Monday, October 17, 2011

CD38 and the BCR

Clones with higher numbers of CD38+ cells are generally those more responsive to BCR signaling in vitro, whereas CD38− clones are generally anergic, although exceptions exist. The same phenomena are observed at the intraclonal level as CD38+ cells respond more readily to BCR stimulation than CD38− cells of the same clone. However, evidence for involvement of CD38 in the BCR signaling pathway is indirect and linked to lateral associations with CD19 and CD81 (in turn part of the BCR complex) and colocalization in the same lipid rafts as the BCR.

The most favorable conditions for expansion of CLL clones exist in discrete anatomic sites, such as Proliferation Centers (PC) in Lymph Nodes (LN) and in the Bone Marrow, where leukemic cells come into contact with accessory cells and the appropriate array of cytokines and chemokines. These sites contain more CD38+ CLL cells than detected in the blood, implying that CD38 is involved in the expansion process and/or results from it.

These findings may indicate that a trafficking fraction of CLL cells may enter PCs of peripheral LNs, become activated, and express (more) CD38 as well as ZAP-70 and other activation markers. Additional stimulatory signals may also be delivered directly via CD38. The degree of activation would influence a cell's capacity to up-regulate the number of markers per cell and the percentage of positive cells. On re-entry into the peripheral circulation, CLL cells may express more activation markers (CD38, ZAP-70, CD49d, and others), thereby representing important predictors of disease outcome. Besides the BCR, CD38+ cells also respond better to signals coming through chemokine and other receptors (eg Toll-like receptors). Therefore, signals emanating initially and subsequently from this pathway probably provide molecular bridges to the extended CLL microenvironment, thereby favoring survival/proliferation of CLL cells.

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