":4.5,"publicationDate":"2025-02-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143448424","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}

引用次数: 0

Stimulation of endothelin-1 production by autoantibodies present in patients with scleroderma renal crisis 硬皮病肾危重患者自身抗体对内皮素-1产生的刺激。

IF 4.5 3区医学

Clinical immunology Pub Date : 2025-02-14 DOI: 10.1016/j.clim.2025.110454

Pinchao Wang , Dashan Wu , Zexian Gong , Michael Adu-Gyamfi , Julian Kamhieh-Milz , Dennyson Leandro Mathias da Fonseca , Gülistan Sürücü , Muhammad I. Ashraf , Harald Heidecke , Dorota Sikorska , Otavio Cabral-Marques , Guido Moll , Gabriela Riemekasten , Janusz Witowski , Rusan Catar

{"title":"Stimulation of endothelin-1 production by autoantibodies present in patients with scleroderma renal crisis","authors":"Pinchao Wang , Dashan Wu , Zexian Gong , Michael Adu-Gyamfi , Julian Kamhieh-Milz , Dennyson Leandro Mathias da Fonseca , Gülistan Sürücü , Muhammad I. Ashraf , Harald Heidecke , Dorota Sikorska , Otavio Cabral-Marques , Guido Moll , Gabriela Riemekasten , Janusz Witowski , Rusan Catar","doi":"10.1016/j.clim.2025.110454","DOIUrl":"10.1016/j.clim.2025.110454","url":null,"abstract":"<div><div>Here, we investigate how autoantibodies against G protein-coupled receptors (GPCRs) on endothelial cells, which are present in patients with scleroderma renal crisis (SRC) impact on endothelin-1 (ET-1) production in human microvascular endothelial cells (HMECs). To this end, serum IgG fraction was isolated from SRC patients and applied to HMECs in culture. Compared to cells treated with either plain control medium or serum IgG from healthy individuals, exposure of HMECs to SRC-IgG resulted in a time- and concentration-dependent increase in ET-1 expression and release. This effect could be blocked by the protease activated receptor 1 (PAR1) inhibitor and mimicked by thrombin, the PAR1 activator. Transcription factor C-FOS/AP-1 and tissue factor (TF) were identified as mediators of these responses. Thus, it can be concluded that serum IgG fraction from SRC patients stimulates endothelial cells to produce ET-1, acting through PAR1 in cooperation with TF.</div></div>","PeriodicalId":10392,"journal":{"name":"Clinical immunology","volume":"273 ","pages":"Article 110454"},"PeriodicalIF":4.5,"publicationDate":"2025-02-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143432418","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}

引用次数: 0

Novel janus kinase 3 inhibitor ritlecitinib suppresses T and B cell responses to prevent acute cardiac allograft rejection in mice 新型janus激酶3抑制剂利来替尼抑制T细胞和B细胞反应，防止小鼠心脏移植急性排斥反应

IF 4.5 3区医学

Clinical immunology Pub Date : 2025-02-13 DOI: 10.1016/j.clim.2025.110445

Rumin Liu , Xiaoyi Shi , Wenli Zeng , Yuchen Wang , Ziyan Yan , Wenfeng Deng , Jialiang Hui , Renfei Xia , Liqian Mo , Jian Xu , Tao Liao , Yun Miao

{"title":"Novel janus kinase 3 inhibitor ritlecitinib suppresses T and B cell responses to prevent acute cardiac allograft rejection in mice","authors":"Rumin Liu , Xiaoyi Shi , Wenli Zeng , Yuchen Wang , Ziyan Yan , Wenfeng Deng , Jialiang Hui , Renfei Xia , Liqian Mo , Jian Xu , Tao Liao , Yun Miao","doi":"10.1016/j.clim.2025.110445","DOIUrl":"10.1016/j.clim.2025.110445","url":null,"abstract":"<div><div>Acute rejection is the main contributor to early allograft failure. Current immunosuppressive regimens have shortcomings, such as toxicity and minimal inhibitory effects on B cells. Hence, developing novel, effective, and selective anti-acute rejection drugs is crucial. Therefore, this study aimed to investigate the inhibitory effect of ritlecitinib (PF-06651600), a new janus kinase 3 inhibitor, on T and B cells, as well its preventive effects on acute allograft rejection. A murine cardiac transplantation model coupled with cell culture- and immunohistochemistry-based techniques was used. <em>In vitro</em> assays demonstrated that ritlecitinib inhibits naïve CD4<sup>+</sup> T cell differentiation into T helper (Th)1 and Th17 cells, reduces relative inflammatory cytokines, and suppresses CD4<sup>+</sup> and CD8<sup>+</sup> T cell proliferation. Furthermore, ritlecitinib inhibited B cell activation and differentiation and antibody production. <em>In vivo</em> experiments revealed that ritlecitinib significantly prolongs allograft survival, decreases serum donor-specific antibody immunoglobulin G levels, alleviats allograft damage, and reduces C4d deposition and T, B, and plasma cell infiltration in allografts. Moreover, B and plasma cell percentages and counts were significantly decreased in recipient spleen, lymph nodes, bone marrow, and blood. Overall, ritlecitinib prevented acute rejection in cardiac transplantation by inhibiting T and B cells, suggesting its potential as a novel clinical immunosuppressant.</div></div>","PeriodicalId":10392,"journal":{"name":"Clinical immunology","volume":"273 ","pages":"Article 110445"},"PeriodicalIF":4.5,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143421736","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}

引用次数: 0