CD38: what is it there for?

Terry J. Hamblin

CD38 is very much a molecule of the moment. Since it has been mentioned in well over 1000 articles in the past 5 years, we are entitled to ask, “What is it there for?” It is a type II transmembrane glycoprotein, the extracellular domain acting as an ectoenzyme, catalyzing the conversion of nicotinamide adenine dinucleotide (NAD+) into nicotinamide, adenosine diphosphate–ribose (ADPR), and cyclic ADPR. CD38 is expressed on many types of cells, but recent interest focuses on its role on B lymphocytes. Its expression during B-cell ontogeny is tightly regulated: it appears on bone marrow precursor cells but is lost on mature lymphocytes; on germinal center cells it protects against apoptosis, but on leaving the germinal center, memory cells lack the antigen; on terminally differentiated plasma cells it is one of the few surface antigens present. In chronic lymphocytic leukemia (CLL), expression of CD38 signifies a poor prognosis, though it does not correlate precisely with the presence of unmutated immunoglobulin variable region (IgV) genes and may vary during the course of the disease.1


Is it more than a prognostic marker? Deaglio and colleagues (page 2146) suggest that CD38 is involved in signaling through the B-cell receptor (BCR). Unfortunately, even CD38+ CLL cells express the molecule at such low density that few cells show detectable signals on ligation by antibody. However, when the expression of CD38 was upregulated by exposing the cells to interleukin 2 (IL-2), incubation with anti-CD38 antibodies mediated a signal that could be detected by Ca++ flux. Because CD38 patches on the surface also contained the GM1 ganglio-side and CD81 with significant lateral associations with the immunoglobulin accessory molecules CD79a and CD79b and with CD19, they have suggested that CD38 forms part of the positive receptor complex on the cell membrane.

Does this paper advance our understanding of the nature of CLL? Some of the characteristics of the CLL cell such as CD5 and CD23 positivity and its resistance to apoptosis in vivo seem to be intrinsic to its nature, whereas other characteristics vary between benign and aggressive disease. Whether or not there are somatic mutations of the IgV genes seems to be hardwired in CLL and seems to predetermine the likelihood that subsequent adverse events will occur. The upregulation of CD38 and its incorporation into lipid rafts may be one of these adverse events. Its function there may be to enhance signals transduced by the BCR with consequent increased proliferation and risk of genetic error.2