The Journal of Pathology最新文献

{"title":"Multiregion exome sequencing indicates a monoclonal origin of esophageal spindle-cell squamous cell carcinoma","authors":"Yulu Wang,&nbsp;Qian Zhu,&nbsp;Yaqing Wu,&nbsp;Boyi Li,&nbsp;Xiaoxing Su,&nbsp;Chan Xiang,&nbsp;Yuchen Han","doi":"10.1002/path.6324","DOIUrl":"10.1002/path.6324","url":null,"abstract":"<p>Esophageal spindle-cell squamous cell carcinoma (ESS) is a rare biphasic neoplasm composed of a carcinomatous component (CaC) and a sarcomatous component (SaC). However, the genomic origin and gene signature of ESS remain unclear. Using whole-exome sequencing of laser-capture microdissection (LCM) tumor samples, we determined that CaC and SaC showed high mutational commonality, with the same top high-frequency mutant genes, mutation signatures, and tumor mutation burden; paired samples shared a median of 25.5% mutation sites. Focal gains were found on chromosomes 3q29, 5p15.33, and 11q13.3. Altered genes were mainly enriched in the RTK–RAS signaling pathway. Phylogenetic trees showed a monoclonal origin of ESS. The most frequently mutated oncogene in the trunk was <i>TP53</i>, followed by <i>NFE2L2</i>, <i>KMT2D</i>, and <i>MUC16</i>. Prognostic associations were found for <i>CDC27</i>, <i>LRP2</i>, <i>APC</i>, and <i>SNAPC4</i>. Our data highlight the monoclonal origin of ESS with <i>TP53</i> as a potent driver oncogene, suggesting new targeted therapies and immunotherapies as treatment options. © 2024 The Pathological Society of Great Britain and Ireland.</p>","PeriodicalId":232,"journal":{"name":"The Journal of Pathology","volume":"264 1","pages":"55-67"},"PeriodicalIF":5.6,"publicationDate":"2024-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141632175","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Disorganisation of basement membrane zone architecture impairs melanocyte residence in vitiligo","authors":"Fei Yang,&nbsp;Lingli Yang,&nbsp;Yasutaka Kuroda,&nbsp;Sylvia Lai,&nbsp;Yoshito Takahashi,&nbsp;Tetsuya Sayo,&nbsp;Takeshi Namiki,&nbsp;Kimiko Nakajima,&nbsp;Shigetoshi Sano,&nbsp;Shintaro Inoue,&nbsp;Daisuke Tsuruta,&nbsp;Ichiro Katayama","doi":"10.1002/path.6321","DOIUrl":"10.1002/path.6321","url":null,"abstract":"<p>The basement membrane zone is the interface between the epidermis and dermis, and it is disrupted in several skin conditions. Here, we report the results of a comprehensive investigation into the structural and molecular factors of the basement membrane zone in vitiligo, a dermatological disorder characterised by depigmented patches on the skin. Using electron microscopy and immunofluorescence staining, we confirmed abnormal basement membrane zone morphology and disrupted basement membrane zone architecture in human vitiliginous skin. Furthermore, we identified elevated expression of matrix metalloproteinase 2 (MMP2) in human dermal fibroblasts as a key factor responsible for basement membrane zone matrix degradation. In our <i>in vitro</i> and <i>ex vivo</i> models, overexpression of MMP2 in fibroblasts led to basement membrane zone disruption and melanocyte disappearance. Importantly, we reveal that the loss of melanocytes in vitiligo is primarily linked to their weakened adhesion to the basement membrane, mediated by binding between integrin β1 and laminin and discoidin domain receptor 1 and collagen IV. Finally, inhibition of matrix metalloproteinase 2 expression reversed depigmentation in a mouse model of vitiligo. In conclusion, our research shows the importance of basement membrane zone integrity in melanocyte residence and offers new avenues for therapeutic interventions to address this challenging skin condition. © 2024 The Author(s). <i>The Journal of Pathology</i> published by John Wiley &amp; Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.