Our department analyzes various immunological aspects in host–pathogen interactions and autoimmune diseases. In particular, we are analyzing receptor pairs that consist of an activating and an inhibitory receptor, and that are expressed on immune cells to test the hypothesis that these paired receptors may have evolved with pathogens. Moreover, since infections are often followed by autoimmune diseases, we are also analyzing how infection abrogates the homeostasis of the immune system.
(1) Immune regulation by paired receptors
Immune cells express cell surface receptor pairs that consist of activating and inhibitory receptors. The inhibitory receptors recognize self-antigens such as MHC class I molecules. We have found that these paired receptors also recognize viral proteins and play an important role in determining host resistance to pathogens (Figure 1). We are presently analyzing the functions of these receptors in immune regulation and host–pathogen interactions by using various pathogens, including viruses, parasites and bacteria.
(2) Entry mechanism of virus into cells
Several viruses that exhibit persistent infection downregulate their host’s immune response by stimulating the host’s inhibitory receptors. We have found that some viruses further exploit the host’s inhibitory receptors to enter the cells. For example, interactions between immune receptors and viral proteins play an important role in membrane fusion during the infection of herpes simplex virus (HSV) and varicella-zoster virus (VZV) (Figure 2). Since other viruses may also use similar receptors to enter cells, we intend to further investigate the molecular mechanisms involved in viral entry of cells.
Figure 1. Paired receptor |
Figure 2. Paired receptor mediated viral infection. |
(3) Mechanism of autoimmune pathogenesis
MHC class II allelic polymorphisms associate with susceptibility to many autoimmune diseases. However, it has been unclear how MHC class II molecules regulate autoimmune disease susceptibility. We found that cellular misfolded autoantigens that are rescued from protein degradation and complex with MHC class II molecules can become targets for autoantibodies in patients with autoimmune diseases. Moreover, autoantibodies recognize misfolded proteins that are complexed with MHC class II molecules of disease-susceptible alleles but not disease-resistant MHC class II alleles. In addition, autoantibody binding to misfolded proteins that are transported by MHC class II molecules correlates strongly with susceptibility to autoimmune disease. This suggests that misfolded proteins complexed with MHC class II molecules are natural autoantigens for autoantibodies. Therefore, misfolded proteins, which normally would not be exposed to the immune system, can become targets for autoantibodies when they avoid protein degradation (Figure 3). Notably, MHC class II molecules are both induced by inflammation during infections and aberrantly expressed in many autoimmune diseased tissues. This suggests that the rescue of misfolded proteins in the context of infection may promote the development of autoimmune diseases. This notion is supported by the fact that autoimmune disease onset is often preceded by an infection. We are further analyzing how aberrant misfolded protein/MHC class II molecule complexes are generated and how they induce autoimmune diseases.
Figure 3. Misfolded proteins complexed with MHC class II molecules are targets for autoantibodies.
Cellular misfolded proteins are transported to the cell surface without processing to peptides by associating with MHC class II molecules at ER (Jiang et al. Int. Immunol. 2013). Furthermore, misfolded proteins complexed with MHC class II molecules of disease-susceptible alleles are specifically recognized by autoantibodies. This suggested that misfolded proteins complexed with MHC class II molecules are natural autoantigens for autoantibodies, which affects autoimmune disease susceptibility (Jin et al. Proc. Natl. Acad. Sci. USA. 2014).