Journal of immunology最新文献_第3页

Calcitriol Impairs the Secretion of IL-4 and IL-13 in Th2 Cells via Modulating the VDR-Gata3-Gfi1 Axis. 骨化三醇通过调节 VDR-Gata3-Gfi1 轴影响 Th2 细胞分泌 IL-4 和 IL-13

IF 3.6 3区医学

Journal of immunology Pub Date : 2024-09-15 DOI: 10.4049/jimmunol.2400078

Biswajit Biswas, Shagnik Chattopadhyay, Sayantee Hazra, Ritobrata Goswami

{"title":"Calcitriol Impairs the Secretion of IL-4 and IL-13 in Th2 Cells via Modulating the VDR-Gata3-Gfi1 Axis.","authors":"Biswajit Biswas, Shagnik Chattopadhyay, Sayantee Hazra, Ritobrata Goswami","doi":"10.4049/jimmunol.2400078","DOIUrl":"10.4049/jimmunol.2400078","url":null,"abstract":"Calcitriol, the bioactive form of vitamin D, exerts its biological functions by binding to its cognate receptor, the vitamin D receptor (VDR). The indicators of the severity of allergies and asthma have been linked to low vitamin D levels. However, the role of calcitriol in regulating IL-4 and IL-13, two cytokines pivotal to allergic inflammation, remained unclear. Our study observed diminished IL-4 and IL-13 secretion in murine and human Th2 cells treated with calcitriol. In murine Th2 cells, Gata3 expression was attenuated by calcitriol. However, the expression of the transcriptional repressor Gfi1, too, was attenuated in the presence of calcitriol. Ectopic expression of either Gfi1 or VDR impaired the secretion of IL-13 in Th2 cells. In murine Th2 cells, VDR interacted with Gata3 but not Gfi1. Gfi1 significantly impaired Il13 promoter activation, which calcitriol failed to restore. Conversely, calcitriol augmented Gfi1 recruitment to the Il13 promoter. Ecr, a conserved region between these two genes, which enhanced the transactivation of Il4 and Il13 promoters, is essential for calcitriol-mediated suppression of both the genes. Calcitriol augmented the recruitment of VDR to the Il13 promoter and Ecr regions. Gata3 recruitment was significantly impaired at the Il13 and Ecr loci in the presence of calcitriol but increased at the Il4 promoter. Furthermore, the recruitment of the histone deacetylase HDAC1 was universally increased at the promoters of Il4, Il13, and Ecr when calcitriol was present. Together, our data clearly elucidate that calcitriol modulates VDR, Gata3, and Gfi1 to suppress IL-4 and IL-13 production in Th2 cells.","PeriodicalId":16045,"journal":{"name":"Journal of immunology","volume":null,"pages":null},"PeriodicalIF":3.6,"publicationDate":"2024-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141855722","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Activin A Promotes Differentiation of a Pathogenic Multicytokine IL-9-secreting CD4+ T Cell Population. 活化素 A 促进分泌多种致病因子 IL-9 的 CD4+ T 细胞群的分化

IF 3.6 3区医学

Journal of immunology Pub Date : 2024-09-15 DOI: 10.4049/jimmunol.2300635

Benjamin J Ulrich, Wenwu Zhang, Blake T Kenworthy, Rakshin Kharwadkar, Matthew R Olson, Mark H Kaplan