</p>","PeriodicalId":232,"journal":{"name":"The Journal of Pathology","volume":"264 1","pages":"30-41"},"PeriodicalIF":5.6,"publicationDate":"2024-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/path.6321","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141578490","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Development of a multi-scanner facility for data acquisition for digital pathology artificial intelligence","authors":"Matthew P Humphries,&nbsp;Danny Kaye,&nbsp;Gaby Stankeviciute,&nbsp;Jacob Halliwell,&nbsp;Alexander I Wright,&nbsp;Daljeet Bansal,&nbsp;David Brettle,&nbsp;Darren Treanor","doi":"10.1002/path.6326","DOIUrl":"10.1002/path.6326","url":null,"abstract":"<p>Whole slide imaging (WSI) of pathology glass slides using high-resolution scanners has enabled the large-scale application of artificial intelligence (AI) in pathology, to support the detection and diagnosis of disease, potentially increasing efficiency and accuracy in tissue diagnosis. Despite the promise of AI, it has limitations. ‘Brittleness’ or sensitivity to variation in inputs necessitates that large amounts of data are used for training. AI is often trained on data from different scanners but not usually by replicating the same slide across scanners. The utilisation of multiple WSI instruments to produce digital replicas of the same slides will make more comprehensive datasets and may improve the robustness and generalisability of AI algorithms as well as reduce the overall data requirements of AI training. To this end, the National Pathology Imaging Cooperative (NPIC) has built the AI FORGE (Facilitating Opportunities for Robust Generalisable data Emulation), a unique multi-scanner facility embedded in a clinical site in the NHS to (1) compare scanner performance, (2) replicate digital pathology image datasets across WSI systems, and (3) support the evaluation of clinical AI algorithms. The NPIC AI FORGE currently comprises 15 scanners from nine manufacturers. It can generate approximately 4,000 WSI images per day (approximately 7 TB of image data). This paper describes the process followed to plan and build such a facility. © 2024 The Author(s). <i>The Journal of Pathology</i> published by John Wiley &amp; Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.</p>","PeriodicalId":232,"journal":{"name":"The Journal of Pathology","volume":"264 1","pages":"80-89"},"PeriodicalIF":5.6,"publicationDate":"2024-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/path.6326","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141562163","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The genomic trajectory of ovarian high-grade serous carcinoma can be observed in STIC lesions","authors":"Zhao Cheng,&nbsp;Darren P Ennis,&nbsp;Bingxin Lu,&nbsp;Hasan B Mirza,&nbsp;Chishimba Sokota,&nbsp;Baljeet Kaur,&nbsp;Naveena Singh,&nbsp;Olivia Le Saux,&nbsp;Giorgia Russo,&nbsp;Gaia Giannone,&nbsp;Laura A Tookman,&nbsp;Jonathan Krell,&nbsp;Chris Barnes,&nbsp;Jackie McDermott,&nbsp;Iain A McNeish","doi":"10.1002/path.6322","DOIUrl":"10.1002/path.6322","url":null,"abstract":"<p>Ovarian high-grade serous carcinoma (HGSC) originates in the fallopian tube, with secretory cells carrying a <i>TP53</i> mutation, known as p53 signatures, identified as potential precursors. p53 signatures evolve into serous tubal intraepithelial carcinoma (STIC) lesions, which in turn progress into invasive HGSC, which readily spreads to the ovary and disseminates around the peritoneal cavity. We recently investigated the genomic landscape of early- and late-stage HGSC and found higher ploidy in late-stage (median 3.1) than early-stage (median 2.0) samples. Here, to explore whether the high ploidy and possible whole-genome duplication (WGD) observed in late-stage disease were determined early in the evolution of HGSC, we analysed archival formalin-fixed paraffin-embedded (FFPE) samples from five HGSC patients. p53 signatures and STIC lesions were