Mucosal Macrophages and Tertiary Lymphoid Structures in IBD

IBD 中的粘膜巨噬细胞和三级淋巴结构

• 批准号: 10605344
• 负责人: Milena Bogunovic
• 金额: $ 54.7万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-16 至 2026-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10605344
• 关键词: Affect; Anti-Tumor Necrosis Factor Therapy; Antigen Presentation; Antigen-Presenting Cells; Automobile Driving; B-Cell Activation; Biological Products; Cells; Chronic; Clinical; Colitis; Colon; Communication; Crohn' s disease; Cytokine Network Pathway; Data; Dendritic Cells; Development; Epithelial Cells; Genetic; Genetic Transcription; Goals; Heterogeneity; Human; Immune; Immune response; Immunity; Immunoglobulin A; Immunoglobulin G; Incidence; Infectious colitis; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Interleukin-10; Interleukin-4; Intestinal Mucosa; Intestines; Lesion; Lymphoid; Macrophage; Mediator; Modeling; Mononuclear; Mucous Membrane; Mus; Outcome; Pathogenesis; Pathogenicity; Pathologic; Patients; Phagocytes; Play; Prevalence; Production; Publishing; Regulation; Resistance; Role; Salmonella; Signal Transduction; Stromal Cells; Structure; T cell differentiation; T-Lymphocyte; TNF gene; Testing; Time; Transgenic Mice; Tumor Necrosis Factor Receptor; Ulcerative Colitis; dimensional analysis; insight; mouse model; murine colitis; novel; pathobiont; pathogen; potential biomarker; prevent; response; salmonella colitis; spatiotemporal; tertiary lymphoid organ; therapeutic target

The incidence and prevalence of inflammatory bowel disease (IBD), which includes Crohn’s disease (CD) and ulcerative colitis (UC), are increasing worldwide, and the treatment options for IBD are still limited for a large number of patients despite the development of targeted biologics. A mechanistic model of pathogenic communication among immune, stromal and epithelial cells controlled by elaborate cytokine networks that underlies pathogenesis of inflammatory bowel disease (IBD) has been proposed. The next critical step is to establish the spatiotemporal organization of this abnormal immune response. Tertiary lymphoid structures (TLS) are ectopic disorganized lymphoid aggregates found around intestinal inflammatory lesions in patients with CD and UC, possibly in response to persisting pathobionts that breach intestinal mucosa. TLS are recognized as a pathologic hallmark in IBD, however, their precise cellular composition and mechanistic contribution to intestinal immunity and pathogenesis of IBD are largely unknown. The overall goal of this proposal is to unravel the mechanisms that drive TLS formation and elucidate their function in mouse models of colitis relevant to IBD Mononuclear phagocytes (MNPs) that comprise dendritic cell (DC) and macrophage (M) subsets are an important constituent of TLS. In a model of Salmonella colitis, we identified a subset of mucosa-resident (CX3CR1hi) Ms that functions as an antigen-presenting cell driving TLS formation and a Salmonella-specific T cell-dependent IgA response in TLS. We found that TLS play a protective role in Salmonella colitis by restricting systemic pathogen dissemination, but under conditions of chronic inflammation observed in IBD, TLS are likely to acquire a proinflammatory role. Such conversion of TLS function may occur via promotion of TLS-associated pathogenic T cell differentiation and proinflammatory IgG instead of IgA responses as suggested by recent single cell transcriptional analyses of human IBD. Our overall hypothesis is that a key step in the pathogenesis of IBD is dysregulation of CX3CR1hi Ms, and that such dysregulated Ms promote IBD by driving the development of pathogenic TLS that produce T-cell dependent IgG instead of IgA. We will test our hypothesis in three specific aims. Aim 1 will determine the role of antigen-presentation and B cell activation by CX3CR1hi Ms in the development of pathogenic TLS; and Aim 2 will establish the role of TNF signaling in CX3CR1hi Ms in the regulation of TLS function. If successful, the study will provide novel insight into the pathogenesis of IBD and identify potential biomarkers and therapeutic targets (e.g., CX3CR1hi M-derived mediators) associated with TLS in IBD.

炎症性肠病(IBD)包括克罗恩病(CD)和溃疡性结肠炎(UC)，其发病率和流行率在全球范围内呈上升趋势，尽管有靶向生物制剂的开发，但IBD的治疗选择对大量患者来说仍然有限。炎症性肠病(IBD)的发病机制是由复杂的细胞因子网络控制的免疫细胞、间质细胞和上皮细胞之间的致病通讯机制。下一个关键步骤是建立这种异常免疫反应的时空组织。第三级淋巴结构(TLS)是CD和UC患者肠道炎性病变周围发现的异位无序淋巴集合体，可能是对持续存在的破坏肠粘膜的病原体的反应。TLS被认为是IBD的病理标志，但其确切的细胞组成及其在肠道免疫和IBD发病机制中的作用尚不清楚。该方案的总体目标是揭示TLS形成的机制，并阐明其在与IBD相关的结肠炎小鼠模型中的功能。单核巨噬细胞(MNPs)包括树突状细胞(DC)和巨噬细胞(M)亚群，是TLS的重要组成部分。在沙门氏菌结肠炎模型中，我们确定了粘膜驻留(CX3CR1hi)ms的一个子集，其功能是作为抗原提呈细胞驱动TLS的形成和TLS中沙门氏菌特异性T细胞依赖的IgA反应。我们发现TLS通过抑制全身病原体的传播而在沙门氏菌结肠炎中起到保护作用，但在IBD观察到的慢性炎症条件下，TLS可能获得促炎作用。这种TLS功能的转换可能是通过促进TLS相关的致病T细胞分化和促炎免疫球蛋白，而不是最近对人IBD的单细胞转录分析所提示的IgA反应来实现的。我们的总体假设是，IBD发病机制中的一个关键步骤是MS中CX3CR1的失调，这种失调的Ms通过推动病理性TLS的发展而促进IBD的发展，TLS产生T细胞依赖的IgG而不是IgA。我们将在三个具体目标上检验我们的假设。目的1研究CX3CR1hms的抗原提呈和B细胞活化在TLS发病过程中的作用；Aim 2研究CX3CR1hms中的肿瘤坏死因子信号在调节TLS功能中的作用。如果成功，这项研究将为IBD的发病机制提供新的见解，并确定与IBD中TLS相关的潜在生物标志物和治疗靶点(例如，CX3CR1和M衍生介质)。