Distinguished guests, ladies and gentlemen, it is a great honor for me to receive Eugen und Ilse Seibold prize for my contribution to academic exchange between Japan and Germany.
My connection to Germany started almost thirty years ago in 1988 when I joined the laboratory of Dr. Michael Reth initially in Cologne and later in Freiburg as an Alexander von Humboldt fellow. During my stay in Germany for three years, I got acquainted with many German scientists working in the field of B lymphocyte biology, which is an integral part of immunology. Fortunately, I could continue my research in this field since then, and therefore I have been able to work together with a number of German scientists and keep friendship with them.
I would like to briefly describe my scientific achievements. The immune system in our body attacks pathogens, but not other substances. If the immune system attacks other substances such as food, pollen or components of our body, we develop immunological diseases categorized as allergy and autoimmune diseases. Therefore, the normal immune system must be equipped with the mechanisms that distinguish pathogens from other substances. Now, I would like to introduce the term antigen. Antigen is the substance that is attacked by the immune system. In another word, antigen is the substance to which antibody is produced. Another term I would like to ask you to remember is B lymphocyte. B lymphocyte is the immune cell that produces antibody. When you get infection with the influenza virus for example, B lymphocytes in your body interact with the virus antigens and then produce antibodies that specifically bind to the influenza virus. These specific antibodies inactivate and remove the virus.
Initially, scientists believed that interaction with the antigen activates B lymphocytes and makes them to produce antibodies. However, I demonstrated that interaction with antigens rather kills B lymphocytes. This finding made us to anticipate the mechanism that rescues such B lymphocytes from cell death upon interaction with pathogens, otherwise B lymphocytes cannot produce antibodies to pathogens. We elucidated that the molecule called CD40 plays a role in this mechanism. CD40 is located on the surface of B lymphocytes and collects information from other immune cells whether the antigens are derived from pathogens or not. If antigens are from pathogens, CD40 rescues B lymphocytes from cell death induced by the antigens, and allows them to produce antibodies. If antigens are not from pathogens, CD40 does not rescue B lymphocytes from cell death. As a consequence, antibodies are not produced. Therefore, CD40 is a molecular switch, which turns on antibody production when B lymphocytes interact with pathogens, thereby allowing antibody production to pathogens but not other antigens. This switch function of CD40 contribute to the maintenance of normal immune system in which antibodies are produced to pathogens but not other antigens, Our findings were later reproduced by other scientists, and then the crucial role of CD40 in antibody production was established.
Antibody was first discovered in Germany by the German-Japanese collaboration more than 120 years ago. The German scientist Emil von Boehring and the Japanese scientist Shibasaburo Kitasato discovered antibody, and then applied their finding to the development of serum therapy, which saved lives of millions of patients with diphtheria and other diseases. After Kitasato came back to Japan, he founded several institutions for medical research and education. It was documented that he often said to younger scientists “It is not enough to do science alone, to make use of the outcome the research for the society must be pursued”
After CD40 was shown to play a crucial role in the immune system by us and also many others, a couple of pharmaceutical companies did a clinical trial of the therapy to block CD40 in patients with systemic lupus erythematosus, which is the prototype systemic autoimmune disease. I was not involved in this trial, but was able to continuously obtain the information on this trial from a Japanese pharmaceutical company. Initially trial was successful because the activity of the disease was strongly suppressed. However, undesired adverse effects appeared in patients, and the trial was suspended. It is a pity that our findings have not been translated to clinics. However, a recent study showed a hopeful result suggesting that the adverse effect of CD40 blocking therapy can be overcome by modification of the drug.
I already talked about immune responses to influenza virus, and the autoimmune disease called systemic lupus erythematosus. In both of these examples, nucleic acids including DNA and RNA play an important role. As you know DNA encodes a blueprint of life regardless of microbes or human. Immune cells possess various sensors for nucleic acids, which sense DNA and RNA derived from virus and other microbes, and then activate immune cells. However, these nucleic acid sensors sense self nucleic acids as well though weakly. Because of the immune activation by self nucleic acids, the patients with lupus produce autoantibodies to nucleic acids, which trigger development of the disease.
Some years ago, American scientists Ann Rothstein and Mark Schlomchik discovered that some of the nucleic acid sensors possess the activity of a molecular switch similar to CD40. Nucleic acid sensors sense self nucleic acids, and then turn on B cells to produce autoantibodies to nucleic acids. This is a very important finding that contributes our understandings of the mechanisms how autoantibodies to nucleic acids are produced in lupus patients. However, if self nucleic acids stimulate nucleic acid sensors and cause autoantibody production, how does healthy immune system avoid autoantibody production? We recently obtained the answer to this question. We discovered the presence of the inhibitory molecule that senses self-nuclei acids but not microbial nucleic acids, and then cancels the effect of activating nucleic acid sensors. This nucleic acid sensor is a molecular switch that turns off antibody production to self nucleic acids but not to microbes, and protect healthy individuals from autoimmunity without inhibiting immune responses to microbes. If we generate a drug that augments the switch off function of this molecule, we may be able to treat lupus patients without perturbing defense against microbes.
In 2005, I received Phillip Franz von Siebeld Prize from the federal president in Germany. Since then, I had more communications with the head quoter of the Alxander von Humboldt foundation than before. Probably you might know that the number of Alexander von Humboldt fellows from Japan has been reduced dramatically in the last 30 years. There was a rumor that the foundation changed the policy in such a way that they no longer support Japanese but support the emerging countries like China more. However, I leaned this was not true by talking with the people at AvH foundation. The reason was simply the reduction of the young Japanese scientists who apply for research stay in Germany. Probably, this is also the case for those supported by other fellowships. The Humboldt allumuni in Japan took this situation seriously and started the projects a few years ago to encourage young Japanese scientists and doctoral students to do research stay in Germany. I am leading a team to provide information in science in Germany and research stay in Germany, and also to organize information sessions where those who are interested in research stay in Germany can meet those who just came back Japan from research stay in Germany. Each time we have around 100 participants to the information session. We have many feedbacks where the participants said yes to the question whether they have changed their view on research stay in Germany by attending the information session. Many of them said after the session they feel it is achievable for them. I hope research stay in Germany becomes reality for all these young people. International collaboration is a strong promoter of advancement of science already at the era of Kitasato and Boehling, and those who know the people and culture on the other sides will do international collaboration most effectively.
Thank you very much for your kind attention.