laser-capture microdissected and sequenced using shallow whole-genome sequencing (sWGS), while invasive ovarian/fallopian tube and metastatic carcinoma samples underwent macrodissection and were profiled using both sWGS and targeted next-generation sequencing. Results showed highly similar patterns of global copy number change between STIC lesions and invasive carcinoma samples within each patient. Ploidy changes were evident in STIC lesions, but not p53 signatures, and there was a strong correlation between ploidy in STIC lesions and invasive ovarian/fallopian tube and metastatic samples in each patient. The reconstruction of sample phylogeny for each patient from relative copy number indicated that high ploidy, when present, occurred early in the evolution of HGSC, which was further validated by copy number signatures in ovarian and metastatic tumours. These findings suggest that aberrant ploidy, suggestive of WGD, arises early in HGSC and is detected in STIC lesions, implying that the trajectory of HGSC may be determined at the earliest stages of tumour development. © 2024 The Author(s). <i>The Journal of Pathology</i> published by John Wiley &amp; Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.</p>","PeriodicalId":232,"journal":{"name":"The Journal of Pathology","volume":"264 1","pages":"42-54"},"PeriodicalIF":5.6,"publicationDate":"2024-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/path.6322","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141490296","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Air pollution aggravates renal ischaemia–reperfusion-induced acute kidney injury","authors":"Talita Rojas Sanches,&nbsp;Antonio Carlos Parra,&nbsp;Peiqi Sun,&nbsp;Mariana Pereira Graner,&nbsp;Lucas Yuji Umesaki Itto,&nbsp;Loes Maria Butter,&nbsp;Nike Claessen,&nbsp;Joris JTH Roelofs,&nbsp;Sandrine Florquin,&nbsp;Mariana Matera Veras,&nbsp;Maria de Fatima Andrade,&nbsp;Paulo Hilário Nascimento Saldiva,&nbsp;Jesper Kers,&nbsp;Lucia Andrade,&nbsp;Alessandra Tammaro","doi":"10.1002/path.6302","DOIUrl":"10.1002/path.6302","url":null,"abstract":"<p>Chronic kidney disease (CKD) has emerged as a significant global public health concern. Recent epidemiological studies have highlighted the link between exposure to fine particulate matter (PM_2.5) and a decline in renal function. PM_2.5 exerts harmful effects on various organs through oxidative stress and inflammation. Acute kidney injury (AKI) resulting from ischaemia–reperfusion injury (IRI) involves biological processes similar to those involved in PM_2.5 toxicity and is a known risk factor for CKD. The objective of this study was to investigate the impact of PM_2.5 exposure on IRI-induced AKI. Through a unique environmentally controlled setup, mice were exposed to urban PM_2.5 or filtered air for 12 weeks before IRI followed by euthanasia 48 h after surgery. Animals exposed to PM_2.5 and IRI exhibited reduced glomerular filtration, impaired urine concentration ability, and significant tubular damage. Further, PM_2.5 aggravated local innate immune responses and mitochondrial dysfunction, as well as enhancing cyclic GMP–AMP synthase-stimulator of interferon genes (cGAS–STING) pathway activation. This increased renal senescence and suppressed the anti-ageing protein klotho, leading to early fibrotic changes. <i>In vitro</i> studies using proximal tubular epithelial cells exposed to PM_2.5 and hypoxia/reoxygenation revealed heightened activation of the STING pathway triggered by cytoplasmic mitochondrial DNA, resulting in increased tubular damage and a pro-inflammatory phenotype. In summary, our findings imply a role for PM_2.5 in sensitising proximal tubular epithelial cells to IRI-induced damage, suggesting a plausible association between PM_2.5 exposure and heightened susceptibility to CKD in individuals experiencing AKI. Strategies aimed at reducing PM_2.5 concentrations and implementing preventive measures may improve outcomes for AKI patients and mitigate the progression from AKI to CKD. © 2024 The Authors. <i>The Journal of Pathology</i> published by John Wiley &amp; Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.