Arase Lab／Division of Host Defense Department of Immunochemistry
We have been studying interactions between pathogens and various paired receptors. In addition, we found that MHC class II molecules function as molecular chaperones to transport misfolded proteins to the cell surface. Analyses of misfolded proteins transported to the cell surface revealed that they are involved in autoimmune diseases by acting as a target for autoantibodies.
Interaction between immune receptors and pathogens
Immune cells express "paired" activating and inhibitory receptors that are highly homologous. The inhibitory receptors recognize self-antigens and downregulate immune response to the self. On the other hand, we found that some inhibitory receptors are used by pathogens for immune evasion (Fig. 1). By contrast, we found that LILRA2, an orphan activating receptor expressed on human myeloid cells, recognizes abnormal immunoglobulins cleaved by microbial proteases but not normal immunoglobulins. Because immunoglobulins are important for host defense, their degradation is very dangerous in terms of immunity (Fig. 2). In this way, paired receptors play an important role not only in immune regulation but also in host defense against pathogens.
Misfolded proteins complexed with MHC class II molecules trigger autoimmune disease
Allelic polymorphisms in MHC class II molecules are strongly associated with susceptibility to many autoimmune diseases. However, it is unclear how MHC class II molecules are involved in autoimmune disease susceptibility. We found that misfolded cellular autoantigens are rescued from protein degradation by MHC class II molecules. Furthermore, we found that misfolded proteins complex with MHC class II molecules and become targets for autoantibodies.
Autoantibody binding to misfolded proteins that are transported to the cell surface by MHC class II molecules correlated strongly with susceptibility to autoimmune disease, suggesting that misfolded proteins, which normally would not be presented to the immune system, can be targets for autoantibodies by acting as “neo self” antigens, which are involved in the pathogenicity of autoimmune diseases (Fig.3).
- Prof. : Hisashi Arase (concur.)
- Associ. Prof. : Masako Kohyama
- Asst. Prof. : Wataru Nakai
- SA Asst. Prof : Jin Hui
- (1) Abrogation of self-tolerance by misfolded self-antigens complexed with MHC class II molecules. Jin et al., Science Advances (2022) 8:eabj9867
(2) An infectivity-enhancing site on the SARS-CoV-2 spike protein targeted by antibodies. Liu et al., Cell (2021) 184:3452-3466
(3) Immune evasion of Plasmodium falciparum by RIFIN via inhibitory receptors. Saito F., et al., Nature (2017) 552:101–105.
(4) LILRA2 is an innate immune sensor for microbially cleaved immunoglobulins. Hirayasu K., et al., Nature Microbiology. (2016) 6:16054. doi: 10.1038/nmicrobiol.2016.54.
(4) Neutrophil infiltration during inflammation is regulated by PILRα via modulation of integrin activation. Wang J., et al., Nature Immunology (2013) 14:34-40.
(6) PILRα is a herpes simplex virus-1 entry co-receptor that associates with glycoprotein B. Satoh T., et al., Cell (2008) 132:935-44.