Pub Date : 2024-06-01DOI: 10.1016/j.mucimm.2024.03.003
Breanne E. Haskins , Jodi A. Gullicksrud , Bethan A. Wallbank , Jennifer E. Dumaine , Amandine Guérin , Ian S. Cohn , Keenan M. O'Dea , Ryan D. Pardy , Maria I. Merolle , Lindsey A. Shallberg , Emma N. Hunter , Jessica H. Byerly , Eleanor J. Smith , Gracyn Y. Buenconsejo , Briana I. McLeod , David A. Christian , Boris Striepen , Christopher A. Hunter
Cryptosporidium causes debilitating diarrheal disease in patients with primary and acquired defects in T cell function. However, it has been a challenge to understand how this infection generates T cell responses and how they mediate parasite control. Here, Cryptosporidium was engineered to express a parasite effector protein (MEDLE-2) that contains the major histocompatibility complex-I restricted SIINFEKL epitope which is recognized by T cell receptor transgenic OT-I(OVA-TCR-I) clusters of differentiation (CD)8+ T cells. These modified parasites induced expansion of endogenous SIINFEKL-specific and OT-I CD8+ T cells that were a source of interferon-gamma (IFN-γ) that could restrict growth of Cryptosporidium. This T cell response was dependent on the translocation of the effector and similar results were observed with another secreted parasite effector (rhoptry protein 1). Although infection and these translocated effector proteins are restricted to intestinal epithelial cells, type 1 conventional dendritic cells were required to generate CD8+ T cell responses to these model antigens. These data sets highlight Cryptosporidium effectors as potential targets of the immune system and suggest that crosstalk between enterocytes and type 1 conventional dendritic cells is crucial for CD8+ T cell responses to Cryptosporidium.
然而,了解这种感染如何产生 T 细胞反应以及它们如何介导寄生虫控制一直是个挑战。在这里,我们设计表达了一种寄生虫效应蛋白(MEDLE-2),它含有 MHC-I 限制性 SIINFEKL 表位,可被 TCR 转基因 OT-I CD8 T 细胞识别。这些改造过的寄生虫诱导了内源性 SIINFEKL 特异性和 OT-I CD8 T 细胞的扩增,这些 T 细胞是 IFN-γ 的来源,可以限制 SIINFEKL 的生长。 这种 T 细胞反应依赖于效应物的易位,在另一种分泌型寄生虫效应物(ROP1)上也观察到了类似的结果。虽然感染和这些转位效应蛋白仅限于肠上皮细胞(IEC),但需要 I 型树突状细胞(cDC1)才能产生 CD8 T 细胞对这些模型抗原的反应。这些数据集强调了效应蛋白是免疫系统的潜在靶标,并表明肠细胞和 cDC1 之间的串联对于 CD8 T 细胞对......的应答至关重要。
{"title":"Dendritic cell-mediated responses to secreted Cryptosporidium effectors promote parasite-specific CD8+ T cell responses","authors":"Breanne E. Haskins , Jodi A. Gullicksrud , Bethan A. Wallbank , Jennifer E. Dumaine , Amandine Guérin , Ian S. Cohn , Keenan M. O'Dea , Ryan D. Pardy , Maria I. Merolle , Lindsey A. Shallberg , Emma N. Hunter , Jessica H. Byerly , Eleanor J. Smith , Gracyn Y. Buenconsejo , Briana I. McLeod , David A. Christian , Boris Striepen , Christopher A. Hunter","doi":"10.1016/j.mucimm.2024.03.003","DOIUrl":"10.1016/j.mucimm.2024.03.003","url":null,"abstract":"<div><p><em>Cryptosporidium</em> causes debilitating diarrheal disease in patients with primary and acquired defects in T cell function<em>.</em> However, it has been a challenge to understand how this infection generates T cell responses and how they mediate parasite control. Here, <em>Cryptosporidium</em> was engineered to express a parasite effector protein (MEDLE-2) that contains the major histocompatibility complex-I restricted SIINFEKL epitope which is recognized by T cell receptor transgenic OT-I(OVA-TCR-I) clusters of differentiation (CD)8<sup>+</sup> T cells. These modified parasites induced expansion of endogenous SIINFEKL-specific and OT-I CD8<sup>+</sup> T cells that were a source of interferon-gamma (IFN-γ) that could restrict growth of <em>Cryptosporidium</em>. This T cell response was dependent on the translocation of the effector and similar results were observed with another secreted parasite effector (rhoptry protein 1). Although infection and these translocated effector proteins are restricted to intestinal epithelial cells, type 1 conventional dendritic cells were required to generate CD8<sup>+</sup> T cell responses to these model antigens. These data sets highlight <em>Cryptosporidium</em> effectors as potential targets of the immune system and suggest that crosstalk between enterocytes and type 1 conventional dendritic cells is crucial for CD8<sup>+</sup> T cell responses to <em>Cryptosporidium</em>.</p></div>","PeriodicalId":18877,"journal":{"name":"Mucosal Immunology","volume":null,"pages":null},"PeriodicalIF":8.0,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1933021924000229/pdfft?md5=a9bd515cf942f6de6950501be580bb73&pid=1-s2.0-S1933021924000229-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140154533","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}
Pub Date : 2024-06-01DOI: 10.1016/j.mucimm.2024.03.007
Lukas F. Mager , Tim Krause , Kathy D. McCoy
The microbiome has emerged as a crucial modulator of host-immune interactions and clearly impacts tumor development and therapy efficacy. The microbiome is a double-edged sword in cancer development and therapy as both pro-tumorigenic and anti-tumorigenic bacterial taxa have been identified. The staggering number of association-based studies in various tumor types has led to an enormous amount of data that makes it difficult to identify bacteria that promote tumor development or modulate therapy efficacy from bystander bacteria. Here we aim to comprehensively summarize the current knowledge of microbiome-host immunity interactions and cancer therapy in various mucosal tissues to find commonalities and thus identify potential functionally relevant bacterial taxa. Moreover, we also review recent studies identifying specific bacteria and mechanisms through which the microbiome modulates cancer development and therapy efficacy.
