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.
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