GERMINAL CENTER ADHESION OF NORMAL/NEOPLASTIC B CELLS

人B细胞在三维空间内定位和分化， 淋巴生发中心（GC）的结构。 的结构和 GC的细胞组成反映了其功能，即抗原 驱动B细胞增殖和分化，并产生B 细胞记忆体 GC提供了一个微环境，其中活化的B 细胞与其他细胞包括T细胞和 B淋巴细胞、巨噬细胞和GC特有的细胞-- 滤泡树突状细胞（FDC）。 在这个微环境中， 已知的细胞粘附机制和功能性 这些互动的后果。 具体来说，粘附受体 已被证明在监管的核心作用， 免疫反应 我们最近开发了一种冷冻切片GC绑定 自然再现人类之间的细胞相互作用的测定 体内B细胞和GC组分。 使用该分析， 配体对（VLA-4：VCAM-1）被鉴定为参与结合 正常和肿瘤性B细胞转化为GC内的FDC。 这些研究 这表明，尽管VLA 4参与结合，但无论是定性的还是定量的， VLA-4或其他结构的变化是必要的，以解释 活化的B细胞与GC的结合。 本提案的目的 是检测正常和肿瘤性B细胞的粘附相互作用 与GC的组成部分。 具体目标是：1）检查 B细胞活化对VLA-4介导的与GC的粘附的作用; 2） 确定VLA 4是否参与B细胞功能的调节;和 3)鉴定参与B细胞-GC结合的其他结构。 这些 研究将可能确定介导细胞-细胞 GC内部的互动。 更重要的是，这些功能 B细胞上的粘附受体将被广泛研究， 深入了解B细胞分化的调节， 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。 滤泡性淋巴瘤是形态和表型肿瘤 正常生发中心B细胞的对应物。 这些肿瘤重演了 正常GC和肿瘤性B细胞的结构采用 VLA-4：VCAM-1作为恶性细胞定位的一种机制。 以来 实际上所有这些肿瘤在诊断时都广泛扩散， 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， 与此同时，考虑对增长和传播的监管， 滤泡NHL，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.