GERMINAL CENTER ADHESION OF NORMAL/NEOPLASTIC B CELLS

人类B细胞在三维空间内定位和分化 淋巴生发中心(GC)的结构。结构和 GC的细胞组成反映了它的功能，即抗原 驱动B细胞的增殖和分化，以及B细胞的产生 细胞记忆。GC提供了一个激活B的微环境 细胞与其他细胞物理关联并相互作用，包括T和 B淋巴细胞、巨噬细胞和一种GC特有的细胞-- 滤泡树突状细胞(FDC)。在这个微环境中，几乎没有 了解细胞黏附的机制和功能 这些相互作用的后果。具体地说，黏附受体 已被证明在监管 免疫反应。我们最近开发了一种冰冻切片GC结合 一种自然复制人与人之间的细胞相互作用的方法 活体中的B细胞和GC组分。使用这种检测方法，一种受体 配基对(VLA-4：VCAM-1)被确定参与结合 正常和肿瘤B细胞向GC内的FDCs转化。这些研究 提示虽然VLA4参与了结合，但无论是定性的 VLA-4或其他结构的变化是解释 激活的B细胞与GC的结合。这项提议的目的是 是研究正常和肿瘤B细胞之间的黏附相互作用 使用GC的组件。具体目标是：1)审查 作用B细胞激活VLA-4介导的与GC的黏附；2) 确定VLA4是否参与B细胞功能的调节；以及 3)鉴定参与B细胞-GC结合的其他结构。这些 研究可能会确定调节细胞-细胞的结构 GC内部的交互作用。更重要的是，这些功能 将对B细胞上的黏附受体进行广泛研究，并可能提供 洞察B细胞分化的调节发生在 GC.这些研究不仅对理解 正常的B细胞生物学，但可能会提供一个基础 了解滤泡性非霍奇金淋巴瘤(NHL)的生物学。 滤泡性淋巴瘤是一种形态和表型相同的肿瘤。 正常生发中心B细胞的对应物。这些肿瘤可重复出现 正常GC和肿瘤B细胞的构筑采用 VLA-4：VCAM-1作为恶性细胞定位的一种机制。自.以来 事实上，所有这些肿瘤在确诊时都会广泛传播， 对正常和肿瘤GC微环境的研究应该提供一个 了解临床表现和病程的基础 这种疾病。此外，这些研究可能提供新的方法。 以此来考虑对病毒的增长和传播的监管 滤泡性非霍奇金淋巴瘤，从而提出新的治疗方法。

Human B cells localize and differentiate within the three dimensional architecture of lymphoid germinal centers (GC). The structural and cellular composition of the GC reflects its function, which is antigen driven B-cell proliferation and differentiation, and the generation of B cell memory. The GC provides a microenvironment in which activated B cells physically associate and interact with other cells including T and B lymphocytes, macrophages, and a cell which is unique to the GC--the follicular dendritic cell (FDC). Within this microenvironment, little is known about the mechanisms of cellular adhesion and the functional consequences of these interactions. Specifically, adhesion receptors have been demonstrated to play a central role in the regulation of the immune response. We have recently developed a frozen section GC binding assay which naturally reproduces the cellular interactions between human B cells and components of GCs in vivo. Using this assay, a receptor ligand pair (VLA-4:VCAM-1) was identified to be involved in the binding of normal and neoplastic B cells to FDCs within the GC. These studies suggested that although VLA4 is involved in binding, either qualitative changes in VLA-4 or additional structures are necessary to explain the binding of activated B cells to the GC. The objective of this proposal is to examine the adhesive interactions of normal and neoplastic B cells with the components of the GC. The specific aims are: 1) To examine the role B cell activation on VLA-4 mediated adhesion to the GC; 2) To determine if VLA4 is involved in the regulation of B cell function; and 3) To identify other structures involved in B cell-GC binding. These studies will likely identify the structures which mediate cell-cell interactions within the GC. More importantly, the function of these adhesion receptors on B cells will be extensively studied and may provide insight into the regulation of B cell differentiation which occurs in the GC. These studies will not only be important in the understanding of normal B cell biology but will likely provide a foundation upon which to understand the biology of follicular non-Hodgkins lymphomas (NHL). Follicular lymphomas are the morphologic and phenotypic neoplastic counterparts of normal germinal center B cells. These tumor recapitulate the architecture of the normal GC and the neoplastic B cells employ VLA-4:VCAM-1 as one mechanism of malignant cell localization. Since virtually all of these tumors are widely disseminated at diagnosis, studies of normal and neoplastic GC microenvironments should provide a foundation upon which to understand the clinical presentation and course of this disease. Moreover, these studies may provide novel approaches with which to consider the regulation of the growth and dissemination of follicular NHLs and thereby suggesting new therapeutic approaches.