Figure 4.

Possible origin of WM precursors from IgM⁺ memory cells. Of human splenic and peripheral blood B cells, ~70% are CD27⁻ and ~30% are CD27⁺. The CD27⁻ cells comprise a mixed population that contains both naive IgM⁺ B cells that express germ line IgV genes and IgG⁺/IgA⁺ memory B cells that harbor mutated IgV genes (not shown). Naive B cells have not yet participated in an immune response and not yet modified their expressed IgV genes using the somatic hypermutation (SHM) pathway. In contrast, memory B cells are immunologically experienced and have engaged the SHM machinery to increase the affinity of the expressed IgV gene to the underlying antigen. The CD27⁺ compartment is composed equally of “switched” IgM⁻ B cells and “unswitched” IgM⁺IgD⁺ B cells. The former have performed H chain class switch recombination (CSR) and, thereby, replaced their μH with γ/α/εH chains, while the latter have not. The great majority of CD27⁺IgM⁺ cells coexpress IgD (IgM⁺IgD⁺)—a compartment that is often referred to as “natural effector” memory. CD27⁺IgM⁺IgD⁻ B cells, sometimes called “IgM-only” cells for short, only represent a minor population (1%) in peripheral blood and spleen. Both CD27⁺IgM⁺IgD⁺ and CD27⁺IgM⁺IgD⁻ memory B cells may be precursors of WM, although the weight of the evidence seems to favor the IgM⁺IgD⁺ compartment as the stronger candidate. This compartment likely constitutes a mixture of marginal zone (MZ)-, B1- and germinal-center- (GC-) derived B cells. The CD27⁺IgM⁺IgD⁻ compartment is better defined as it originates from a single source: the primary GC response, which often selects for mutated IGKV3-20 alleles.