In the B cell biology research group we take advantage of different cellular, histological and molecular techniques to address basic questions related to the regulation of B cell activation and antibody production. B cells are a type of lymphocyte whose main function is to fight infections by producing antibodies.
Our research group is especially interested in the immunoglobulin class switching of the antibody heavy chains, which by this process switch from the Immunoglobulin M isotype (IgM) to IgG, IgA or IgE isotypes.
This process is critical for the diversification of the antibody repertoire and in general is thought to be highly dependent on the activation of B cells by another type of immune system lymphocyte known as CD4+ T cells, via CD40 ligand-CD40 interaction (Cerutti et al, Immunity 1998; Cerutti et al., Nature Immunol. 2001).
Our group had previously identified an evolutionarily primitive pathway that stimulates class switching in B cells independently of CD4+ T cells and CD40 (He et al., Immunity 2007; Xu et al, Nature Immunol. 2007). This pathway involves the activation of B cells by BAFF (B cell-Activation Factor of the TNF Family) and APRIL (A Proliferation-Inducing Ligand) (Litinskiy et al., Nature Immunol. 2002), two innate B cell-stimulating factors structurally and functionally related to CD40 ligand. We found that dendritic cells, macrophages, neutrophils and epithelial cells release BAFF and APRIL upon sensing highly conserved microbial molecular patterns through Toll-like receptors (TLRs) (Cerutti and Rescigno, Immunity 2008). This process ultimately triggers class switching and antibody production as a result of the linking together of BAFF and APRIL with three distinct B cell receptors, known as TACI, BCMA and BAFF-R (Cerutti, Nature Rev. Immunol. 2008). Antibodies produced through this T cell-independent pathway are important for controlling fast replicating pathogens, commensal bacteria and dietary antigens.
We are currently studying the mechanism by which BAFF and APRIL stimulate class switching in systemic and mucosal B cells (He et al., Nature Immunol. 2010). A better understanding of these mechanisms may lead to the identification of novel vaccine strategies to boost vaccine-induced antibody production (Cerutti, Science 2010). Recently, we found that BAFF and APRIL stimulate a non-canonical form of class switching from IgM to IgD in the upper respiratory mucosa (Chen et al., Nature Immunol. 2009). Ongoing efforts are aimed at characterizing the function of IgD antibodies and determining their pathogenic role in autoinflammatory syndromes with periodic fever, such as hyper-IgD syndrome.
We are also studying the role of BAFF and APRIL in various B cell tumors, as well as the fact that HIV and HIV-associated opportunistic agents, such as the EBV virus, dysregulate BAFF and APRIL production (Qiao et al., Nature Immunol. 2006; Xu et al., Nature Immunol. 2009).
Lastly, infections caused by encapsulated bacteria like Haemophilus influenzae, Streptococcus pneumoniae and Neisseria meningitidis are the causes of the high infantile mortality due to the absence of Marginal Zone B cells (MZB) in children. These cells are a specific type of B cells found in the spleen that can generate antibodies against the polysaccharides of encapsulated bacteria. To avoid these infections in children efficient vaccines are required and that is why another of our group’s aims is the characterization of these still highly unknown MZB cells. When characterizing these cells it is essential to determine the role that other cells, such as macrophages, dendritic and endothelial cells can play in expressing BAFF or APRIL and in inducing T-independent responses in MZB cells.