Pub Date : 2025-03-09DOI: 10.1016/j.clim.2025.110472
Changming Lu, Shanrun Liu, Min Gao, Jose Rubio, W Winn Chatham, Hui-Chen Hsu, John D Mountz
TLR7 stimulation of T-bet+CD11c+IgD-CD27- double-negative 2 (DN2) B cells is crucial for autoantibody formation in systemic lupus erythematosus (SLE). Here, we show that administration of IL-4 for five weeks significantly reduced autoantibodies and T-bet+CD11c+ IgD- B cells in autoimmune BXD2 mice treated with R848, a TLR7 agonist. Single-cell transcriptomics analysis indicates that following two doses of in vivo administration, IL-4 redirected development toward follicular, CD23+ germinal center (GC), and DN4-like memory B cells compared to treatment with R848 alone. While IL-4 enhanced genes related to antigen processing and presentation, it also suppressed R848-induced Ki67+ GC B cells in vivo. In vitro stimulation of SLE patient B cells with a DN2 polarizing cocktail revealed that IL-4 reduced the expression of interferon response and DN2 signature genes, promoting a population of CD23+T-bet- DN4 B population. These findings suggest that developmental reprogramming by IL-4 counteracts TLR7-promoted DN2 and GC B cells in SLE.
{"title":"IL-4 alters TLR7-induced B cell developmental program in lupus.","authors":"Changming Lu, Shanrun Liu, Min Gao, Jose Rubio, W Winn Chatham, Hui-Chen Hsu, John D Mountz","doi":"10.1016/j.clim.2025.110472","DOIUrl":"https://doi.org/10.1016/j.clim.2025.110472","url":null,"abstract":"<p><p>TLR7 stimulation of T-bet<sup>+</sup>CD11c<sup>+</sup>IgD<sup>-</sup>CD27<sup>-</sup> double-negative 2 (DN2) B cells is crucial for autoantibody formation in systemic lupus erythematosus (SLE). Here, we show that administration of IL-4 for five weeks significantly reduced autoantibodies and T-bet<sup>+</sup>CD11c<sup>+</sup> IgD<sup>-</sup> B cells in autoimmune BXD2 mice treated with R848, a TLR7 agonist. Single-cell transcriptomics analysis indicates that following two doses of in vivo administration, IL-4 redirected development toward follicular, CD23<sup>+</sup> germinal center (GC), and DN4-like memory B cells compared to treatment with R848 alone. While IL-4 enhanced genes related to antigen processing and presentation, it also suppressed R848-induced Ki67<sup>+</sup> GC B cells in vivo. In vitro stimulation of SLE patient B cells with a DN2 polarizing cocktail revealed that IL-4 reduced the expression of interferon response and DN2 signature genes, promoting a population of CD23<sup>+</sup>T-bet<sup>-</sup> DN4 B population. These findings suggest that developmental reprogramming by IL-4 counteracts TLR7-promoted DN2 and GC B cells in SLE.</p>","PeriodicalId":10392,"journal":{"name":"Clinical immunology","volume":" ","pages":"110472"},"PeriodicalIF":4.5,"publicationDate":"2025-03-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143604214","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 : 2025-03-03DOI: 10.1016/j.clim.2025.110471
Marie Brinkmann , Ludwig Traby , Manuel Kussmann , Matthias Weiss-Tessbach , Nina Buchtele , Thomas Staudinger , Elias Gaidoschik , Thomas Perkmann , Helmuth Haslacher , Franz Ratzinger , Winfried F. Pickl , Karim El-Gedawi , Melanie Feichter , Ellen Gelpi , Romana Höftberger , Peter Quehenberger , Rodrig Marculescu , Daniel Mrak , Kastriot Kastrati , Helga Lechner-Radner , Lisa Göschl
Viral infections, including respiratory diseases such as Coronavirus disease 2019 (COVID-19), are hypothesized to contribute to the onset of autoimmune disorders. Although elevated levels of autoantibodies have been observed following COVID-19, the role of specific autoantibodies linked to autoimmune diseases and their correlation with disease severity remains poorly defined.
In this study, we used a comprehensive autoantibody panel to assess the autoantibody production across different cohorts of COVID-19 patients, categorized by disease severity. We also compared patients with severe COVID-19 to a control group with other severe, non-COVID-related diseases.
Our findings indicate that the severity of COVID-19 corresponds to the overall production of specific autoantibodies, which are particularly associated with COVID-19. This association might predispose to an increased risk for the development of autoimmune conditions after a severe course of COVID-19.
