Pub Date : 2024-09-18DOI: 10.1016/j.immuni.2024.08.013
Samantha Y. Tse-Kang, Khursheed A. Wani, Nicholas D. Peterson, Amanda Page, Fiachra Humphries, Read Pukkila-Worley
Toll/interleukin-1/resistance (TIR)-domain proteins with enzymatic activity are essential for immunity in plants, animals, and bacteria. However, it is not known how these proteins function in pathogen sensing in animals. We discovered that the lone enzymatic TIR-domain protein in the nematode C. elegans (TIR-1, homolog of mammalian sterile alpha and TIR motif-containing 1 [SARM1]) was strategically expressed on the membranes of a specific intracellular compartment called lysosome-related organelles. The positioning of TIR-1 on lysosome-related organelles enables intestinal epithelial cells in the nematode C. elegans to survey for pathogen effector-triggered host damage. A virulence effector secreted by the bacterial pathogen Pseudomonas aeruginosa alkalinized and condensed lysosome-related organelles. This pathogen-induced morphological change in lysosome-related organelles triggered TIR-1 multimerization, which engaged its intrinsic NAD+ hydrolase (NADase) activity to activate the p38 innate immune pathway and protect the host against microbial intoxication. Thus, TIR-1 is a guard protein in an effector-triggered immune response, which enables intestinal epithelial cells to survey for pathogen-induced host damage.
{"title":"Intestinal immunity in C. elegans is activated by pathogen effector-triggered aggregation of the guard protein TIR-1 on lysosome-related organelles","authors":"Samantha Y. Tse-Kang, Khursheed A. Wani, Nicholas D. Peterson, Amanda Page, Fiachra Humphries, Read Pukkila-Worley","doi":"10.1016/j.immuni.2024.08.013","DOIUrl":"https://doi.org/10.1016/j.immuni.2024.08.013","url":null,"abstract":"<p>Toll/interleukin-1/resistance (TIR)-domain proteins with enzymatic activity are essential for immunity in plants, animals, and bacteria. However, it is not known how these proteins function in pathogen sensing in animals. We discovered that the lone enzymatic TIR-domain protein in the nematode <em>C. elegans</em> (TIR-1, homolog of mammalian sterile alpha and TIR motif-containing 1 [SARM1]) was strategically expressed on the membranes of a specific intracellular compartment called lysosome-related organelles. The positioning of TIR-1 on lysosome-related organelles enables intestinal epithelial cells in the nematode <em>C. elegans</em> to survey for pathogen effector-triggered host damage. A virulence effector secreted by the bacterial pathogen <em>Pseudomonas aeruginosa</em> alkalinized and condensed lysosome-related organelles. This pathogen-induced morphological change in lysosome-related organelles triggered TIR-1 multimerization, which engaged its intrinsic NAD<sup>+</sup> hydrolase (NADase) activity to activate the p38 innate immune pathway and protect the host against microbial intoxication. Thus, TIR-1 is a guard protein in an effector-triggered immune response, which enables intestinal epithelial cells to survey for pathogen-induced host damage.</p>","PeriodicalId":13269,"journal":{"name":"Immunity","volume":null,"pages":null},"PeriodicalIF":32.4,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142237023","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-13DOI: 10.1016/j.immuni.2024.08.014
Johanna Chiffelle, David Barras, Rémy Pétremand, Angela Orcurto, Sara Bobisse, Marion Arnaud, Aymeric Auger, Blanca Navarro Rodrigo, Eleonora Ghisoni, Christophe Sauvage, Damien Saugy, Alexandra Michel, Baptiste Murgues, Noémie Fahr, Martina Imbimbo, Maria Ochoa de Olza, Sofiya Latifyan, Isaac Crespo, Fabrizio Benedetti, Raphael Genolet, George Coukos
Adoptive cell therapy (ACT) using in vitro expanded tumor-infiltrating lymphocytes (TILs) has inconsistent clinical responses. To better understand determinants of therapeutic success, we tracked TIL clonotypes from baseline tumors to ACT products and post-ACT blood and tumor samples in melanoma patients using single-cell RNA and T cell receptor (TCR) sequencing. Patients with clinical responses had baseline tumors enriched in tumor-reactive TILs, and these were more effectively mobilized upon in vitro expansion, yielding products enriched in tumor-specific CD8+ cells that preferentially infiltrated tumors post-ACT. Conversely, lack of clinical responses was associated with tumors devoid of tumor-reactive resident clonotypes and with cell products mostly composed of blood-borne clonotypes that persisted in blood but not in tumors post-ACT. Upon expansion, tumor-specific TILs lost tumor-associated transcriptional signatures, including exhaustion, and responders exhibited an intermediate exhausted effector state after TIL engraftment in the tumor, suggesting functional reinvigoration. Our findings provide insight into the nature and dynamics of tumor-specific clonotypes associated with clinical response to TIL-ACT, with implications for treatment optimization.
