Study Group 1
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Study Group 1
■Understanding autoimmune bullous diseases and developing their treatment
Team leader: Chiharu Tateishi
At present, our major theme is to identify the pathogenesis of autoimmune bullous diseases, especially bullous pemphigoid and mucous membrane pemphigoid. We are also conducting research on epidermolysis bullosa, which is caused by genetic abnormalities that affect the molecules involved in autoimmune bullous diseases. These diseases occur when molecules that make up the structures known as “hemidesmosomes” and “focal contacts” are destroyed by autoantibodies, or when they either are not produced or have structural abnormalities due to genetic mutations. It was previously suggested that usually, when hemidesmosomes are affected, focal contacts compensate for their loss, and vice versa. However, the interaction between these structures remained unknown. Our group firstly conducted research designed to reveal this interaction, and the results have been published (Tsuruta et al., FASEB J 2002; Tsuruta et al., Cell Motil Cytoskel 2003; Tsuruta et al., J Cell Sci 2003; Tsuruta et al., J Biol Chem 2003; Ozawa et al., J Invest Dermatol 2010; Tsuruta et al., J Dermatol Sci). The methods used in these studies involved transfecting epidermal keratinocytes with GFP-tagged hemidesmosome protein molecules and focal contact protein molecules, and then looking at the dynamics of these molecules in the presence and absence of patients’ autoantibodies using live cell imaging.
We then conducted research to help us understand the pathogenesis of bullous pemphigoid. It had previously been suggested that bullous pemphigoid occurs by the following mechanism: after autoantibodies bind to the molecule called type XVII collagen/BP180, activation of complement and neutrophil migration follow, and finally breakdown by proteolytic enzymes such as elastase occurs. However, we revealed that prior to this process autoantibodies induce type XVII collagen/BP180 internalization in cells, via a mechanism called macropinocytosis, resulting in decreased adhesive strength of the cells, and blistering occurs when proteolytic enzymes work in areas where the adhesive strength is weakened (Hiroyasu et al. [Tsuruta; Correspondence] Am J Pathol 2013).
These results suggest that the development of agents that inhibit macropinocytosis may be helpful in future treatment of pemphigoid.
I make it a rule to conduct “research that is transparent and comprehensible to everyone.” Certainly, topics such as immunoblotting and identification of gene abnormalities are easily understood by researchers. However, they may be rather more difficult for non-specialists. When I conduct research, my motto is, “Be clear”.
In recent years, more and more people have set the goal of just becoming a clinician. Of course, as dermatologists we must pay attention to clinical practice. However, in order to understand skin diseases, which are on the “macroscopic” level, I believe that one needs to develop an in-depth perspective by going down one step to the “microscopic” level. If understanding of diseases at the individual and histopathological level is essential for dermatologists in clinical practice, only physicians who have had experience of study at the cytochemical, electron-microscopic, or molecular level can truly understand the patients. For this reason, I recommend that physicians conduct a thorough study at the microscopic level at least once while they are young and have an abundance of energy.
Diseases we want to understand using live cell imaging
Picture of Hemidesmosome disease
Hemidesmosome disease
Umekoji, Tsuruta (Correspondence) et al., J Dermatol 2010

 Picture of Focal contact disease; Kindler syndrome
Focal contact disease; Kindler syndrome
Figure
Tsuruta et al., Curr Med Chem 2008