{"title":"Interaction of microbiota, mucosal malignancies, and immunotherapy—Mechanistic insights","authors":"Lukas F. Mager , Tim Krause , Kathy D. McCoy","doi":"10.1016/j.mucimm.2024.03.007","DOIUrl":"10.1016/j.mucimm.2024.03.007","url":null,"abstract":"<div><p>The microbiome has emerged as a crucial modulator of host-immune interactions and clearly impacts tumor development and therapy efficacy. The microbiome is a double-edged sword in cancer development and therapy as both pro-tumorigenic and anti-tumorigenic bacterial taxa have been identified. The staggering number of association-based studies in various tumor types has led to an enormous amount of data that makes it difficult to identify bacteria that promote tumor development or modulate therapy efficacy from bystander bacteria. Here we aim to comprehensively summarize the current knowledge of microbiome-host immunity interactions and cancer therapy in various mucosal tissues to find commonalities and thus identify potential functionally relevant bacterial taxa. Moreover, we also review recent studies identifying specific bacteria and mechanisms through which the microbiome modulates cancer development and therapy efficacy.</p></div>","PeriodicalId":18877,"journal":{"name":"Mucosal Immunology","volume":null,"pages":null},"PeriodicalIF":8.0,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1933021924000266/pdfft?md5=fcaad5e230d25d4930a988d7cccd8485&pid=1-s2.0-S1933021924000266-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140194213","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}
Pub Date : 2024-06-01DOI: 10.1016/j.mucimm.2023.11.008
Zihao Liu , He Xie , Ling Li , Dan Jiang , Yuna Qian , Xinhao Zhu , Mali Dai , Yanxiao Li , Ruifen Wei , Zan Luo , Weihao Xu , Qinxiang Zheng , Jianliang Shen , Meng Zhou , Wenwen Zeng , Wei Chen
Dry eye disease (DED) is a prevalent chronic eye disease characterized by an aberrant inflammatory response in ocular surface mucosa. The immunological alterations underlying DED remain largely unknown. In this study, we employed single-cell transcriptome sequencing of conjunctival tissue from environment-induced DED mice to investigate multicellular ecosystem and functional changes at different DED stages. Our results revealed an epithelial subtype with fibroblastic characteristics and pro-inflammatory effects emerging in the acute phase of DED. We also found that T helper (Th)1, Th17, and regulatory T cells (Treg) were the dominant clusters of differentiation (CD)4+ T-cell types involved in regulating immune responses and identified three distinct macrophage subtypes, with the CD72+CD11c+ subtype enhancing chronic inflammation. Furthermore, bulk transcriptome analysis of video display terminal-induced DED consistently suggested the presence of the pro-inflammatory epithelial subtype in human conjunctiva. Our findings have uncovered a DED-associated pro-inflammatory microenvironment in the conjunctiva, centered around epithelial cells, involving interactions with macrophages and CD4+ T cells, which deepens our understanding of ocular surface mucosal immune responses during DED progression.
{"title":"Single-cell landscape reveals the epithelial cell-centric pro-inflammatory immune microenvironment in dry eye development","authors":"Zihao Liu , He Xie , Ling Li , Dan Jiang , Yuna Qian , Xinhao Zhu , Mali Dai , Yanxiao Li , Ruifen Wei , Zan Luo , Weihao Xu , Qinxiang Zheng , Jianliang Shen , Meng Zhou , Wenwen Zeng , Wei Chen","doi":"10.1016/j.mucimm.2023.11.008","DOIUrl":"10.1016/j.mucimm.2023.11.008","url":null,"abstract":"<div><p>Dry eye disease (DED) is a prevalent chronic eye disease characterized by an aberrant inflammatory response in ocular surface mucosa. The immunological alterations underlying DED remain largely unknown. In this study, we employed single-cell transcriptome sequencing of conjunctival tissue from environment-induced DED mice to investigate multicellular ecosystem and functional changes at different DED stages. Our results revealed an epithelial subtype with fibroblastic characteristics and pro-inflammatory effects emerging in the acute phase of DED. We also found that T helper (Th)1, Th17, and regulatory T cells (Treg) were the dominant clusters of differentiation (CD)4<sup>+</sup> T-cell types involved in regulating immune responses and identified three distinct macrophage subtypes, with the CD72<sup>+</sup>CD11c<sup>+</sup> subtype enhancing chronic inflammation. Furthermore, bulk transcriptome analysis of video display terminal-induced DED consistently suggested the presence of the pro-inflammatory epithelial subtype in human conjunctiva. Our findings have uncovered a DED-associated pro-inflammatory microenvironment in the conjunctiva, centered around epithelial cells, involving interactions with macrophages and CD4<sup>+</sup> T cells, which deepens our understanding of ocular surface mucosal immune responses during DED progression.</p></div>","PeriodicalId":18877,"journal":{"name":"Mucosal Immunology","volume":null,"pages":null},"PeriodicalIF":8.0,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1933021923000910/pdfft?md5=ca16c64a73aee82ce10e872e6b3af91e&pid=1-s2.0-S1933021923000910-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138440936","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}
Pub Date : 2024-06-01DOI: 10.1016/j.mucimm.2024.03.002
Nicolas Jacquelot , Le Xiong , Wang H.J. Cao , Qiutong Huang , Huiyang Yu , Azin Sayad , Casey J.A. Anttila , Tracey M. Baldwin , Peter F. Hickey , Daniela Amann-Zalcenstein , Pamela S. Ohashi , Stephen L. Nutt , Gabrielle T. Belz , Cyril Seillet