{"title":"Tumor-reactive T cell clonotype dynamics underlying clinical response to TIL therapy in melanoma","authors":"Johanna Chiffelle, David Barras, Rémy Pétremand, Angela Orcurto, Sara Bobisse, Marion Arnaud, Aymeric Auger, Blanca Navarro Rodrigo, Eleonora Ghisoni, Christophe Sauvage, Damien Saugy, Alexandra Michel, Baptiste Murgues, Noémie Fahr, Martina Imbimbo, Maria Ochoa de Olza, Sofiya Latifyan, Isaac Crespo, Fabrizio Benedetti, Raphael Genolet, George Coukos","doi":"10.1016/j.immuni.2024.08.014","DOIUrl":"https://doi.org/10.1016/j.immuni.2024.08.014","url":null,"abstract":"<p>Adoptive cell therapy (ACT) using <em>in vitro</em> expanded tumor-infiltrating lymphocytes (TILs) has inconsistent clinical responses. To better understand determinants of therapeutic success, we tracked TIL clonotypes from baseline tumors to ACT products and post-ACT blood and tumor samples in melanoma patients using single-cell RNA and T cell receptor (TCR) sequencing. Patients with clinical responses had baseline tumors enriched in tumor-reactive TILs, and these were more effectively mobilized upon <em>in vitro</em> expansion, yielding products enriched in tumor-specific CD8<sup>+</sup> cells that preferentially infiltrated tumors post-ACT. Conversely, lack of clinical responses was associated with tumors devoid of tumor-reactive resident clonotypes and with cell products mostly composed of blood-borne clonotypes that persisted in blood but not in tumors post-ACT. Upon expansion, tumor-specific TILs lost tumor-associated transcriptional signatures, including exhaustion, and responders exhibited an intermediate exhausted effector state after TIL engraftment in the tumor, suggesting functional reinvigoration. Our findings provide insight into the nature and dynamics of tumor-specific clonotypes associated with clinical response to TIL-ACT, with implications for treatment optimization.</p>","PeriodicalId":13269,"journal":{"name":"Immunity","volume":null,"pages":null},"PeriodicalIF":32.4,"publicationDate":"2024-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142211518","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-10DOI: 10.1016/j.immuni.2024.08.001
Janssen M. Kotah, Bart J.L. Eggen
Aging leads to alterations that precipitate or aggravate several diseases that occur across our lifespan. In the CNS, aging affects the capacity to maintain and repair the myelin sheaths that protect axons and facilitate neuronal signaling. Tiwari et al. report aging-associated transcriptional responses in microglia after demyelination, which could be reversed by epigenetic remodeling after BCG vaccination.
{"title":"An anti-aging vaccine: BCG turns back the clock on remyelination failure","authors":"Janssen M. Kotah, Bart J.L. Eggen","doi":"10.1016/j.immuni.2024.08.001","DOIUrl":"https://doi.org/10.1016/j.immuni.2024.08.001","url":null,"abstract":"<p>Aging leads to alterations that precipitate or aggravate several diseases that occur across our lifespan. In the CNS, aging affects the capacity to maintain and repair the myelin sheaths that protect axons and facilitate neuronal signaling. Tiwari et al. report aging-associated transcriptional responses in microglia after demyelination, which could be reversed by epigenetic remodeling after BCG vaccination.</p>","PeriodicalId":13269,"journal":{"name":"Immunity","volume":null,"pages":null},"PeriodicalIF":32.4,"publicationDate":"2024-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142161039","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-10DOI: 10.1016/j.immuni.2024.08.009
Sarah Adamo, Marcus Buggert
Tissue-resident memory CD8+ T cells serve as a first-line defense against many pathogens. In this issue of Immunity, Buquicchio et al. unveil the epigenomic landscapes of virus-specific CD8+ T cell subsets, highlighting common and organ-specific regulators driving their differentiation.
