Malignant B Cells from Hairy Cell Leukemia Express an Innate Phenotype and Undergo IgD Class Switching in Response to Innate Environmental Factors, Including BAFF and APRIL.

Hairy cell leukemia (HCL) is a rare chronic lymphoproliferative disorder characterized by massive infiltration of the spleen by malignant B cells displaying a distinctive “hairy” morphology. These hairy cells (HCs) often contain hypermutated Ig genes, suggesting an ontogenetic relationship with post-germinal center memory B cells. However, unlike memory B cells, HCs usually express CD11c and CD103, two molecules typically associated with mucosal innate immune cells. The goal of this study was to elucidate the ontogeny and growth mechanisms of HCs. We found that HCs interacted with splenic endothelial cells expressing B cell-activating factor of the TNF family (BAFF) and a proliferation-inducing ligand (APRIL), two innate B cell-stimulating factors involved in T cell-independent antibody responses, including Ig class switching. In agreement with prior studies indicating that BAFF and APRIL play an important role in B cell tumors, HCs expressed transmembrane activator and calcium modulator and cyclophylin ligand interactor (TACI), B cell maturation antigen (BCMA), and BAFF receptor (BAFF-R), three receptors that bind BAFF and APRIL. In addition, HCs expressed microbial carbohydrate and endocytic receptors usually expressed by innate immune cells, including DEC-205 (CD205), mannose receptor (CD206), langerin (CD207) and dendritic cell-specific ICAM-3-grabbing non-integrin (CD209). This phenotype was different from that of naïve, germinal center, memory and plasmacytoid B cells, but similar to that of a subset of splenic marginal zone and mucosal B cells. Like these innate B cells, HCs contained activation-induced cytidine deaminase, a DNA-editing enzyme required for class switching, and showed signs of ongoing IgM-to-IgD class switching, a mucosal Ig diversifying process typically triggered by BAFF and APRIL. Our findings suggest that HCL may emerge as a result of chronic stimulation of an innate B cell precursor through a T-cell independent pathway involving microbial carbohydrates, BAFF and APRIL.