Interleukin-(IL) 22 production by intestinal group 3 innate lymphoid cells (ILC3) is critical to maintain gut homeostasis. However, IL-22 needs to be tightly controlled; reduced IL-22 expression is associated with intestinal epithelial barrier defect while its overexpression promotes tumor development. Here, using a single-cell ribonucleic acid sequencing approach, we identified a core set of genes associated with increased IL-22 production by ILC3. Among these genes, programmed cell death 1 (PD-1), extensively studied in the context of cancer and chronic infection, was constitutively expressed on a subset of ILC3. These cells, found in the crypt of the small intestine and colon, displayed superior capacity to produce IL-22. PD-1 expression on ILC3 was dependent on the microbiota and was induced during inflammation in response to IL-23 but, conversely, was reduced in the presence of Notch ligand. PD-1+ ILC3 exhibited distinct metabolic activity with increased glycolytic, lipid, and polyamine synthesis associated with augmented proliferation compared with their PD-1− counterparts. Further, PD-1+ ILC3 showed increased expression of mitochondrial antioxidant proteins which enable the cells to maintain their levels of reactive oxygen species. Loss of PD-1 signaling in ILC3 led to reduced IL-22 production in a cell-intrinsic manner. During inflammation, PD-1 expression was increased on natural cytotoxicity receptor (NCR)− ILC3 while deficiency in PD-1 expression resulted in increased susceptibility to experimental colitis and failure to maintain gut barrier integrity. Collectively, our findings uncover a new function of the PD-1 and highlight the role of PD-1 signaling in the maintenance of gut homeostasis mediated by ILC3 in mice.
{"title":"PD-1 regulates ILC3-driven intestinal immunity and homeostasis","authors":"Nicolas Jacquelot , Le Xiong , Wang H.J. Cao , Qiutong Huang , Huiyang Yu , Azin Sayad , Casey J.A. Anttila , Tracey M. Baldwin , Peter F. Hickey , Daniela Amann-Zalcenstein , Pamela S. Ohashi , Stephen L. Nutt , Gabrielle T. Belz , Cyril Seillet","doi":"10.1016/j.mucimm.2024.03.002","DOIUrl":"10.1016/j.mucimm.2024.03.002","url":null,"abstract":"<div><p>Interleukin-(IL) 22 production by intestinal group 3 innate lymphoid cells (ILC3) is critical to maintain gut homeostasis. However, IL-22 needs to be tightly controlled; reduced IL-22 expression is associated with intestinal epithelial barrier defect while its overexpression promotes tumor development. Here, using a single-cell ribonucleic acid sequencing approach, we identified a core set of genes associated with increased IL-22 production by ILC3. Among these genes, programmed cell death 1 (PD-1), extensively studied in the context of cancer and chronic infection, was constitutively expressed on a subset of ILC3. These cells, found in the crypt of the small intestine and colon, displayed superior capacity to produce IL-22. PD-1 expression on ILC3 was dependent on the microbiota and was induced during inflammation in response to IL-23 but, conversely, was reduced in the presence of Notch ligand. PD-1<sup>+</sup> ILC3 exhibited distinct metabolic activity with increased glycolytic, lipid, and polyamine synthesis associated with augmented proliferation compared with their PD-1<sup>−</sup> counterparts. Further, PD-1<sup>+</sup> ILC3 showed increased expression of mitochondrial antioxidant proteins which enable the cells to maintain their levels of reactive oxygen species. Loss of PD-1 signaling in ILC3 led to reduced IL-22 production in a cell-intrinsic manner. During inflammation, PD-1 expression was increased on natural cytotoxicity receptor (NCR)<sup>−</sup> ILC3 while deficiency in PD-1 expression resulted in increased susceptibility to experimental colitis and failure to maintain gut barrier integrity. Collectively, our findings uncover a new function of the PD-1 and highlight the role of PD-1 signaling in the maintenance of gut homeostasis mediated by ILC3 in mice.</p></div>","PeriodicalId":18877,"journal":{"name":"Mucosal Immunology","volume":null,"pages":null},"PeriodicalIF":8.0,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1933021924000217/pdfft?md5=39c9e9f5ee203de18930f74b9b8c8cae&pid=1-s2.0-S1933021924000217-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140140482","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}
Pub Date : 2024-06-01DOI: 10.1016/j.mucimm.2023.12.001
Biyan Zhang , Shuting Chen , Xiangyun Yin , Caleb D. McBride , Jake A. Gertie , Marina Yurieva , Agata A. Bielecka , Brian Hoffmann , J. Travis Hinson , Jessica Grassmann , Lan Xu , Emily R. Siniscalco , Arielle Soldatenko , Laura Hoyt , Julie Joseph , Elizabeth B. Norton , Gowthaman Uthaman , Noah W. Palm , Elise Liu , Stephanie C. Eisenbarth , Adam Williams
Dedicator of cytokinesis 8 (DOCK8) mutations lead to a primary immunodeficiency associated with recurrent gastrointestinal infections and poor antibody responses but, paradoxically, heightened IgE to food antigens, suggesting that DOCK8 is central to immune homeostasis in the gut. Using Dock8-deficient mice, we found that DOCK8 was necessary for mucosal IgA production to multiple T cell-dependent antigens, including peanut and cholera toxin. Yet DOCK8 was not necessary in T cells for this phenotype. Instead, B cell-intrinsic DOCK8 was required for maintenance of antigen-specific IgA-secreting plasma cells (PCs) in the gut lamina propria. Unexpectedly, DOCK8 was not required for early B cell activation, migration, or IgA class switching. An unbiased interactome screen revealed novel protein partners involved in metabolism and apoptosis. Dock8-deficient IgA+ B cells had impaired cellular respiration and failed to engage glycolysis appropriately. These results demonstrate that maintenance of the IgA+ PC compartment requires DOCK8 and suggest that gut IgA+ PCs have unique metabolic requirements for long-term survival in the lamina propria.