</p>","PeriodicalId":232,"journal":{"name":"The Journal of Pathology","volume":"263 4-5","pages":"496-507"},"PeriodicalIF":5.6,"publicationDate":"2024-06-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/path.6302","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141454301","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Interaction of the tumor suppressor SMAD4 and WNT signaling in progression to oral squamous cell carcinoma","authors":"Jing Yang,&nbsp;James S Lewis,&nbsp;Jinghuan Zi,&nbsp;Thomas Andl,&nbsp;Ethan Lee,&nbsp;Claudia D Andl,&nbsp;Qi Liu,&nbsp;Robert D Beauchamp,&nbsp;Anna L Means","doi":"10.1002/path.6318","DOIUrl":"10.1002/path.6318","url":null,"abstract":"<p>SMAD4 is a tumor suppressor mutated or silenced in multiple cancers, including oral cavity squamous cell carcinoma (OSCC). Human clinical samples and cell lines, mouse models and organoid culture were used to investigate the role that SMAD4 plays in progression from benign disease to invasive OSCC. Human OSCC lost detectable SMAD4 protein within tumor epithelium in 24% of cases, and this loss correlated with worse progression-free survival independent of other major clinical and pathological features. A mouse model engineered for <i>Kras</i>^G12D expression in the adult oral epithelium induced benign papillomas, however the combination of <i>Kras</i>^G12D with loss of epithelial <i>Smad4</i> expression resulted in rapid development of invasive carcinoma with features of human OSCC. Examination of regulatory pathways in 3D organoid cultures of SMAD4+ and SMAD4− mouse tumors with <i>Kras</i> mutation found that either loss of SMAD4 or inhibition of TGFβ signaling upregulated the WNT pathway and altered the extracellular matrix. The gene signature of the mouse tumor organoids lacking SMAD4 was highly similar to the gene signature of human head and neck squamous cell carcinoma. In summary, this work has uncovered novel mechanisms by which SMAD4 acts as a tumor suppressor in OSCC. © 2024 The Author(s). <i>The Journal of Pathology</i> published by John Wiley &amp; Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.</p>","PeriodicalId":232,"journal":{"name":"The Journal of Pathology","volume":"264 1","pages":"4-16"},"PeriodicalIF":5.6,"publicationDate":"2024-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11300146/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141454302","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Liver-specific DICER1 syndrome model mice develop cystic liver tumors with defective primary cilia","authors":"Keiki Oikawa,&nbsp;Shin-ichiro Ohno,&nbsp;Kana Ono,&nbsp;Kaito Hirao,&nbsp;Ayano Murakami,&nbsp;Yuichirou Harada,&nbsp;Katsuyoshi Kumagai,&nbsp;Katsuko Sudo,&nbsp;Masakatsu Takanashi,&nbsp;Akio Ishikawa,&nbsp;Shouichirou Mineo,&nbsp;Koji Fujita,&nbsp;Tomohiro Umezu,&nbsp;Noriko Watanabe,&nbsp;Yoshiki Murakami,&nbsp;Shinichiro Ogawa,&nbsp;Kris Ann Schultz,&nbsp;Masahiko Kuroda","doi":"10.1002/path.6320","DOIUrl":"10.1002/path.6320","url":null,"abstract":"<p>DICER1 syndrome is a tumor predisposition syndrome caused by familial genetic mutations in <i>DICER1</i>. Pathogenic variants of <i>DICER1</i> have been discovered in many rare cancers, including cystic liver tumors. However, the molecular mechanisms underlying liver lesions induced by these variants remain unclear. In the present study, we sought to gain a better understanding of the pathogenesis of these variants by generating a mouse model of liver-specific DICER1 syndrome. The mouse model developed bile duct hyperplasia with fibrosis, similar to congenital hepatic fibrosis, as well