{"title":"Autoantibody development is associated with clinical severity of COVID-19: A cohort study","authors":"Marie Brinkmann , Ludwig Traby , Manuel Kussmann , Matthias Weiss-Tessbach , Nina Buchtele , Thomas Staudinger , Elias Gaidoschik , Thomas Perkmann , Helmuth Haslacher , Franz Ratzinger , Winfried F. Pickl , Karim El-Gedawi , Melanie Feichter , Ellen Gelpi , Romana Höftberger , Peter Quehenberger , Rodrig Marculescu , Daniel Mrak , Kastriot Kastrati , Helga Lechner-Radner , Lisa Göschl","doi":"10.1016/j.clim.2025.110471","DOIUrl":"10.1016/j.clim.2025.110471","url":null,"abstract":"<div><div>Viral infections, including respiratory diseases such as Coronavirus disease 2019 (COVID-19), are hypothesized to contribute to the onset of autoimmune disorders. Although elevated levels of autoantibodies have been observed following COVID-19, the role of specific autoantibodies linked to autoimmune diseases and their correlation with disease severity remains poorly defined.</div><div>In this study, we used a comprehensive autoantibody panel to assess the autoantibody production across different cohorts of COVID-19 patients, categorized by disease severity. We also compared patients with severe COVID-19 to a control group with other severe, non-COVID-related diseases.</div><div>Our findings indicate that the severity of COVID-19 corresponds to the overall production of specific autoantibodies, which are particularly associated with COVID-19. This association might predispose to an increased risk for the development of autoimmune conditions after a severe course of COVID-19.</div></div>","PeriodicalId":10392,"journal":{"name":"Clinical immunology","volume":"274 ","pages":"Article 110471"},"PeriodicalIF":4.5,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143548331","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}
IKAROS, encoded by IKZF1, is a crucial transcription factor regulating hematopoiesis and B cell development. While IKZF1 haploinsufficiency variants are associated with various immunological disorders, inflammatory bowel disease (IBD) has been rarely reported. We report a case of IKZF1 haploinsufficiency presenting with an atypical IBD phenotype and its response to filgotinib. The patient was previously diagnosed with IKZF1 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 IKZF1 haploinsufficiency. A JAK1 inhibitor is considered to be useful for IKZF1 haploinsufficiency-associated IBD.
{"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}
Pub Date : 2025-02-28DOI: 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
IKAROS, encoded by IKZF1, is a six zinc-finger (ZF) transcription factor integral to lymphocyte development and function. IKZF1 mutations affecting DNA-binding (ZF1–4) and dimerization (ZF5–6) have been extensively reported and result in human disease. Herein, we investigated IKZF1 mutations affecting protein stability.
We identified ten individuals in three families carrying IKZF1 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.
{"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}
Pub Date : 2025-02-27DOI: 10.1016/j.clim.2025.110468
Zhixin Xu , Haoting Zhan , Jingdi Zhang, Zhan Li, Linlin Cheng, Qian Chen, Ye Guo, Yongzhe Li
Currently, IgA nephropathy (IgAN) is the most common cause of chronic renal failure in patients with primary glomerulonephritis. However, IgAN diagnosis is usually performed by collecting a renal biopsy as gold standard to visualize pathological changes in the glomeruli. The randomized nature of this invasive procedure in clinical practice, together with the need to exclude patients with contraindications, often results in a limited number of eligible people. Therefore, over the past two decades, researchers have explored new biomarkers for IgAN to meet the urgent clinical need for rapid diagnosis and prognosis, as well as realistic prediction of IgAN progression. In addition to traditional common markers with low specificity to detect renal diseases, the classical antibody targeting galactose-deficient IgA1 has been progressively discovered. In addition, new types of diagnostic or prognostic biomarkers are emerging, including microRNA, complement factors, proteases, inflammatory molecules and serum or urinary metabolite profiles.
{"title":"New biomarkers in IgA nephropathy","authors":"Zhixin Xu , Haoting Zhan , Jingdi Zhang, Zhan Li, Linlin Cheng, Qian Chen, Ye Guo, Yongzhe Li","doi":"10.1016/j.clim.2025.110468","DOIUrl":"10.1016/j.clim.2025.110468","url":null,"abstract":"<div><div>Currently, IgA nephropathy (IgAN) is the most common cause of chronic renal failure in patients with primary glomerulonephritis. However, IgAN diagnosis is usually performed by collecting a renal biopsy as gold standard to visualize pathological changes in the glomeruli. The randomized nature of this invasive procedure in clinical practice, together with the need to exclude patients with contraindications, often results in a limited number of eligible people. Therefore, over the past two decades, researchers have explored new biomarkers for IgAN to meet the urgent clinical need for rapid diagnosis and prognosis, as well as realistic prediction of IgAN progression. In addition to traditional common markers with low specificity to detect renal diseases, the classical antibody targeting galactose-deficient IgA1 has been progressively discovered. In addition, new types of diagnostic or prognostic biomarkers are emerging, including microRNA, complement factors, proteases, inflammatory molecules and serum or urinary metabolite profiles.</div></div>","PeriodicalId":10392,"journal":{"name":"Clinical immunology","volume":"274 ","pages":"Article 110468"},"PeriodicalIF":4.5,"publicationDate":"2025-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143520272","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 : 2025-02-22DOI: 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
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.