细胞分裂诱导因子 8(DOCK8)突变会导致一种原发性免疫缺陷,这种缺陷与反复胃肠道感染和抗体反应低下有关,但矛盾的是,对食物抗原的 IgE 会增加,这表明 DOCK8 是肠道免疫平衡的核心。利用 Dock8 缺陷小鼠,我们发现 DOCK8 对多种 T 细胞依赖性抗原(包括花生和霍乱毒素)的粘膜 IgA 生成是必需的。然而 DOCK8 并不是 T 细胞产生这种表型的必要条件。相反,肠道固有层中抗原特异性 IgA 分泌浆细胞(PCs)的维持需要 B 细胞固有的 DOCK8。意想不到的是,DOCK8 并非早期 B 细胞活化、迁移或 IgA 类别转换所必需。一项无偏见的相互作用组筛选发现了参与新陈代谢和细胞凋亡的新型蛋白质伙伴。Dock8缺陷的IgA+ B细胞细胞呼吸功能受损,不能适当地参与糖酵解。这些结果表明,维持 IgA+ PC 区需要 DOCK8,并表明肠道 IgA+ PC 在固有膜中长期存活有独特的代谢要求。
{"title":"Metabolic fitness of IgA+ plasma cells in the gut requires DOCK8","authors":"Biyan Zhang , Shuting Chen , Xiangyun Yin , Caleb D. McBride , Jake A. Gertie , Marina Yurieva , Agata A. Bielecka , Brian Hoffmann , J. Travis Hinson , Jessica Grassmann , Lan Xu , Emily R. Siniscalco , Arielle Soldatenko , Laura Hoyt , Julie Joseph , Elizabeth B. Norton , Gowthaman Uthaman , Noah W. Palm , Elise Liu , Stephanie C. Eisenbarth , Adam Williams","doi":"10.1016/j.mucimm.2023.12.001","DOIUrl":"10.1016/j.mucimm.2023.12.001","url":null,"abstract":"<div><p>Dedicator of cytokinesis 8 (DOCK8) mutations lead to a primary immunodeficiency associated with recurrent gastrointestinal infections and poor antibody responses but, paradoxically, heightened IgE to food antigens, suggesting that DOCK8 is central to immune homeostasis in the gut. Using <em>Dock8</em>-deficient mice, we found that DOCK8 was necessary for mucosal IgA production to multiple T cell-dependent antigens, including peanut and cholera toxin. Yet DOCK8 was not necessary in T cells for this phenotype. Instead, B cell-intrinsic DOCK8 was required for maintenance of antigen-specific IgA-secreting plasma cells (PCs) in the gut lamina propria. Unexpectedly, DOCK8 was not required for early B cell activation, migration, or IgA class switching. An unbiased interactome screen revealed novel protein partners involved in metabolism and apoptosis. <em>Dock8</em>-deficient IgA<sup>+</sup> B cells had impaired cellular respiration and failed to engage glycolysis appropriately. These results demonstrate that maintenance of the IgA<sup>+</sup> PC compartment requires DOCK8 and suggest that gut IgA<sup>+</sup> PCs have unique metabolic requirements for long-term survival in the lamina propria.</p></div>","PeriodicalId":18877,"journal":{"name":"Mucosal Immunology","volume":null,"pages":null},"PeriodicalIF":8.0,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1933021923000971/pdfft?md5=3fc5cbb06a9251e14eb8f2e4c3be6155&pid=1-s2.0-S1933021923000971-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139074612","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}
Pub Date : 2024-06-01DOI: 10.1016/j.mucimm.2023.12.003
Anwari Akhter , Juan I. Moliva , Abul K. Azad , Angélica Olmo-Fontánez , Andreu Garcia-Vilanova , Julia M. Scordo , Mikhail A. Gavrilin , Phillip T. Diaz , Janice J. Endsley , Susan T. Weintraub , Larry S. Schlesinger , Mark D. Wewers , Jordi B. Torrelles
Tuberculosis is the leading cause of death for people living with HIV (PLWH). We hypothesized that altered functions of innate immune components in the human alveolar lining fluid of PLWH (HIV-ALF) drive susceptibility to Mycobacterium tuberculosis (M.tb) infection. Our results indicate a significant increase in oxidation of innate proteins and chemokine levels and significantly lower levels and function of complement components and Th1/Th2/Th17 cytokines in HIV-ALF versus control-ALF (non-HIV-infected people). We further found a deficiency of surfactant protein D (SP-D) and reduced binding of SP-D to M.tb that had been exposed to HIV-ALF. Primary human macrophages infected with M.tb exposed to HIV-ALF were significantly less capable of controlling the infection, which was reversed by SP-D replenishment in HIV-ALF. Thus, based on the limited number of participants in this study, our data suggest that PLWH without antiretroviral therapy (ART) have declining host innate defense function in their lung mucosa, thereby favoring M.tb and potentially other pulmonary infections.