as cystic liver tumors resembling those in Caroli's syndrome, intrahepatic cholangiocarcinoma, and hepatocellular carcinoma. Interestingly, the mouse model of DICER1 syndrome showed abnormal formation of primary cilia in the bile duct epithelium, which is a known cause of bile duct hyperplasia and cyst formation. These results indicated that <i>DICER1</i> mutations contribute to cystic liver tumors by inducing defective primary cilia. The mouse model generated in this study will be useful for elucidating the potential mechanisms of tumorigenesis induced by <i>DICER1</i> variants and for obtaining a comprehensive understanding of DICER1 syndrome. © 2024 The Pathological Society of Great Britain and Ireland.</p>","PeriodicalId":232,"journal":{"name":"The Journal of Pathology","volume":"264 1","pages":"17-29"},"PeriodicalIF":5.6,"publicationDate":"2024-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141454303","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The E3 ubiquitin ligase TRIP12 is required for pancreatic acinar cell plasticity and pancreatic carcinogenesis","authors":"Manon Brunet,&nbsp;Claire Vargas,&nbsp;Marjorie Fanjul,&nbsp;Damien Varry,&nbsp;Naïma Hanoun,&nbsp;Dorian Larrieu,&nbsp;Laetitia Pieruccioni,&nbsp;Guillaume Labrousse,&nbsp;Hubert Lulka,&nbsp;Florence Capilla,&nbsp;Alban Ricard,&nbsp;Janick Selves,&nbsp;Anne Couvelard,&nbsp;Véronique Gigoux,&nbsp;Pierre Cordelier,&nbsp;Julie Guillermet-Guibert,&nbsp;Marlène Dufresne,&nbsp;Jérôme Torrisani","doi":"10.1002/path.6298","DOIUrl":"10.1002/path.6298","url":null,"abstract":"<p>The E3 ubiquitin ligase thyroid hormone receptor interacting protein 12 (TRIP12) has been implicated in pancreatic adenocarcinoma (PDAC) through its role in mediating the degradation of pancreas transcription factor 1a (PTF1a). PTF1a is a transcription factor essential for the acinar differentiation state that is notably diminished during the early steps of pancreatic carcinogenesis. Despite these findings, the direct involvement of TRIP12 in the onset of pancreatic cancer has yet to be established. In this study, we demonstrated that TRIP12 protein was significantly upregulated in human pancreatic preneoplastic lesions. Furthermore, we observed that TRIP12 overexpression varied within PDAC samples and PDAC-derived cell lines. We further demonstrated that TRIP12 was required for PDAC-derived cell growth and for the expression of E2F-targeted genes. Acinar-to-ductal cell metaplasia (ADM) is a reversible process that reflects the high plasticity of acinar cells. ADM becomes irreversible in the presence of oncogenic <i>Kras</i> mutations and leads to the formation of preneoplastic lesions. Using two genetically modified mouse models, we showed that a loss of TRIP12 prevented acini from developing ADM in response to pancreatic injury. With two additional mouse models, we further discovered that a depletion of TRIP12 prevented the formation of Kras^G12D-induced preneoplastic lesions and impaired metastasis formation in the presence of mutated <i>Kras</i>^G12D and <i>Trp53</i>^R172H genes. In summary our study identified an overexpression of TRIP12 from the early stages of pancreatic carcinogenesis and proposed this E3 ubiquitin ligase as a novel regulator of acinar plasticity with an important dual role in initiation and metastatic steps of PDAC. © 2024 The Authors. <i>The Journal of Pathology</i> published by John Wiley &amp; Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.