组织驻留记忆 CD8+ T 细胞是抵御许多病原体的第一道防线。在本期《免疫》杂志上,Buquicchio 等人揭示了病毒特异性 CD8+ T 细胞亚群的表观基因组图谱,强调了驱动其分化的共同和器官特异性调控因子。
{"title":"The epigenomic matrix of tissue-specific immune memory","authors":"Sarah Adamo, Marcus Buggert","doi":"10.1016/j.immuni.2024.08.009","DOIUrl":"https://doi.org/10.1016/j.immuni.2024.08.009","url":null,"abstract":"<p>Tissue-resident memory CD8<sup>+</sup> T cells serve as a first-line defense against many pathogens. In this issue of <em>Immunity</em>, Buquicchio et al. unveil the epigenomic landscapes of virus-specific CD8<sup>+</sup> T cell subsets, highlighting common and organ-specific regulators driving their differentiation.</p>","PeriodicalId":13269,"journal":{"name":"Immunity","volume":null,"pages":null},"PeriodicalIF":32.4,"publicationDate":"2024-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142161069","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-10DOI: 10.1016/j.immuni.2024.08.012
Giuseppe Giuliani, Jayajit Das
Intestinal macrophages play a key role in regulating immune tolerance in the gut. In this issue of Immunity, Mertens et al. uncover a mechanism for the establishment of memory in macrophage tolerance in the gut involving a bistable metabolic switch in macrophages and an intercellular positive feedback between macrophages and intestinal epithelial cells (IECs).
{"title":"Neighbor’s feedback helps macrophages learn tolerance in the gut","authors":"Giuseppe Giuliani, Jayajit Das","doi":"10.1016/j.immuni.2024.08.012","DOIUrl":"https://doi.org/10.1016/j.immuni.2024.08.012","url":null,"abstract":"<p>Intestinal macrophages play a key role in regulating immune tolerance in the gut. In this issue of <em>Immunity</em>, Mertens et al. uncover a mechanism for the establishment of memory in macrophage tolerance in the gut involving a bistable metabolic switch in macrophages and an intercellular positive feedback between macrophages and intestinal epithelial cells (IECs).</p>","PeriodicalId":13269,"journal":{"name":"Immunity","volume":null,"pages":null},"PeriodicalIF":32.4,"publicationDate":"2024-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142161038","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-10DOI: 10.1016/j.immuni.2024.08.010
Saad Khan, Veronica Chang, Daniel A. Winer
Chronic inflammation is considered a hallmark of aging. In a recent issue of Nature, Widjaja et al. examined genetic and pharmacologic inhibition of interleukin (IL)-11 on aging pathology and found that inhibiting IL-11 signaling increases lifespan and healthspan in mice.
{"title":"The inflammaging clock strikes IL-11!","authors":"Saad Khan, Veronica Chang, Daniel A. Winer","doi":"10.1016/j.immuni.2024.08.010","DOIUrl":"https://doi.org/10.1016/j.immuni.2024.08.010","url":null,"abstract":"<p>Chronic inflammation is considered a hallmark of aging. In a recent issue of <em>Nature</em>, Widjaja et al. examined genetic and pharmacologic inhibition of interleukin (IL)-11 on aging pathology and found that inhibiting IL-11 signaling increases lifespan and healthspan in mice.</p>","PeriodicalId":13269,"journal":{"name":"Immunity","volume":null,"pages":null},"PeriodicalIF":32.4,"publicationDate":"2024-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142161040","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-10DOI: 10.1016/j.immuni.2024.08.011
Eran Elinav, Suzanne Devkota, Marlies Meisel, Shu Zhu, Hiutung Chu, Haiwei Chen, Jens Puschhof, Florencia McAllister, Randall Jeffrey Platt, Kenya Honda
The immune system has a vital, albeit complex, relationship with the microbes residing within us, one that we are only beginning to understand. We asked investigators what they felt were the fundamental challenges we currently face in unraveling the impacts of microbes and their metabolites on host immunity and to discuss key opportunities toward achieving future insights and innovation.
{"title":"Microbes and metabolites in immunity","authors":"Eran Elinav, Suzanne Devkota, Marlies Meisel, Shu Zhu, Hiutung Chu, Haiwei Chen, Jens Puschhof, Florencia McAllister, Randall Jeffrey Platt, Kenya Honda","doi":"10.1016/j.immuni.2024.08.011","DOIUrl":"https://doi.org/10.1016/j.immuni.2024.08.011","url":null,"abstract":"<p>The immune system has a vital, albeit complex, relationship with the microbes residing within us, one that we are only beginning to understand. We asked investigators what they felt were the fundamental challenges we currently face in unraveling the impacts of microbes and their metabolites on host immunity and to discuss key opportunities toward achieving future insights and innovation.</p>","PeriodicalId":13269,"journal":{"name":"Immunity","volume":null,"pages":null},"PeriodicalIF":32.4,"publicationDate":"2024-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142161036","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-10DOI: 10.1016/j.immuni.2024.08.006
Yanxia Rao, Bo Peng
Our brain is not an immune-privileged island isolated from peripheries, but how non-neuronal brain cells interact with the peripheral system is not well understood. Wei et al. report that microglia in the hypothalamic paraventricular nucleus (PVN) with unique vasculature can detect ATP derived from hemodynamic disturbance. These microglia in the PVN regulate the response to hypertension via ATP-P2Y12-C/EBPβ signaling.