{"title":"HIV infection impairs the host response to Mycobacterium tuberculosis infection by altering surfactant protein D function in the human lung alveolar mucosa","authors":"Anwari Akhter , Juan I. Moliva , Abul K. Azad , Angélica Olmo-Fontánez , Andreu Garcia-Vilanova , Julia M. Scordo , Mikhail A. Gavrilin , Phillip T. Diaz , Janice J. Endsley , Susan T. Weintraub , Larry S. Schlesinger , Mark D. Wewers , Jordi B. Torrelles","doi":"10.1016/j.mucimm.2023.12.003","DOIUrl":"10.1016/j.mucimm.2023.12.003","url":null,"abstract":"<div><p>Tuberculosis is the leading cause of death for people living with HIV (PLWH). We hypothesized that altered functions of innate immune components in the human alveolar lining fluid of PLWH (HIV-ALF) drive susceptibility to <em>Mycobacterium tuberculosis</em> (<em>M.tb</em>) infection. Our results indicate a significant increase in oxidation of innate proteins and chemokine levels and significantly lower levels and function of complement components and Th1/Th2/Th17 cytokines in HIV-ALF versus control-ALF (non-HIV-infected people). We further found a deficiency of surfactant protein D (SP-D) and reduced binding of SP-D to <em>M.tb</em> that had been exposed to HIV-ALF. Primary human macrophages infected with <em>M.tb</em> exposed to HIV-ALF were significantly less capable of controlling the infection, which was reversed by SP-D replenishment in HIV-ALF. Thus, based on the limited number of participants in this study, our data suggest that PLWH without antiretroviral therapy (ART) have declining host innate defense function in their lung mucosa, thereby favoring <em>M.tb</em> and potentially other pulmonary infections.</p></div>","PeriodicalId":18877,"journal":{"name":"Mucosal Immunology","volume":null,"pages":null},"PeriodicalIF":8.0,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1933021923000995/pdfft?md5=5038782cf5b1e5d8d20c0cb80bf79121&pid=1-s2.0-S1933021923000995-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139111099","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}
Pub Date : 2024-06-01DOI: 10.1016/j.mucimm.2024.02.009
Yunxia Xue , Pengyang Xu , Yu Hu , Sijing Liu , Ruyu Yan , Shutong Liu , Yan Li , Jun Liu , Ting Fu , Zhijie Li
Sleep deprivation (SD) has a wide range of adverse health effects. However, the mechanisms by which SD influences corneal pathophysiology and its post-wound healing remain unclear. This study aimed to examine the basic physiological characteristics of the cornea in mice subjected to SD and determine the pathophysiological response to injury after corneal abrasion. Using a multi-platform water environment method as an SD model, we found that SD leads to disturbances of corneal proliferative, sensory, and immune homeostasis as well as excessive inflammatory response and delayed repair after corneal abrasion by inducing hyperactivation of the sympathetic nervous system and hypothalamic-pituitary-adrenal axis. Pathophysiological changes in the cornea mainly occurred through the activation of the IL-17 signaling pathway. Blocking both adrenergic and glucocorticoid synthesis and locally neutralizing IL-17A significantly improved corneal homeostasis and the excessive inflammatory response and delay in wound repair following corneal injury in SD-treated mice. These results indicate that optimal sleep quality is essential for the physiological homeostasis of the cornea and its well-established repair process after injury. Additionally, these observations provide potential therapeutic targets to ameliorate SD-induced delays in corneal wound repair by inhibiting or blocking the activation of the stress system and its associated IL-17 signaling pathway.
{"title":"Stress systems exacerbate the inflammatory response after corneal abrasion in sleep-deprived mice via the IL-17 signaling pathway","authors":"Yunxia Xue , Pengyang Xu , Yu Hu , Sijing Liu , Ruyu Yan , Shutong Liu , Yan Li , Jun Liu , Ting Fu , Zhijie Li","doi":"10.1016/j.mucimm.2024.02.009","DOIUrl":"10.1016/j.mucimm.2024.02.009","url":null,"abstract":"<div><p>Sleep deprivation (SD) has a wide range of adverse health effects. However, the mechanisms by which SD influences corneal pathophysiology and its post-wound healing remain unclear. This study aimed to examine the basic physiological characteristics of the cornea in mice subjected to SD and determine the pathophysiological response to injury after corneal abrasion. Using a multi-platform water environment method as an SD model, we found that SD leads to disturbances of corneal proliferative, sensory, and immune homeostasis as well as excessive inflammatory response and delayed repair after corneal abrasion by inducing hyperactivation of the sympathetic nervous system and hypothalamic-pituitary-adrenal axis. Pathophysiological changes in the cornea mainly occurred through the activation of the IL-17 signaling pathway. Blocking both adrenergic and glucocorticoid synthesis and locally neutralizing IL-17A significantly improved corneal homeostasis and the excessive inflammatory response and delay in wound repair following corneal injury in SD-treated mice. These results indicate that optimal sleep quality is essential for the physiological homeostasis of the cornea and its well-established repair process after injury. Additionally, these observations provide potential therapeutic targets to ameliorate SD-induced delays in corneal wound repair by inhibiting or blocking the activation of the stress system and its associated IL-17 signaling pathway.</p></div>","PeriodicalId":18877,"journal":{"name":"Mucosal Immunology","volume":null,"pages":null},"PeriodicalIF":8.0,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1933021924000187/pdfft?md5=7f86074878fe6227aa9a8ccfc2a8589a&pid=1-s2.0-S1933021924000187-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140013016","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}
Pub Date : 2024-06-01DOI: 10.1016/j.mucimm.2024.03.001
Melanie R. Neeland , Liam Gubbels , Anson Tsz Chun Wong , Hannah Walker , Sarath C. Ranganathan , Shivanthan Shanthikumar
Suppurative lung disease and wheezing are common respiratory diseases of childhood, however, due to poor understanding of underlying pathobiology, there are limited treatment options and disease recurrence is common. We aimed to profile the pulmonary and systemic immune response in children with wheeze and chronic suppurative lung disease for identification of endotypes that can inform improved clinical management. We used clinical microbiology data, highly multiplexed flow cytometry and immunoassays to compare pulmonary [bronchoalveolar lavage (BAL)] and systemic immunity in children with lung disease and controls. Unsupervised analytical approaches were applied to BAL immune data to explore biological endotypes. We identified two endotypes that were analogous in both frequency and immune signature across both respiratory diseases. The hyper-inflammatory endotype had a 12-fold increase in neutrophil infiltration and upregulation of 14 soluble signatures associated with type 2 inflammation and cell recruitment to tissue. The non-inflammatory endotype was not significantly different from controls. We showed these endotypes are measurable in a clinical setting and can be defined by measuring only three immune factors in BAL. We identified hyper-inflammatory and non-inflammatory endotypes common across pediatric wheeze and chronic suppurative lung disease that, if validated in future studies, have the potential to inform clinical management.