</p>","PeriodicalId":232,"journal":{"name":"The Journal of Pathology","volume":"263 4-5","pages":"466-481"},"PeriodicalIF":5.6,"publicationDate":"2024-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/path.6298","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141454273","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Novel chemokine biomarkers in melanoma†","authors":"Alessio Giubellino,&nbsp;Sara E Hamilton","doi":"10.1002/path.6323","DOIUrl":"10.1002/path.6323","url":null,"abstract":"<p>The melanoma tumor microenvironment is a complex milieu of cancer, inflammatory, and stromal cells. In this context, chemokines play a pivotal role in recruiting inflammatory cells and influence the tumor, exerting both pro-tumorigenic and anti-tumoral roles. Interactions between these cells is what ultimately hold together and transform the tumor into an efficient machine. A recent study found that chemokines CCL8, CCL15, and CCL20 were upregulated in melanoma cells when co-cultured with macrophages and were associated with poor survival rates. CCL8 and CCL15 also stimulated melanoma cell growth, invasion, and metastasis, and were highly expressed in tumors prone to metastasize, suggesting these chemokines are attractive and independent biomarkers. Understanding the intricated interactions within the tumor microenvironment could lead to prognostic biomarkers and to the development of new therapeutic strategies for melanoma. © 2024 The Author(s). <i>The Journal of Pathology</i> published by John Wiley &amp; Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.</p>","PeriodicalId":232,"journal":{"name":"The Journal of Pathology","volume":"264 1","pages":"1-3"},"PeriodicalIF":5.6,"publicationDate":"2024-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/path.6323","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141454272","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Agalactosyl IgG induces liver fibrogenesis via Fc gamma receptor 3a on human hepatic stellate cells","authors":"Cheng-Hsun Ho,&nbsp;Ting-Tsung Chang,&nbsp;Hsien-Chang Lin,&nbsp;Sheng-Fan Wang","doi":"10.1002/path.6303","DOIUrl":"10.1002/path.6303","url":null,"abstract":"<p>The relevance of aberrant serum IgG <i>N</i>-glycosylation in liver fibrosis has been identified; however, its causal effect remains unclear. Because hepatic stellate cells (HSCs) contribute substantially to liver fibrosis, we investigated whether and through which mechanisms IgG <i>N</i>-glycosylation affects the fibrogenic properties of HSCs. Analysis of serum IgG₁ <i>N</i>-glycome from 151 patients with chronic hepatitis B or liver cirrhosis revealed a positive correlation between Ishak fibrosis grading and IgG₁ with agalactosyl <i>N</i>-glycoforms on the crystallizable fragment (Fc). Fc gamma receptor (FcγR) IIIa was observed in cultured human HSCs and HSCs in human liver tissues, and levels of FcγRIIIa in HSCs correlated with the severity of liver fibrosis. Additionally, agalactosyl IgG treatment caused HSCs to have a fibroblast-like morphology, enhanced migration and invasion capabilities, and enhanced expression of the FcγRIIIa downstream tyrosine-protein kinase SYK. Furthermore, agalactosyl IgG treatment increased fibrogenic factors in HSCs, including transforming growth factor (TGF)-β1, total collagen, platelet-derived growth factor subunit B and its receptors, pro-collagen I-α1, α-smooth muscle actin, and matrix metalloproteinase 9. These effects were more pronounced in HSCs that stably expressed <i>FCGR3A</i> and were reduced in <i>FCGR3A</i> knockout cells. Agalactosyl IgG and TGF-β1 each increased <i>FCGR3A</i> in HSCs. Furthermore, serum TGF-β1 concentrations in patients were positively correlated with agalactosyl IgG₁ levels and liver fibrosis severity, indicating a positive feedback loop involving agalactosyl IgG, HSC-FcγRIIIa, and TGF-β1. In conclusion, agalactosyl IgG promotes fibrogenic characteristics in HSCs through FcγRIIIa. © 2024 The Pathological Society of Great Britain and Ireland.</p>","PeriodicalId":232,"journal":{"name":"The Journal of Pathology","volume":"263 4-5","pages":"508-519"},"PeriodicalIF":5.6,"publicationDate":"2024-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141417050","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}