論文 / 著書情報
Article / Book Information
題目(和文)

末梢における免疫細胞の生存制御機構の解明に向けたB細胞の非線形的刺激応答の解析

Title(English)
著者(和文)

安田翔也

Author(English)

Shoya Yasuda

出典(和文)

学位:博士(理学),学位授与機関:東京工業大学,
報告番号:甲第11032号,
授与年月日:2019年3月26日,
学位の種別:課程博士,
審査員:山村 雅幸,秋山 泰,小長谷 明彦,青西 亨,瀧ノ上 正浩

Citation(English)

Degree:Doctor (Science),Conferring organization: Tokyo Institute of Technology,
Report number:甲第11032号,
Conferred date:2019/3/26,
Degree Type:Course doctor,
Examiner:,,,,

学位種別(和文)

博士論文

Category(English)

Doctoral Thesis

種別(和文)

論文要旨

Type(English)

Summary

Powered by T2R2 (Tokyo Institute Research Repository)

（博士課程）Doctoral Program論 文 要 旨ＴＨＥＳＩＳ ＳＵＭＭＡＲＹ

専攻：
Department of知能システム科学

学生氏名：
Student’s Name

安田翔也

専攻

申請学位（専攻分野）： 博士
Academic Degree Requested

指導教員（主）：Academic Supervisor(main)

Doctor of（理学）山村雅幸

指導教員（副）：Academic Supervisor(sub)要旨（英文 800 語程度）
Thesis Summary （approx.800 English Words ）B cells express an enormously diversified antigen receptors (BCR) capable of recognizing various foreign antigens (Ag).
Such diversified BCR may also react with self Ag. Immunological tolerance functions to prevent the appearance or activationof potentially self-reactive B cells. Breakdown of immune tolerance can lead to severe immune disorders such as rheumatoid
arthritis and type I diabetes. It is now clear that the B cell central tolerance is achieved by self Ag-mediated apoptosis ofself-reactive immature B cells in the bone marrow. However, it remains elusive how self-reactive mature B cells in the spleenor lymph node are inactivated.
As a clue to elucidate peripheral immune tolerance, we focused on the following two unexplained phenomena. One is that
B cells exhibit a nonlinear survival response against antigenic stimulation. In general, B cells are more activated dependingon Ag doses. However, it is also known that B cells will not respond until Ag stimulation reaches certain strength. Besides,
the current study has revealed that B cells tend to die at very low doses of Ag stimulation. Therefore, even with the same Ag
stimulation, as the Ag dose increases, B cells change their responses from death to non-responsiveness and then to increased
survival. Such distinct responses to different doses of Ag stimulation are likely related to B cell peripheral tolerance but themechanism remains unknown.
The other phenomenon is that BCR change from IgM highIgD- to IgMlowIgDhigh during B cell maturation. Some functional
differences between IgM and IgD have been noted. However, the function of one of them can be compensated for by theother so it is unclear why both are needed for B cells. Studies thus far indicate that IgD responds poorly to Ag stimulationsuggesting that B cells become less sensitive as they mature and express higher levels of IgD. The increased IgD expressionis also likely related to peripheral B cell tolerance but again the mechanism is unclear.
There are several reasons that prevent detailed investigation of these phenomena. The tonic signal, which has been shownby genetic studies to support B cell survival in the periphery, is very weak and difficult to be detected by conventional
experiments. B cell lines, which are derived from B lymphomas and can survive indefinitely, are obviously not suitable forthe current study and therefore purified primary B cells are used. To overcome these difficulties and to obtain key
suggestions for future experiments, we decided to take a mathematical/computational approach.
In this study, we first constructed a mathematical model taking into consideration of B cell signaling pathway and binding
reaction between BCR and the Ag (in this case F(ab’)2-anti-IgM antibodies as pseudo Ag). Next, we analyzed the above two
phenomena through computer simulations. As a result, we confirmed the existence of a threshold for B cell survival upon Ag
stimulation. Interestingly, this threshold was found to depend not on the amount, but the density, of Ag-bound BCR. In
addition, by shifting to the IgMlowIgDhigh type B cells decrease their responsiveness to Ag stimulation as a safety guard toprevent unwanted activation while maintaining the tonic signal required for their survival. These findings provide a new andreasonable principle for understanding the mechanism of immune tolerance that is critical for preventing autoimmune
diseases.
Based on these results, we proposed several practical experiments that might lead to additional discovery in peripheral
tolerance. One is to examine the relationship between B cell survival and the amount and density of antigen-bound BCR. In
this experiment, the density of antigen-bound BCR may have a greater influence on survival than the amount ofantigen-bound BCR. The second is an experiment to investigate the relationship between BCR expression level anddifferentiation. In our insight, the ability to differentiate into memory B cells or antibody-secreting plasma cells may bedetermined by the BCR expression level. Finally, we proposed to investigate the relationship between the ratio of IgM/IgDand B cell activation in individual cells. Cells with higher IgD level may be more difficult to be activated. These new ideas
have been raised based on the results of our mathematical modeling, and have been overlooked from the perspective ofexperimental immunology.

We hope that our suggested experiments will lead to further understanding of the mechanism of immune tolerance andprovide additional clue for treating autoimmune diseases. Moreover, we expect that our approach on B cells will also beapplicable to other immune cells such as T cells.

備考 : 論文要旨は、和文 2000 字と英文 300 語を 1 部ずつ提出するか、もしくは英文 800 語を 1 部提出してください。
Note : Thesis Summary should be submitted in either a copy of 2000 Japanese Characters and 300 Words (Engｌish) or 1copy of 800
Words (English).
注意：論文要旨は、東工大リサーチリポジトリ（T2R2）にてインターネット公表されますので、公表可能な範囲の内容で作成してください。
Attention: Thesis Summary will be published on Tokyo Tech Research Repository Website (T2R2).