化脓性肺病和喘息是儿童时期常见的呼吸系统疾病,但由于对其潜在的病理生物学缺乏了解,治疗方案有限,疾病复发也很常见。我们的目的是分析喘息和 CSLD 儿童的肺部和全身免疫反应,以确定内型,为改善临床管理提供依据。我们利用临床微生物学数据、高度复用流式细胞术和免疫测定来比较肺病患儿和对照组的肺部(支气管肺泡灌洗液(BAL))和全身免疫。我们将无监督分析方法应用于 BAL 免疫数据,以探索生物内型。我们发现了两种内型,它们在两种呼吸系统疾病中的频率和免疫特征都类似。高炎症性内型的中性粒细胞浸润增加了 12 倍,与 2 型炎症和组织细胞募集相关的 14 个可溶性特征上调。非炎症内型与对照组无明显差异。我们的研究表明,这些内型在临床环境中是可以测量的,而且只需测量 BAL 中的三种免疫因子就能确定。我们确定了儿科喘息和 CSLD 中常见的高炎症性和非炎症性内型,如果在未来的研究中得到验证,将有可能为临床管理提供依据。
{"title":"Pulmonary immune profiling reveals common inflammatory endotypes of childhood wheeze and suppurative lung disease","authors":"Melanie R. Neeland , Liam Gubbels , Anson Tsz Chun Wong , Hannah Walker , Sarath C. Ranganathan , Shivanthan Shanthikumar","doi":"10.1016/j.mucimm.2024.03.001","DOIUrl":"10.1016/j.mucimm.2024.03.001","url":null,"abstract":"<div><p>Suppurative lung disease and wheezing are common respiratory diseases of childhood, however, due to poor understanding of underlying pathobiology, there are limited treatment options and disease recurrence is common. We aimed to profile the pulmonary and systemic immune response in children with wheeze and chronic suppurative lung disease for identification of endotypes that can inform improved clinical management. We used clinical microbiology data, highly multiplexed flow cytometry and immunoassays to compare pulmonary [bronchoalveolar lavage (BAL)] and systemic immunity in children with lung disease and controls. Unsupervised analytical approaches were applied to BAL immune data to explore biological endotypes. We identified two endotypes that were analogous in both frequency and immune signature across both respiratory diseases. The hyper-inflammatory endotype had a 12-fold increase in neutrophil infiltration and upregulation of 14 soluble signatures associated with type 2 inflammation and cell recruitment to tissue. The non-inflammatory endotype was not significantly different from controls. We showed these endotypes are measurable in a clinical setting and can be defined by measuring only three immune factors in BAL. We identified hyper-inflammatory and non-inflammatory endotypes common across pediatric wheeze and chronic suppurative lung disease that, if validated in future studies, have the potential to inform clinical management.</p></div>","PeriodicalId":18877,"journal":{"name":"Mucosal Immunology","volume":null,"pages":null},"PeriodicalIF":8.0,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1933021924000205/pdfft?md5=195478082c90fee15472a0be587e30e1&pid=1-s2.0-S1933021924000205-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140140483","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}
Pub Date : 2024-06-01DOI: 10.1016/j.mucimm.2023.12.002
Yue Tang , Xiaoqian Feng , Qing Lu , Chaoqun Cui , Meiping Yu , Zichao Wen , Yingying Luan , Lulu Dong , Ziying Hu , Runyun Zhang , Chunhui Lu , Jie Liu , Reiko Shinkura , Koji Hase , Ji-Yang Wang
Colorectal cancer (CRC) ranks among the top causes of mortality globally. Gut inflammation is one crucial risk factor that augments CRC development since patients suffering from inflammatory bowel disease have an increased incidence of CRC. The role of immunoglobulin (Ig)A in maintaining gut homeostasis and preventing inflammation has been well established. Our earlier work demonstrated that the marginal zone and B1 cell-specific protein (MZB1) promotes gut IgA secretion and its absence results in pronounced dextran sulfate sodium salt (DSS)-induced colitis. In the present study, we explored the role of MZB1 in CRC development using the azoxymethane (AOM)/DSS-induced CRC model. We observed an increase in both the number and size of the tumor nodules in Mzb1−/− mice compared with Mzb1+/+ mice. The increase in CRC development and progression in Mzb1−/− mice was associated with reduced intestinal IgA levels, altered gut flora, and more severe gut and systemic inflammation. Oral administration of the monoclonal IgA, W27, alleviated both the gut inflammation and AOM/DSS-induced CRC. Notably, cohousing Mzb1+/+ and Mzb1−/− mice from the 10th day after birth led to similar CRC development. Our findings underscore the pivotal role of MZB1-mediated IgA secretion in suppressing the onset and progression of CRC triggered by gut inflammation. Moreover, our study highlights the profound impact of microbiota composition, modulated by gut IgA levels, on gut inflammation. Nonetheless, establishing a direct correlation between the severity of colitis and subsequent CRC development and the presence or absence of a particular microbiota is challenging.