{"title":"Activin A Promotes Differentiation of a Pathogenic Multicytokine IL-9-secreting CD4+ T Cell Population.","authors":"Benjamin J Ulrich, Wenwu Zhang, Blake T Kenworthy, Rakshin Kharwadkar, Matthew R Olson, Mark H Kaplan","doi":"10.4049/jimmunol.2300635","DOIUrl":"10.4049/jimmunol.2300635","url":null,"abstract":"The development of Th subsets results from cellular and cytokine cues that are present in the inflammatory environment. The developing T cell integrates multiple signals from the environment that sculpt the cytokine-producing capacity of the effector T cell. Importantly, T cells can discriminate similar cytokine signals to generate distinct outcomes, and that discrimination is critical in Th subset development. IL-9-secreting Th9 cells regulate multiple immune responses, including immunity to pathogens and tumors, allergic inflammation, and autoimmunity. In combination with IL-4, TGF-β or activin A promotes IL-9 production; yet, it is not clear if both TGF-β family members generate Th9 cells with identical phenotype and function. We observed that in contrast to TGF-β that efficiently represses Th2 cytokines in murine Th9 cultures, differentiation with activin A produced a multicytokine T cell phenotype with secretion of IL-4, IL-5, IL-13, and IL-10 in addition to IL-9. Moreover, multicytokine secreting cells are more effective at promoting allergic inflammation. These observations suggest that although TGF-β and IL-4 were identified as cytokines that stimulate optimal IL-9 production, they might not be the only cytokines that generate optimal function from IL-9-producing T cells in immunity and disease.","PeriodicalId":16045,"journal":{"name":"Journal of immunology","volume":null,"pages":null},"PeriodicalIF":3.6,"publicationDate":"2024-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11371476/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141759145","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Mitochondrial DNA Programs Lactylation of cGAS to Induce IFN Responses in Patients with Systemic Lupus Erythematosus. 线粒体 DNA 对 cGAS 进行乳化编程，诱导系统性红斑狼疮患者产生 IFN 反应。

IF 3.6 3区医学

Journal of immunology Pub Date : 2024-09-15 DOI: 10.4049/jimmunol.2300758

Juan Zhang, Huiyan Ji, Mengdi Liu, Ming Zheng, Zhenke Wen, Haili Shen

{"title":"Mitochondrial DNA Programs Lactylation of cGAS to Induce IFN Responses in Patients with Systemic Lupus Erythematosus.","authors":"Juan Zhang, Huiyan Ji, Mengdi Liu, Ming Zheng, Zhenke Wen, Haili Shen","doi":"10.4049/jimmunol.2300758","DOIUrl":"10.4049/jimmunol.2300758","url":null,"abstract":"Mitochondrial DNA (mtDNA) is frequently released from mitochondria, activating cGAS-STING signaling and inducing type I IFNs (IFN-Is) in systemic lupus erythematosus (SLE). Meanwhile, whether and how the glycolytic pathway was involved in such IFN-I responses in human SLE remain unclear. In this study, we found that monocytes from SLE patients exerted robust IFN-I generation and elevated level of cytosolic mtDNA. Transfection of mtDNA into THP-1 macrophages was efficient in inducing IFN-I responses, together with the strong glycolytic pathway that promoted lactate production, mimicking the SLE phenotype. Blockade of lactate generation abrogated such IFN-I responses and, vice versa, exogenous lactate enhanced the IFN-I generation. Mechanistically, lactate promoted the lactylation of cGAS, which inhibited its binding to E3 ubiquitination ligase MARCHF5, blocking cGAS degradation and leading to strong IFN-I responses. In accordance, targeting lactate generation alleviated disease development in humanized SLE chimeras. Collectively, cytosolic mtDNA drives metabolic adaption toward the glycolytic pathway, promoting lactylation of cGAS for licensing IFN-I responses in human SLE and thereby assigning the glycolytic pathway as a promising therapeutic target for SLE.","PeriodicalId":16045,"journal":{"name":"Journal of immunology","volume":null,"pages":null},"PeriodicalIF":3.6,"publicationDate":"2024-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141875011","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Vaccination with O-linked Mannans Protects against Systemic Candidiasis through Innate Lymphocyte Populations. 接种 O 链甘露聚糖疫苗可通过先天性淋巴细胞群预防全身性念珠菌病

