Role of B Cells in Synovial Inflammation & LN Remodeling in RA Arthritis

B 细胞在滑膜炎症中的作用

• 批准号: 8380633
• 负责人: Edward M. Schwarz
• 金额: $ 38.89万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8380633
• 关键词: Address; Affect; Animals; Arthritis; B-Lymphocyte Subsets; B-Lymphocytes; Biological Response Modifier Therapy; CXCL13 gene; Cell Count; Cells; Chemotaxis; Clinical; Discontinuous Capillary; Disease; Equilibrium; Etiology; Event; Evolution; Flare; Flow Cytometry; Health; Histology; Image; Inflammation; Inflammation Mediators; Inflammatory; Invaded; Joints; Knee; Knee joint; Lead; Lymphatic; Magnetic Resonance Imaging; Mediating; Modeling; Mouse Strains; Nodal; Obstruction; Outcome Measure; Pathway interactions; Patients; Phase; Phenotype; Population; Production; Recovery; Recruitment Activity; Rheumatoid Arthritis; Role; Series; Signal Transduction; Sinus; Staging; Structure; Surface; Synovitis; TNF gene; Testing; Transgenic Mice; Transgenic Organisms; Treatment Efficacy; arthropathies; base; cytokine; density; improved; in vivo; joint destruction; lymph flow; lymph nodes; migration; novel; rituximab; success; treatment response

The efficacy of TNF antagonists and B cell depletion therapy (BCDT) in rheumatoid arthritis (RA) have fundamentally altered pathophysiologic paradigms and raised new quesfions about disease mechanisms. The observation that both TNF and B cells are of central importance provides a strong impetus to improve our understanding ofthe relationship between TNF over-production and infiammation pathways mediated by B cells, particulady in regards to disease flares and inadequate treatment response. The TNF-transgenic (TNF-tg) mouse strain is the only chronically progressive model for RA with a clinically proven etiology, and thus invaluable to address the cellular and immunological events in RA. We have developed a series of novel small animal imaging approaches, including contrast enhanced (CE) MRI, in vivo micro-CT and nearinfrared indocyanin green (NIR-ICG) analysis of lymphatic flow, to study longitudinally the events associated with progression of joint arthritis. The results from these studies, combined with histology and flow cytometry, showed dramatic changes unfolding in a predictable temporal sequence in the draining popliteal lymph-node (PLN) before and duhng the onset of knee disease. Pnor to knee synovitis, the draining PLNs "expand", as evidenced by increased volume and CE values (i.e. lower density), and histology of the node shows markedly dilated, enlarged sinusoids. This nodal expansion is also characterized by increased PLN B cell numbers, primanly due to accumulation of a B cell subset with a unique surface phenotype ("B-in" cells). This phase is followed by a rapid decrease in node size and CE, by invasion and "plugging" ofthe lymphatic sinuses by B cells, and reduced lymphatic flow through the node. The onset of knee synovitis and focal erosions follows PLN collapse. Both BCDT and anti-CXCL13 treatment result in TNF-tg disease ameliorafion and recovery of PLN size, CE and histology, pointing to a pathogenetic role of both B cells and chemotaxis. Thus, we hypothesize that evolution of knee arthritis and PLN function in TNF-tg mice proceed from an early stage during which pathogenetic B cells are recruited to and accumulate in the draining nodes, which increase in size and CE. At a later stage PLN-intrinsic or external (e.g. from the joint) signals induce migration ofthe expanded B cell population to the sinusoidal spaces, resulting in the obstruction of lymph flow and changes in the local cytokine balance. This leads to accumulation of pro-inflammatory mediators in the knee joint, triggering the "flare". Here we propose to test this model by: 1) identifying the mechanisms that lead to B cell accumulation in the PLNs and their subsequent migration to lymphatic spaces; 2) demonstrating the pathogenetic role of adoptively transfered PLN B cells, and testing the hypothesis that BCDT efficacy is associated with clearance of sinusoid-invading B cells; 3) testing whether TNF-tg B cells can exert pro-inflammatory effector functions; and d) investigating the applicability of these finding to RA patients in a pilot clinical tnal in which PLN structure and lymphatic function wil be assessed before and after BCDT, and correlated with clinical svmptoms.

TNF拮抗剂和B细胞耗竭治疗（BCDT）在类风湿关节炎（RA）中的功效具有 从根本上改变了病理生理范例，并提出了有关疾病机制的新问题。 TNF和B细胞都至关重要的观察结果为改进提供了强大的动力 我们对TNF生产过量与侵害途径之间的关系的理解 B细胞，特别是疾病耀斑和治疗反应不足的细胞。 TNF转基因 （TNF-TG）小鼠应变是具有临床证明的病因的RA的唯一长期渐进的模型，因此可解决RA中的细胞和免疫学事件。我们已经开发了一系列新型的小动物成像方法，包括对比度增强（CE）MRI，体内微CT和近红外墨蛋白绿色（NIR-ICG）淋巴流的分析，以纵向研究与关节炎进展相关的事件。这些研究的结果以及组织学和流式细胞术结合了，在排水popliteal淋巴结（PLN）中，在可预测的时间序列中发生了巨大变化，并在膝盖疾病的发作之前发生了巨大的变化。 PNOR到膝盖滑膜炎，排水PLN“扩展”，这是由增加的体积和CE值（即较低的密度）所证明的，节点的组织学表现出明显扩张，肿大的正弦曲线。该淋巴结膨胀的特征是PLN B细胞增加 数字，由于具有独特的表面表型（“ b-in”细胞）的B细胞子集的积累。此阶段之后是通过B细胞对淋巴鼻窦的浸润和“堵塞”淋巴鼻窦的迅速降低，并减少了通过淋巴结的淋巴流动。膝关节炎和局灶性侵蚀的发作是PLN塌陷。 BCDT和抗CXCL13治疗都会导致TNF-TG疾病的Ameliorafion以及PLN大小，CE和组织学的恢复，表明B细胞和趋化性的致病作用。因此，我们假设TNF-TG小鼠的膝关节炎和PLN功能的演变从早期阶段开始，在此阶段将致病性B细胞募集到排水淋巴结中，从而增加了大小和CE。在以后的阶段，PLN intrinsic或外部（例如，来自关节的信号）诱导B细胞种群迁移到正弦空间，从而导致淋巴流量阻塞和局部细胞因子平衡的变化。这导致膝关节中促炎性介体的积累，从而触发“耀斑”。在这里，我们建议通过：1）确定导致B细胞在PLN中积累的机制及其随后迁移到淋巴空间的机制； 2）证明了采用转移的PLN B细胞的致病作用，并检验了BCDT疗效与清除正弦曲线的B细胞有关的假设； 3）测试TNF-TG B细胞是否可以发挥促炎作用子功能； d）研究这些发现对RA患者的适用性，在BCDT之前和之后，将评估PLN结构和淋巴功能，并与临床SVM受体相关。