结肠直肠癌(CRC)在全球死亡原因中名列前茅。肠道炎症是诱发 CRC 的一个重要风险因素,因为患有炎症性肠病的患者会增加 CRC 的发病率。IgA 在维持肠道平衡和预防炎症方面的作用已得到公认。我们早前的研究表明,边缘区和 B1 细胞特异性蛋白(MZB1)能促进肠道 IgA 分泌,缺失该蛋白会导致明显的右旋糖酐硫酸钠盐(DSS)诱导的结肠炎。在本研究中,我们利用偶氮甲烷(AOM)/DSS诱导的结直肠癌模型探讨了MZB1在结直肠癌发展中的作用。与 Mzb1+/+ 小鼠相比,我们观察到 Mzb1-/- 小鼠肿瘤结节的数量和大小均有所增加。Mzb1-/-小鼠CRC发病和进展的增加与肠道IgA水平降低、肠道菌群改变以及更严重的肠道和全身炎症有关。口服单克隆 IgA W27 可减轻肠道炎症和 AOM/DSS 诱导的 CRC。值得注意的是,Mzb1+/+和Mzb1-/-小鼠从出生后第10天开始同群饲养会导致相似的CRC发展。我们的发现强调了 MZB1 介导的 IgA 分泌在抑制肠道炎症引发的 CRC 的发生和发展中的关键作用。此外,我们的研究还凸显了微生物群组成对肠道炎症的深远影响,而肠道 IgA 水平则可调节微生物群组成。尽管如此,要在结肠炎的严重程度和随后的 CRC 发展与特定微生物群的存在与否之间建立直接的相关性仍具有挑战性。
{"title":"MZB1-mediated IgA secretion suppresses the development and progression of colorectal cancer triggered by gut inflammation","authors":"Yue Tang , Xiaoqian Feng , Qing Lu , Chaoqun Cui , Meiping Yu , Zichao Wen , Yingying Luan , Lulu Dong , Ziying Hu , Runyun Zhang , Chunhui Lu , Jie Liu , Reiko Shinkura , Koji Hase , Ji-Yang Wang","doi":"10.1016/j.mucimm.2023.12.002","DOIUrl":"10.1016/j.mucimm.2023.12.002","url":null,"abstract":"<div><p>Colorectal cancer (CRC) ranks among the top causes of mortality globally. Gut inflammation is one crucial risk factor that augments CRC development since patients suffering from inflammatory bowel disease have an increased incidence of CRC. The role of immunoglobulin (Ig)A in maintaining gut homeostasis and preventing inflammation has been well established. Our earlier work demonstrated that the marginal zone and B1 cell-specific protein (MZB1) promotes gut IgA secretion and its absence results in pronounced dextran sulfate sodium salt (DSS)-induced colitis. In the present study, we explored the role of MZB1 in CRC development using the azoxymethane (AOM)/DSS-induced CRC model. We observed an increase in both the number and size of the tumor nodules in <em>Mzb1<sup>−/−</sup></em> mice compared with <em>Mzb1<sup>+/+</sup></em> mice. The increase in CRC development and progression in <em>Mzb1<sup>−/−</sup></em> mice was associated with reduced intestinal IgA levels, altered gut flora, and more severe gut and systemic inflammation. Oral administration of the monoclonal IgA, W27, alleviated both the gut inflammation and AOM/DSS-induced CRC. Notably, cohousing <em>Mzb1<sup>+/+</sup></em> and <em>Mzb1<sup>−/−</sup></em> mice from the 10th day after birth led to similar CRC development. Our findings underscore the pivotal role of MZB1-mediated IgA secretion in suppressing the onset and progression of CRC triggered by gut inflammation. Moreover, our study highlights the profound impact of microbiota composition, modulated by gut IgA levels, on gut inflammation. Nonetheless, establishing a direct correlation between the severity of colitis and subsequent CRC development and the presence or absence of a particular microbiota is challenging.</p></div>","PeriodicalId":18877,"journal":{"name":"Mucosal Immunology","volume":null,"pages":null},"PeriodicalIF":8.0,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1933021923000983/pdfft?md5=f327a9bb788a4aabc854cec0d5849fba&pid=1-s2.0-S1933021923000983-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138807986","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}
Pub Date : 2024-06-01DOI: 10.1016/j.mucimm.2023.12.004
Taylor Eddens , Olivia B. Parks , Yu Zhang , Michelle L. Manni , Jean-Laurent Casanova , Masato Ogishi , John V. Williams
Respiratory viral infections, including human metapneumovirus (HMPV), remain a leading cause of morbidity and mortality in neonates and infants. However, the mechanisms behind the increased sensitivity to those respiratory viral infections in neonates are poorly understood. Neonates, unlike adults, have several anti-inflammatory mechanisms in the lung, including elevated baseline expression of programmed death ligand 1 (PD-L1), a ligand for the inhibitory receptor programmed cell death protein 1 (PD-1). We thus hypothesized that neonates would rely on PD-1:PD-L1 signaling to restrain antiviral CD8 responses. To test this, we developed a neonatal primary HMPV infection model using wild-type C57BL/6 (B6) and Pdcd1-/- (lacking PD-1) mice. HMPV-infected neonatal mice had increased PD-L1/PD-L2 co-expression on innate immune cells but a similar number of antigen-specific CD8+ T cells and upregulation of PD-1 to that of adult B6 mice. Neonatal CD8+ T cells had reduced interferon‐gamma (IFN-γ), granzyme B, and interleukin-2 production compared with B6 adults. Pdcd1-/- neonatal CD8+ T cells had markedly increased production of IFN-γ and granzyme B compared with B6 neonates. Pdcd1-/- neonates had increased acute pathology with HMPV or influenza. Pdcd1-/- neonates infected with HMPV had long-term changes in pulmonary physiology with evidence of immunopathology and a persistent CD8+ T-cell response with increased granzyme B production. Using single-cell ribonucleic acid sequencing from a child lacking PD-1 signaling, a similar activated CD8+ T-cell signature with increased granzyme B expression was observed. These data indicate that PD-1 signaling critically limits CD8+ T-cell effector functions and prevents immunopathology in response to neonatal respiratory viral infections.