IF 3.6 3区医学

Journal of immunology Pub Date : 2024-09-15 DOI: 10.4049/jimmunol.2400065

Cleison Ledesma Taira, Lucas Dos Santos Dias, Sarah Lichtenberger, Alexander J Whitehead, Brenda Kischkel, Mihai G Netea, Bruce S Klein, Marcel Wüthrich

{"title":"Vaccination with O-linked Mannans Protects against Systemic Candidiasis through Innate Lymphocyte Populations.","authors":"Cleison Ledesma Taira, Lucas Dos Santos Dias, Sarah Lichtenberger, Alexander J Whitehead, Brenda Kischkel, Mihai G Netea, Bruce S Klein, Marcel Wüthrich","doi":"10.4049/jimmunol.2400065","DOIUrl":"10.4049/jimmunol.2400065","url":null,"abstract":"Candida spp. are the fourth leading cause of bloodstream infections in hospitalized patients and the most common cause of invasive fungal infection. No vaccine against Candida spp. or other fungal pathogens of humans is available. We recently discovered the Blastomyces Dectin-2 ligand endoglucanase 2 that harbors antigenic and adjuvant functions and can function as a protective vaccine against that fungus. We also reported that the adjuvant activity, which is mediated by O-mannans decorating the C terminus of Blastomyces Dectin-2 ligand endoglucanase 2, can augment peptide Ag-induced vaccine immunity against heterologous agents, including Cryptococcus, Candida, and influenza. In this article, we report that the O-linked mannans alone, in the absence of any antigenic peptide, can also protect against systemic candidiasis, reducing kidney fungal load and increasing survival in a Dectin-2-dependent manner. We found that this long-term glycan-induced protection is mediated by innate lymphocyte populations including TCR-γδ+ T cells, innate lymphoid cells, and NK cells that subsequently activate and release reactive oxygen species from neutrophils and monocytes. Our findings suggest that Blastomyces O-mannan displayed by Eng2 induces a form of protective trained immunity mediated by innate lymphocyte populations.","PeriodicalId":16045,"journal":{"name":"Journal of immunology","volume":null,"pages":null},"PeriodicalIF":3.6,"publicationDate":"2024-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11426167/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141897621","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Cloning and Functional Characterization of Novel Human Neutralizing Anti-IFN-α and Anti-IFN-β Antibodies. 新型人中和性抗 IFN-α 和抗 IFN-β 抗体的克隆与功能特征。

IF 3.6 3区医学

Journal of immunology Pub Date : 2024-09-15 DOI: 10.4049/jimmunol.2400265

Emmanouil Papasavvas, Lily Lu, Matthew Fair, Isabela Oliva, Joel Cassel, Sonali Majumdar, Karam Mounzer, Jay R Kostman, Pablo Tebas, Amit Bar-Or, Kar Muthumani, Luis J Montaner

引用次数: 0

CPT2-mediated Fatty Acid Oxidation Is Dispensable for Humoral Immunity. CPT2介导的脂肪酸氧化对体液免疫是不可或缺的

IF 3.6 3区医学

Journal of immunology Pub Date : 2024-09-11 DOI: 10.4049/jimmunol.2400285

Meilu Li, Xian Zhou, Yanfeng Li, Xingxing Zhu, Yuzhen Li, Taro Hitosugi, Hu Zeng

引用次数: 0

Anti-Heat Shock Protein 70 Autoantibodies from Patients with Idiopathic Pulmonary Fibrosis Epigenetically Enhance Lung Fibroblast Apoptosis Resistance and Bcl-2 Expression. 特发性肺纤维化患者的抗热休克蛋白70自身抗体从表观遗传学角度增强了肺成纤维细胞的凋亡抵抗力和Bcl-2表达。

IF 3.6 3区医学

Journal of immunology Pub Date : 2024-09-09 DOI: 10.4049/jimmunol.2400106

Baiyun Zhong, Jennifer Q Zhou, Xing Lyu, Hui Liu, Kayu Yuan, Ming-Lei Guo, Steven R Duncan, Yan Y Sanders