{"title":"Microglia bridge brain activity and blood pressure","authors":"Yanxia Rao, Bo Peng","doi":"10.1016/j.immuni.2024.08.006","DOIUrl":"https://doi.org/10.1016/j.immuni.2024.08.006","url":null,"abstract":"<p>Our brain is not an immune-privileged island isolated from peripheries, but how non-neuronal brain cells interact with the peripheral system is not well understood. Wei et al. report that microglia in the hypothalamic paraventricular nucleus (PVN) with unique vasculature can detect ATP derived from hemodynamic disturbance. These microglia in the PVN regulate the response to hypertension via ATP-P2Y12-C/EBPβ signaling.</p>","PeriodicalId":13269,"journal":{"name":"Immunity","volume":null,"pages":null},"PeriodicalIF":32.4,"publicationDate":"2024-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142161037","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-04DOI: 10.1016/j.immuni.2024.08.008
Dongkyun Kim, Giha Kim, Rongzhen Yu, Juyeun Lee, Sohee Kim, Mia R. Gleason, Kevin Qiu, Elena Montauti, Li Lily Wang, Deyu Fang, Jaehyuk Choi, Navdeep S. Chandel, Samuel Weinberg, Booki Min
Lymphocyte activation gene 3 (Lag3) is an inhibitory co-receptor expressed on activated T cells and has been proposed to regulate regulatory T (Treg) cell function. However, its precise modality and mechanisms remain elusive. We generated Treg cell-specific Lag3-mutant mouse models and found that Lag3 was essential for Treg cell control of autoimmunity. RNA sequencing analysis revealed that Lag3 mutation altered genes associated with metabolic processes, especially Myc target genes. Myc expression in Lag3-mutant Treg cells was increased to the level seen in conventional T helper (Th)1-type effector cells and directly correlated with their metabolic profiles and in vivo suppressive functions. The phosphatidylinositol 3-kinase (PI3K)-Akt-Rictor pathway was activated in Lag3-mutant Treg cells, and inhibiting PI3K, Rictor, or lactate dehydrogenase A (Ldha), a key Myc target enzyme converting pyruvate to lactate, was sufficient to restore normal metabolism and suppressive function in Lag3-mutant Treg cells. These findings indicate that Lag3 supports Treg cell suppression partly by tuning Myc-dependent metabolic programming.
淋巴细胞活化基因 3(Lag3)是一种表达在活化 T 细胞上的抑制性共受体,被认为能调节调节性 T(Treg)细胞的功能。然而,其确切的模式和机制仍然难以捉摸。我们建立了Treg细胞特异性Lag3突变小鼠模型,发现Lag3对Treg细胞控制自身免疫至关重要。RNA测序分析显示,Lag3突变改变了与代谢过程相关的基因,尤其是Myc靶基因。在Lag3突变的Treg细胞中,Myc的表达增加到了传统T辅助细胞(Th)1型效应细胞的水平,并与其代谢特征和体内抑制功能直接相关。Lag3突变Treg细胞中的磷脂酰肌醇3-激酶(PI3K)-Akt-Rictor通路被激活,抑制PI3K、Rictor或乳酸脱氢酶A(Ldha)(一种将丙酮酸转化为乳酸的关键Myc靶酶)足以恢复Lag3突变Treg细胞的正常代谢和抑制功能。这些发现表明,Lag3 部分是通过调整依赖于 Myc 的代谢程序来支持 Treg 细胞的抑制作用。
{"title":"Inhibitory co-receptor Lag3 supports Foxp3+ regulatory T cell function by restraining Myc-dependent metabolic programming","authors":"Dongkyun Kim, Giha Kim, Rongzhen Yu, Juyeun Lee, Sohee Kim, Mia R. Gleason, Kevin Qiu, Elena Montauti, Li Lily Wang, Deyu Fang, Jaehyuk Choi, Navdeep S. Chandel, Samuel Weinberg, Booki Min","doi":"10.1016/j.immuni.2024.08.008","DOIUrl":"https://doi.org/10.1016/j.immuni.2024.08.008","url":null,"abstract":"<p>Lymphocyte activation gene 3 (Lag3) is an inhibitory co-receptor expressed on activated T cells and has been proposed to regulate regulatory T (Treg) cell function. However, its precise modality and mechanisms remain elusive. We generated Treg cell-specific Lag3-mutant mouse models and found that Lag3 was essential for Treg cell control of autoimmunity. RNA sequencing analysis revealed that Lag3 mutation altered genes associated with metabolic processes, especially Myc target genes. Myc expression in Lag3-mutant Treg cells was increased to the level seen in conventional T helper (Th)1-type effector cells and directly correlated with their metabolic profiles and <em>in vivo</em> suppressive functions. The phosphatidylinositol 3-kinase (PI3K)-Akt-Rictor pathway was activated in Lag3-mutant Treg cells, and inhibiting PI3K, Rictor, or lactate dehydrogenase A (Ldha), a key Myc target enzyme converting pyruvate to lactate, was sufficient to restore normal metabolism and suppressive function in Lag3-mutant Treg cells. These findings indicate that Lag3 supports Treg cell suppression partly by tuning Myc-dependent metabolic programming.</p>","PeriodicalId":13269,"journal":{"name":"Immunity","volume":null,"pages":null},"PeriodicalIF":32.4,"publicationDate":"2024-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142138211","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-02DOI: 10.1016/j.immuni.2024.08.007