包括人类偏肺病毒(HMPV)在内的呼吸道病毒感染仍然是新生儿和婴儿发病和死亡的主要原因。然而,人们对新生儿对这些呼吸道病毒感染的敏感性增加背后的机制却知之甚少。与成人不同,新生儿的肺部具有多种抗炎机制,包括抑制受体 PD-1 的配体 PD-L1 的基线表达升高。因此,我们假设新生儿会依赖 PD-1:PD-L1 信号来抑制抗病毒 CD8 反应。为了验证这一假设,我们使用 WT C57BL/6 (B6) 和 Pdcd1-/-(缺乏 PD-1)小鼠建立了新生儿原发性 HMPV 感染模型。与成年 B6 小鼠相比,HMPV 感染的新生小鼠先天性免疫细胞上的 PD-L1/PD-L2 共表达增加,但抗原特异性 CD8+ T 细胞的数量和 PD-1 的上调情况相似。与成年 B6 小鼠相比,新生儿 CD8+ T 细胞产生的 IFN-γ、粒酶 B 和 IL-2 减少了。与 B6 新生儿相比,Pdcd1-/-新生 CD8+ T 细胞产生的 IFN-γ 和颗粒酶 B 明显增加。Pdcd1-/-新生儿在感染HMPV或流感后急性病理变化增加。感染了HMPV的Pdcd1-/-新生儿的肺部生理机能会发生长期变化,并伴有免疫病理和CD8+T细胞持续反应的证据,同时颗粒酶B的生成也会增加。通过对缺乏 PD-1 信号的患儿进行单细胞 RNA 测序,观察到了类似的活化 CD8+ T 细胞特征,颗粒酶 B 表达增加。这些数据表明,PD-1 信号传导严重限制了 CD8+ T 细胞效应功能,并防止了新生儿呼吸道病毒感染引起的免疫病理反应。
{"title":"PD-1 signaling in neonates restrains CD8+ T cell function and protects against respiratory viral immunopathology","authors":"Taylor Eddens , Olivia B. Parks , Yu Zhang , Michelle L. Manni , Jean-Laurent Casanova , Masato Ogishi , John V. Williams","doi":"10.1016/j.mucimm.2023.12.004","DOIUrl":"10.1016/j.mucimm.2023.12.004","url":null,"abstract":"<div><p>Respiratory viral infections, including human metapneumovirus (HMPV), remain a leading cause of morbidity and mortality in neonates and infants. However, the mechanisms behind the increased sensitivity to those respiratory viral infections in neonates are poorly understood. Neonates, unlike adults, have several anti-inflammatory mechanisms in the lung, including elevated baseline expression of programmed death ligand 1 (PD-L1), a ligand for the inhibitory receptor programmed cell death protein 1 (PD-1). We thus hypothesized that neonates would rely on PD-1:PD-L1 signaling to restrain antiviral CD8 responses. To test this, we developed a neonatal primary HMPV infection model using wild-type C57BL/6 (B6) and <em>Pdcd1<sup>-/-</sup></em> (lacking PD-1) mice. HMPV-infected neonatal mice had increased PD-L1/PD-L2 co-expression on innate immune cells but a similar number of antigen-specific CD8<sup>+</sup> T cells and upregulation of PD-1 to that of adult B6 mice. Neonatal CD8<sup>+</sup> T cells had reduced interferon‐gamma (IFN-γ), granzyme B, and interleukin-2 production compared with B6 adults. <em>Pdcd1<sup>-/-</sup></em> neonatal CD8<sup>+</sup> T cells had markedly increased production of IFN-γ and granzyme B compared with B6 neonates. <em>Pdcd1<sup>-/-</sup></em> neonates had increased acute pathology with HMPV or influenza. <em>Pdcd1<sup>-/-</sup></em> neonates infected with HMPV had long-term changes in pulmonary physiology with evidence of immunopathology and a persistent CD8<sup>+</sup> T-cell response with increased granzyme B production. Using single-cell ribonucleic acid sequencing from a child lacking PD-1 signaling, a similar activated CD8<sup>+</sup> T-cell signature with increased granzyme B expression was observed. These data indicate that PD-1 signaling critically limits CD8<sup>+</sup> T-cell effector functions and prevents immunopathology in response to neonatal respiratory viral infections.</p></div>","PeriodicalId":18877,"journal":{"name":"Mucosal Immunology","volume":null,"pages":null},"PeriodicalIF":8.0,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1933021923001009/pdfft?md5=168417d5ea6fad75ba7a7b54af14ef00&pid=1-s2.0-S1933021923001009-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139098280","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}