{"title":"Anti-Heat Shock Protein 70 Autoantibodies from Patients with Idiopathic Pulmonary Fibrosis Epigenetically Enhance Lung Fibroblast Apoptosis Resistance and Bcl-2 Expression.","authors":"Baiyun Zhong, Jennifer Q Zhou, Xing Lyu, Hui Liu, Kayu Yuan, Ming-Lei Guo, Steven R Duncan, Yan Y Sanders","doi":"10.4049/jimmunol.2400106","DOIUrl":"https://doi.org/10.4049/jimmunol.2400106","url":null,"abstract":"IgG autoantibodies to heat shock protein 70 (HSP70) are found in many immune-mediated clinical syndromes, and their presence among patients with idiopathic pulmonary fibrosis (IPF) portends especially poor outcomes. However, pathological effects of IPF anti-HSP70 have not been studied extensively. IPF lung fibroblasts are apoptosis resistant, and this dysregulation contributes to the accumulation of fibroblasts that characterizes the disease. During stress, HSP70 protein is exported extracellularly, where it binds to cognate cell surface receptors that mediate a variety of functional effects, including apoptosis inhibition. We hypothesized anti-HSP70 could engage HSP70-receptor complexes on fibroblasts that alter their apoptosis susceptibility. We found HSP70 is ubiquitously expressed on primary human lung fibroblasts. Treatment with anti-HSP70 isolated from patients with IPF with acute exacerbations increased Bcl-2 expression in human lung fibroblasts and reduced their susceptibility to staurosporine-induced apoptosis. Chromatin immunoprecipitation assays showed Bcl-2 gene promoter regions are enriched with the active histone mark H4 lysine 16 acetylation, and this was increased in the autoantibody-treated fibroblasts. When H4 lysine 16 acetylation was decreased by knocking down its acetyltransferase, MOF (males absent on the first), the anti-HSP70 treatments failed to upregulate Bcl-2. This study describes a heretofore unknown, to our knowledge, pathogenic consequence of autoimmunity in which autoantibodies affect the epigenetic regulation of fibroblast apoptosis. In addition to IPF, this autoimmune process could also have relevance in other immunological syndromes characterized by anti-HSP70 autoimmunity. These findings lend credence to the importance of autoimmunity in IPF and illustrate pathways that could be targeted in innovative therapies for this morbid, medically refractory lung disease.","PeriodicalId":16045,"journal":{"name":"Journal of immunology","volume":null,"pages":null},"PeriodicalIF":3.6,"publicationDate":"2024-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142154346","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Orientation Regulation of Class-switch Recombination in Human B Cells. 人类 B 细胞中类开关重组的方向调控

IF 3.6 3区医学

Journal of immunology Pub Date : 2024-09-09 DOI: 10.4049/jimmunol.2300842

Likun Du, Valentyn Oksenych, Hui Wan, Xiaofei Ye, Junchao Dong, Adam Yongxin Ye, Hassan Abolhassani, Stelios Vlachiotis, Xuefei Zhang, Kathrin de la Rosa, Lennart Hammarström, Mirjam van der Burg, Frederick W Alt, Qiang Pan-Hammarström