{"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}
Pub Date : 2025-02-21DOI: 10.1016/j.clim.2025.110457
Chaoyue Zhang , Xiang Li , Yufei Deng , Haocheng Luo , Shuangshuang Wang , Xianni Yan , Xiaojun Yang , Qilong Jiang
The study examines efgartigimod and intravenous immunoglobulin (IVIg) in elderly patients with generalized myasthenia gravis (GMG), focusing on changes in Myasthenia Gravis Activities of Daily Living (MG-ADL) scores, pyridostigmine dosage, and minimal symptom expression (MSE) over an 8-week period. Among 74 enrolled patients, efgartigimod showed greater reduction in MG-ADL scores compared to IVIg at weeks 4 and 8, with no serious adverse events, suggesting its superior efficacy and safety in elderly Chinese patients with acetylcholine receptor antibody-positive (AChR-Ab(+)) GMG.
{"title":"The efficacy and safety between efgartigimod and intravenous immunoglobulin in elderly generalized myasthenia gravis patients","authors":"Chaoyue Zhang , Xiang Li , Yufei Deng , Haocheng Luo , Shuangshuang Wang , Xianni Yan , Xiaojun Yang , Qilong Jiang","doi":"10.1016/j.clim.2025.110457","DOIUrl":"10.1016/j.clim.2025.110457","url":null,"abstract":"<div><div>The study examines efgartigimod and intravenous immunoglobulin (IVIg) in elderly patients with generalized myasthenia gravis (GMG), focusing on changes in Myasthenia Gravis Activities of Daily Living (MG-ADL) scores, pyridostigmine dosage, and minimal symptom expression (MSE) over an 8-week period. Among 74 enrolled patients, efgartigimod showed greater reduction in MG-ADL scores compared to IVIg at weeks 4 and 8, with no serious adverse events, suggesting its superior efficacy and safety in elderly Chinese patients with acetylcholine receptor antibody-positive (AChR-Ab(+)) GMG.</div></div>","PeriodicalId":10392,"journal":{"name":"Clinical immunology","volume":"274 ","pages":"Article 110457"},"PeriodicalIF":4.5,"publicationDate":"2025-02-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143482349","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 : 2025-02-19DOI: 10.1016/j.clim.2025.110459
Xiao-jie Gong , Jing Huang , Yue Shu , Miao Wang , Jing Ji , Li Yang , Ming-hui Zhao , Zhao Cui
Background
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.
Methods
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.
Results
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.
Conclusions
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.
{"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}
Pub Date : 2025-02-18DOI: 10.1016/j.clim.2025.110458
Suying Liu , Chaowen Luo , Chengmei He , Jinlei Sun , Zhilei Chen , Taibiao Lyu , Lin Qiao , Fengchun Zhang , Hua Chen
Primary Sjögren's syndrome (pSS) is a prevalent autoimmune disease characterized by exocrine gland dysfunction, with hallmarks of B cell and T cell overactivation, whose underlying mechanism remains largely unknown. Herein, we show that pSS plasma contained more extracellular vesicles (EVs) than HC plasma, which promoted CD4+ T cell activation, Th1, and follicular T helper cell (Tfh) differentiation, aggravating pSS immunopathology. Notably, pSS plasma EVs were enriched with miR-501–3p, mediating CD4+ T cell activation and Tfh cell differentiation. Furthermore, miR-501–3p downregulated special AT-rich sequence-binding protein-1 (SATB1) to promote Tfh differentiation. These findings suggested pSS plasma EVs as an important contributor to pSS pathogenesis, which was of potential clinical interest in managing pSS.
{"title":"Plasma extracellular vesicles promote follicular T helper cell expansion in primary Sjögren's syndrome","authors":"Suying Liu , Chaowen Luo , Chengmei He , Jinlei Sun , Zhilei Chen , Taibiao Lyu , Lin Qiao , Fengchun Zhang , Hua Chen","doi":"10.1016/j.clim.2025.110458","DOIUrl":"10.1016/j.clim.2025.110458","url":null,"abstract":"<div><div>Primary Sjögren's syndrome (pSS) is a prevalent autoimmune disease characterized by exocrine gland dysfunction, with hallmarks of B cell and T cell overactivation, whose underlying mechanism remains largely unknown. Herein, we show that pSS plasma contained more extracellular vesicles (EVs) than HC plasma, which promoted CD4<sup>+</sup> T cell activation, Th1, and follicular T helper cell (Tfh) differentiation, aggravating pSS immunopathology. Notably, pSS plasma EVs were enriched with miR-501–3p, mediating CD4<sup>+</sup> T cell activation and Tfh cell differentiation. Furthermore, miR-501–3p downregulated special AT-rich sequence-binding protein-1 (SATB1) to promote Tfh differentiation. These findings suggested pSS plasma EVs as an important contributor to pSS pathogenesis, which was of potential clinical interest in managing pSS.</div></div>","PeriodicalId":10392,"journal":{"name":"Clinical immunology","volume":"273 ","pages":"Article 110458"},"PeriodicalIF":4.5,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143454180","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 : 2025-02-16DOI: 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
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. Ex vivo 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 ex vivo 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 ex vivo T-lymphopoiesis during the diagnostic pathway for genetically undefined T-lymphocytopenia improves patient outcomes by facilitating corrective treatment choice.
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