Regulation of B cell differentiation and antibody production

"Although containing a limited arsenal of immunoglobulin (Ig) genes, B cells express a diverse and flexible Ig repertoire that reacts against virtually all pathogens. In the antigen-independent phase of B cell ontogeny, bone marrow B cell precursors generate antigen recognition diversity by undergoing Ig V(D)J gene recombination, a process that assembles the antigen-binding variable region of an Ig from individual V, D and J gene segments. In the antigen-dependent phase of B cell ontogeny, mature B cells further diversify the Ig repertoire through Ig V(D)J gene somatic hypermutation (SHM) and Ig heavy chain class switch DNA recombination (CSR). SHM increases the antibody affinity for antigen by introducing point mutations within the recombined V(D)J exon, whereas CSR diversifies the Ig effector functions by substituting the primary isotypes, IgM and IgD, with more specialized secondary isotypes, known as IgG, IgA and IgE. Ultimately, hypermutated and class-switched B cells differentiate to long-lived B cells or antibody-secreting plasma cells.

We apply a diverse array of molecular, cellular and histological techniques to address basic questions related to the regulation of human B cell differentiation in health and disease. The prevailing wisdom is that antigen-activated CD4+ T cells expressing CD40 ligand are essential to activate B cells and initiate antibody production. We have recently found that innate immune cells, including dendritic cells, initiate T cell-independent antibody production, including CSR, by activating B cells through BAFF and APRIL. These molecules are induced by pathogen-associated molecular patterns, a large group of microbial molecules with a highly conserved and repetitive structure that activate dendritic cells through innate antigen receptors, including Toll-like receptors. We speculate that BAFF and APRIL are important for the initiation of early antibody responses against fast replicating pathogens, including viruses. The fascinating intricacies of B cell-innate immune cell interaction and the role of Toll-like receptors in "innate" B cell responses are currently under investigation. These studies may lead to the identification of new strategies to boost antibody production in immunocompromised subjects with a T cell insufficiency, including certain cancer patients and HIV-infected individuals.

In addition to playing a key role in the generation of protective antibody responses, BAFF and APRIL are involved in B cell tumors. We recently found that normal B cells aberrantly up-regulate BAFF and APRIL upon infection by EBV, a lymphomagenic herpesvirus. Additional studies show that malignant B cells and non-malignant myeloid cells from patients with non-Hodgkin's lymphomas express increased amounts of BAFF and APRIL. These molecules favor neoplastic B cell accumulation by delivering powerful survival and growth signals through at least three receptors, including TACI, BCMA and BAFF-R. Not only does abnormal BAFF and APRIL expression dysregulate malignant B cell survival, but also triggers unrestrained CSR. The combination of these alterations could lead to the emergence of more aggressive clonal variants. We are currently dissecting the mechanisms by which BAFF and APRIL signal survival and CSR in normal and malignant B cells."