Laboratories

Applied Immunology

Prof. Shinkura
Adjunct Professor
Reiko SHINKURA
Assistant Professor
Keiko NAKANISHI
Labs HP
http://bsw3.naist.jp/shinkura/index-en.html

Outline of Research and Education

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 the 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 the question, ‘How does AID activity specifically target Ig loci?’, using AID mutant protein and mutant knock-in mice, and to understand the precise molecular mechanisms of SHM and CSR.

Recently dysbiosis (gut commensal microbial imbalance) is being 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 focus is on 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 to apply the findings of our basic research to practical medicine.

Major Research Topics

Mechanisms 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 ability to bind specifically against colitogenic bacteria. We are analyzing the bacterial target molecule for W27 to control microbial communities, and will elucidate the reason why IgA selects that target from a physiological point of view. We aim to develop a therapeutic W27 IgA antibody.

Molecular mechanism of SHM

We have found that an 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. By investigating the SHM-specific co-factor, we will elucidate the mechanism by which AID distinguishes SHM from CSR.

Search for IgA CSR inducer

Upon antigen stimulation, B cells can undergo CSR to IgG, IgE or IgA isotypes. However, what induces B cells to each specific isotype is not completely understood. We focus on uncovering a novel IgA CSR inducer, which may drive IgA CSR instead of IgE CSR at the mucosal surface, helping prevent allergies, as well as enhancing mucosal immunity.

References

  1. Okai S. & Usui F. et al., Gut Microbes, 10.1080/19490976, 1310357, 2017
  2. Okai S. et al., Nat. Microbiol., 10.1038/nmicrobiol. 103, 2016
  3. Wei M. et al., Nat. Immunol, 12, 264-270, 2011
  4. Shivarov V. et al., Proc Natl Acad Sci USA, 105, 15866-15871, 2008
  5. Shinkura R. et al., Nat. Immunol, 5, 707-712, 2004
  6. Shinkura R. et al., Nat. Immunol, 4, 435-441, 2003
Two types of intestinal IgA comprises two types: poly-reactive high-affinity IgA and poly-reactive low-affinity IgA. High-affinity IgA is important to control gut lumen microbiota and prevent their invasion.
Fig. 1 Two types of intestinal IgA comprises two types: poly-reactive high-affinity IgA and poly-reactive low-affinity IgA. High-affinity IgA is important to control gut lumen microbiota and prevent their invasion.
Fig. 2 In germinal center (GC) reaction, AID introduces random point mutations in the variable region sequence of Ig genes to diversify its repertoire. As a result, only high-affinity Ig producing B cells are selected in GC.
Fig. 2 In germinal center (GC) reaction, AID introduces random point mutations in the variable region sequence of Ig genes to diversify its repertoire. As a result, only high-affinity Ig producing B cells are selected in GC.
Fig. 3 Selective CSR to IgA can prevent allergic response as well as enhance mucosal defense against a given antigen.
Fig. 3 Selective CSR to IgA can prevent allergic response as well as enhance mucosal defense against a given antigen.
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