{"title":"Orientation Regulation of Class-switch Recombination in Human B Cells.","authors":"Likun Du, Valentyn Oksenych, Hui Wan, Xiaofei Ye, Junchao Dong, Adam Yongxin Ye, Hassan Abolhassani, Stelios Vlachiotis, Xuefei Zhang, Kathrin de la Rosa, Lennart Hammarström, Mirjam van der Burg, Frederick W Alt, Qiang Pan-Hammarström","doi":"10.4049/jimmunol.2300842","DOIUrl":"https://doi.org/10.4049/jimmunol.2300842","url":null,"abstract":"We developed a linear amplification-mediated high-throughput genome-wide translocation sequencing method to profile Ig class-switch recombination (CSR) in human B cells in an unbiased and quantitative manner. This enables us to characterize CSR junctions resulting from either deletional recombination or inversion for each Ig class/subclass. Our data showed that more than 90% of CSR junctions detected in peripheral blood in healthy control subjects were due to deletional recombination. We further identified two major CSR junction signatures/patterns in human B cells. Signature 1 consists of recombination junctions resulting from both IgG and IgA switching, with a dominance of Sµ-Sγ junctions (72%) and deletional recombination (87%). Signature 2 is contributed mainly by Sµ-Sα junctions (96%), and these junctions were almost all due to deletional recombination (99%) and were characterized by longer microhomologies. CSR junctions identified in healthy individuals can be assigned to both signatures but with a dominance of signature 1, whereas almost all CSR junctions found in patients with defects in DNA-PKcs or Artemis, two classical nonhomologous end joining (c-NHEJ) factors, align with signature 2. Thus, signature 1 may represent c-NHEJ activity during CSR, whereas signature 2 is associated with microhomology-mediated alternative end joining in the absence of the studied c-NHEJ factors. Our findings suggest that in human B cells, the efficiency of the c-NHEJ machinery and the features of switch regions are crucial for the regulation of CSR orientation. Finally, our high-throughput method can also be applied to study the mechanism of rare types of recombination, such as switching to IgD and locus suicide switching.","PeriodicalId":16045,"journal":{"name":"Journal of immunology","volume":null,"pages":null},"PeriodicalIF":3.6,"publicationDate":"2024-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142154347","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Sequence Matters: Primary COVID-19 Vaccination after Infection Elicits Similar Anti-spike Antibody Levels, but Stronger Antibody Dependent Cell-mediated Cytotoxicity than Breakthrough Infection. 序列很重要：与突破性感染相比，感染后接种初级 COVID-19 疫苗可产生相似的抗尖峰抗体水平，但抗体依赖性细胞介导的细胞毒性更强。

IF 3.6 3区医学

Journal of immunology Pub Date : 2024-09-09 DOI: 10.4049/jimmunol.2400250

Kayla A Holder, Danielle P Ings, Kathleen E Fifield, David A Barnes, Keeley A Barnable, Debbie O A Harnum, Rodney S Russell, Michael D Grant

{"title":"Sequence Matters: Primary COVID-19 Vaccination after Infection Elicits Similar Anti-spike Antibody Levels, but Stronger Antibody Dependent Cell-mediated Cytotoxicity than Breakthrough Infection.","authors":"Kayla A Holder, Danielle P Ings, Kathleen E Fifield, David A Barnes, Keeley A Barnable, Debbie O A Harnum, Rodney S Russell, Michael D Grant","doi":"10.4049/jimmunol.2400250","DOIUrl":"https://doi.org/10.4049/jimmunol.2400250","url":null,"abstract":"Infection before primary vaccination (herein termed \"hybrid immunity\") engenders robust humoral immunity and broad Ab-dependent cell-mediated cytotoxicity (ADCC) across SARS-CoV-2 variants. We measured and compared plasma IgG and IgA against Wuhan-Hu-1 and Omicron (B.1.1.529) full-length spike (FLS) and receptor binding domain after three mRNA vaccines encoding Wuhan-Hu-1 spike (S) and after Omicron breakthrough infection. We also measured IgG binding to Wuhan-Hu-1 and Omicron S1, Wuhan-Hu-1 S2 and Wuhan-Hu-1 and Omicron cell-based S. We compared ADCC using human embryonic lung fibroblast (MRC-5) cells expressing Wuhan-Hu-1 or Omicron S. The effect of Omicron breakthrough infection on IgG anti-Wuhan-Hu-1 and Omicron FLS avidity was also considered. Despite Omicron breakthrough infection increasing IgG and IgA against FLS and receptor binding domain to levels similar to those seen with hybrid immunity, there was no boost to ADCC. Preferential recognition of Wuhan-Hu-1 persisted following Omicron breakthrough infection, which increased IgG avidity against Wuhan-Hu-1 FLS. Despite similar total anti-FLS IgG levels following breakthrough infection, 4-fold higher plasma concentrations were required to elicit ADCC comparable to that elicited by hybrid immunity. The greater capacity for hybrid immunity to elicit ADCC was associated with a differential IgG reactivity pattern against S1, S2, and linear determinants throughout FLS. Immunity against SARS-CoV-2 following Omicron breakthrough infection manifests significantly less ADCC capacity than hybrid immunity. Thus, the sequence of antigenic exposure by infection versus vaccination and other factors such as severity of infection affect antiviral functions of humoral immunity in the absence of overt quantitative differences in the humoral response.","PeriodicalId":16045,"journal":{"name":"Journal of immunology","volume":null,"pages":null},"PeriodicalIF":3.6,"publicationDate":"2024-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142154348","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Structure of a Human Monoclonal Antibody in Complex with Outer Surface Protein C of the Lyme Disease Spirochete, Borreliella burgdorferi. 人类单克隆抗体与莱姆病螺旋体鲍雷利菌外表面蛋白 C 复合物的结构。

