Recent data to from humans have indicated that mature B-cells are heterogeneous and display characteristic phenotype, morphology, and functions depending upon the site of homing in the peripheral lymphoid tissues (1). In secondary lymphoid organs, B-cells are organized in defined structures, the secondary follicles. However, there also are B-cells that home outside the follicle and are generally referred to as extrafollicular B-cells or other names, depending upon the different lymphoid organs (Fig. 1). The follicles consist of a germinal cen-
From: Methods in Molecular Medicine, Vol. 115: Lymphoma: Methods and Protocols Edited by: T. Illidge and P. W. M. Johnson © Humana Press Inc., Totowa, NJ
ter (GC) and a follicular mantle (FM). B-cells that have been stimulated by T-cell-dependent antigens enter the GC, where they undergo Ig variable (V) gene hypermutation and selection by the stimulating antigen. As a consequence of this process, only B-cells that produce high-affinity antibodies survive and join the memory cell compartment or the long-lived plasma cells pool (2). Somatic hypermutation of Ig VH genes, therefore, appears to be restricted to those B-cells that have passed through GCs and can be considered the hallmark of GC B-cells and descendants (post-GC B-cells ). Some of these memory cells home to the extrafollicular areas. FM B-cells primarily comprise virgin B-cells that express unmutated VH genes. It is conceivable that these cells contribute to the GC B-cell pool after antigenic stimulation, although other B-cell subsets, including extrafollicular B-cells, could migrate into the GC.
The extrafollicular B-cells accumulate in the marginal zone (MZ) of the spleen, in the subepithelial (SE) area of tonsils, in the dome region of the Peyer's patches, in the subcapsular region of lymph nodes, and in the thymic medulla. Also the mucosa associated lymphoid tissue, or MALT, primarily comprises extrafollicular B-cells, and this term is used to indicate the lymphoid tissue that is associated with all the body mucosal linings. Although some of this tissue is normally present at certain sites, such as in Waldeyer's ring, the finding of MALT in certain areas consistently denotes inflammation caused by infection or other events, including autoimmune reactions.
The stomach, for example, normally is devoid of organized lymphoid tissue. This tissue, however, is found in the gastric mucosa that is exposed to chronic infection with Helicobacter pylori (Hp) (4). Likewise, salivary glands do not show accumulation of lymphoid tissue unless they are the targets of an autoimmune injury, as occurs in the Sjogren's syndrome (5). The current trend is to refer to all of these extrafollicular B-cells as MZ or MZ-equivalent B-cells.
The initial studies on MZ B-cells, which were conducted in experimental animals, demonstrated that these cells are heterogeneous and are composed of virgin and memory cells. However, these studies also defined a typical feature of MZ B-cells, that is, their capacity to respond to polysaccharides antigens (generally referred to as Ti-2 Ags as opposed to the lipopolysaccharides Ags, which are referred to as Ti-1 Ags [6,7]). More recently, the advent of a large panel of mAbs and refined cell separation methods has made it possible to purify and characterize such human MZ B-cells.
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