All B cells are not the same: a story of CD40 activation

Comment on Gricks et al, page 4002

The Gricks et al article demonstrates the value of well-thought-out use of powerful microarray analysis to advance overall understanding of B-cell biology.

The specific interactions of CD40, a receptor expressed ubiquitously on B cells, and its ligand CD154, which is expressed on activated T cells, have been described for both normal B cells and transformed chronic lymphocytic leukemia (CLL) cells, acute lymphoblastic leukemia (ALL) cells, multiple myeloma (MM) cells, and follicular lymphoma (FL) cells. In general, CD40 ligation activates both normal and transformed B cells, promoting activation of specific survival pathways and antigens that contribute to immune recognition. While specific changes ascribed to CD40 and differences that exist between normal B cells and transformed cells have been described in isolation, no comprehensive comparison has been made to date. With the advent of therapeutic agents that target CD40 both as an antagonist and agonist, it is quite important to understand what differentiates normal versus transformed response to CD40 signaling. In addition, defects present in CD40 signaling in transformed B cells whose activity can be improved may also serve as a target for future therapeutic application.

In this issue of Blood, an important investigation by Gricks and colleagues describes the physiologic consequences of differential changes in global gene expression following CD40 ligation in normal, nontransformed CD19-selected B cells and transformed B cells derived from patients with CLL. As always, the devil is in the detail of the controls used for comparison, and the use of CD19⁺ B cells most representative of memory B cells is supported by other microarrray studies demonstrating CLL is more representative of this compared with CD5⁺ B1 lymphocytes. Encouraging and validating was the observation that activating molecules including major histocompatibility complex (MHC) class I, MHC class II, CD80, and CD86 gene expression increased over time in both normal B cells and transformed CLL cells. More interesting to future investigation was the finding that 215 genes aberrantly were increased in normal B cells relative to CLL cells and 601 uniquely increased in CLL cells relative to normal cells. Selective down-regulation of genes in either normal B cells or CLL cells was observed. Overexpression of genes in CLL versus normal B cells, such as tumor necrosis factor receptor-associated factor 1 (TRAF-1), that disrupt apoptosis in CLL might point to a death pathway that CLL cells are ultimately more dependent upon and therefore amenable to therapeutic targeting. Unlike some early microarray reports that failed to confirm expression analysis by secondary methods, the authors are commended for validating not only good correlation between expression data and quantitative real-time polymerase chain reaction (RT-PCR), but also for select genes at a translation level. Here again the authors identify and elegantly characterize differential CDK1 expression differences over time between CLL cells and normal B cells. At baseline, CLL cells have more of this target protein than normal B cells, but, with activation by CD40, normal B cells have increased expression relative to the transformed cells. Identifying ways to promote differences in expression of ubiquitous targets that cells depend on for survival is important, as it makes it feasible to administer inhibitors at low concentrations to inhibit biologic effects in tumor cells but not normal cells, thereby abrogating toxicity. Here lies the true value of articles such as this, as it provides a well-characterized library of information for future CD40 signaling investigation in normal B cells and CLL cells.