Konstantin Stark, Badr Kilani, Sven Stockhausen, Johanna Busse, Irene Schubert, Thuy-Duong Tran, Florian Gaertner, Alexander Leunig, Kami Pekayvaz, Leo Nicolai, Valeria Fumagalli, Julia Stermann, Felix Stephan, Christian David, Martin B. Müller, Birgitta Heyman, Anja Lux, Alexandra da Palma Guerreiro, Lukas P. Frenzel, Christoph Q. Schmidt, Steffen Massberg
Venous thromboembolism (VTE) is a common, deadly disease with an increasing incidence despite preventive efforts. Clinical observations have associated elevated antibody concentrations or antibody-based therapies with thrombotic events. However, how antibodies contribute to thrombosis is unknown. Here, we show that reduced blood flow enabled immunoglobulin M (IgM) to bind to FcμR and the polymeric immunoglobulin receptor (pIgR), initiating endothelial activation and platelet recruitment. Subsequently, the procoagulant surface of activated platelets accommodated antigen- and FcγR-independent IgG deposition. This leads to classical complement activation, setting in motion a prothrombotic vicious circle. Key elements of this mechanism were present in humans in the setting of venous stasis as well as in the dysregulated immunothrombosis of COVID-19. This antibody-driven thrombosis can be prevented by pharmacologically targeting complement. Hence, our results uncover antibodies as previously unrecognized central regulators of thrombosis. These findings carry relevance for therapeutic application of antibodies and open innovative avenues to target thrombosis without compromising hemostasis.
{"title":"Antibodies and complement are key drivers of thrombosis","authors":"Konstantin Stark, Badr Kilani, Sven Stockhausen, Johanna Busse, Irene Schubert, Thuy-Duong Tran, Florian Gaertner, Alexander Leunig, Kami Pekayvaz, Leo Nicolai, Valeria Fumagalli, Julia Stermann, Felix Stephan, Christian David, Martin B. Müller, Birgitta Heyman, Anja Lux, Alexandra da Palma Guerreiro, Lukas P. Frenzel, Christoph Q. Schmidt, Steffen Massberg","doi":"10.1016/j.immuni.2024.08.007","DOIUrl":"https://doi.org/10.1016/j.immuni.2024.08.007","url":null,"abstract":"<p>Venous thromboembolism (VTE) is a common, deadly disease with an increasing incidence despite preventive efforts. Clinical observations have associated elevated antibody concentrations or antibody-based therapies with thrombotic events. However, how antibodies contribute to thrombosis is unknown. Here, we show that reduced blood flow enabled immunoglobulin M (IgM) to bind to FcμR and the polymeric immunoglobulin receptor (pIgR), initiating endothelial activation and platelet recruitment. Subsequently, the procoagulant surface of activated platelets accommodated antigen- and FcγR-independent IgG deposition. This leads to classical complement activation, setting in motion a prothrombotic <em>vicious circle</em>. Key elements of this mechanism were present in humans in the setting of venous stasis as well as in the dysregulated immunothrombosis of COVID-19. This antibody-driven thrombosis can be prevented by pharmacologically targeting complement. Hence, our results uncover antibodies as previously unrecognized central regulators of thrombosis. These findings carry relevance for therapeutic application of antibodies and open innovative avenues to target thrombosis without compromising hemostasis.</p>","PeriodicalId":13269,"journal":{"name":"Immunity","volume":null,"pages":null},"PeriodicalIF":32.4,"publicationDate":"2024-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142118150","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}