The immune response has evolved to protect us from pathogenic infectious agents and toxic foreign substances. In acquired immune response, antigen stimulation of B cells induces two distinct genetic alterations in the immunoglobulin (Ig) loci: somatic hypermutation (SHM) and class switch recombination (CSR), both of which require an enzyme, activation-induced cytidine deaminase (AID). After these processes, among diversified Ig repertoire, selected high-affinity Igs efficiently defend host. AID plays a crucial role in host defense but it introduces DNA cleavage into Ig loci and aberrantly into non-Ig loci causing lymphoma. Our aim is to answer ‘how AID’s activity targets Ig loci specifically’ using AID mutant protein and mutant knock-in mice and to understand the precise molecular mechanism of SHM and CSR.
Recently dysbiosis (gut commensal microbial imbalance) is frequently reported to be associated with illnesses such as inflammatory bowel disease (IBD), obesity, cancer, etc. We found that the high-affinity intestinal IgA produced by SHM is important to control non-pathogenic gut bacteria as well as pathogens. Our main question is how intestinal IgA recognizes and targets a huge variety of gut bacteria. We have isolated a useful monoclonal IgA to modulate gut microbiota leading to symbiosis (balanced host-microbial relationship in gut).
We aim at applying the findings of our basic research to practical medicine.
Major Research Topics
- Mechanism of gut microbial regulation by intestinal IgA
We generated hybridomas from IgA producing cells in small intestine of wild type mice. We selected W27 monoclonal IgA as a best gut microbial modulator because of its strong binding ability specifically against colitogenic bacteria. We are analyzing the bacterial target molecule for W27 to control microbial community, and will elucidate the reason why IgA selects that target in the point of physiological view. We aim at the development of therapeutic W27 IgA antibody.
- Molecular mechanism of SHM
We have found that a N-terminal mutant AID (G23S; glycine to serine mutation at the 23rd AA) showed defective SHM but relatively intact CSR both in vitro and in vivo, suggesting the N-terminus of AID may be the domain responsible for SHM-specific co-factor binding. Through the search of SHM-specific co-factor, we will understand how AID distinguishes SHM from CSR.
- Search for IgA CSR inducer
Upon antigen stimulation B cells can undergo CSR to IgG, IgE or IgA isotype. However, what induces B cells to each isotype specifically is not completely understood. We focus on searching a novel IgA CSR inducer, which may drive IgA CSR instead of IgE CSR at mucosal surface, helping prevent allergy, as well as enhance the mucosal immunity.