IF 3.6 3区医学

Journal of immunology Pub Date : 2024-09-06 DOI: 10.4049/jimmunol.2400247

Michael J Rudolph, Yang Chen, Clint Vorauer, David J Vance, Carol Lyn Piazza, Graham G Willsey, Kathleen McCarthy, Beatrice Muriuki, Lisa A Cavacini, Miklos Guttman, Nicholas J Mantis

{"title":"Structure of a Human Monoclonal Antibody in Complex with Outer Surface Protein C of the Lyme Disease Spirochete, Borreliella burgdorferi.","authors":"Michael J Rudolph, Yang Chen, Clint Vorauer, David J Vance, Carol Lyn Piazza, Graham G Willsey, Kathleen McCarthy, Beatrice Muriuki, Lisa A Cavacini, Miklos Guttman, Nicholas J Mantis","doi":"10.4049/jimmunol.2400247","DOIUrl":"10.4049/jimmunol.2400247","url":null,"abstract":"Lyme disease is a tick-borne, multisystem infection caused by the spirochete Borreliella burgdorferi. Although Abs have been implicated in the resolution of Lyme disease, the specific B cell epitopes targeted during human infections remain largely unknown. In this study, we characterized and defined the structural epitope of a patient-derived bactericidal monoclonal IgG (B11) against outer surface protein C (OspC), a homodimeric lipoprotein necessary for B. burgdorferi tick-mediated transmission and early-stage colonization of vertebrate hosts. High-resolution epitope mapping was accomplished through hydrogen deuterium exchange-mass spectrometry and X-ray crystallography. Structural analysis of B11 Fab-OspCA complexes revealed the B11 Fabs associated in a 1:1 stoichiometry with the lateral faces of OspCA homodimers such that the Abs are essentially positioned perpendicular to the spirochete's outer surface. B11's primary contacts reside within the membrane-proximal regions of α-helices 1 and 6 and adjacent loops 5 and 6 in one OspCA monomer. In addition, B11 spans the OspCA dimer interface, engaging opposing α-helix 1', α-helix 2', and loop 2-3' in the second OspCA monomer. The B11-OspCA structure is reminiscent of the recently solved mouse transmission blocking monoclonal IgG B5 in complex with OspCA, indicating a mode of engagement with OspC that is conserved across species. In conclusion, we provide a detailed insight into the interaction between a functional human Ab and an immunodominant Lyme disease Ag long considered an important vaccine candidate.","PeriodicalId":16045,"journal":{"name":"Journal of immunology","volume":null,"pages":null},"PeriodicalIF":3.6,"publicationDate":"2024-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142140268","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0