| Project/Area Number |
16K08837
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Research Field |
Immunology
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| Research Institution | Osaka University |
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Principal Investigator |
Sakakibara Shuhei 大阪大学, 免疫学フロンティア研究センター, 寄附研究部門助教 (10618838)
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| Research Collaborator |
KIKUTANI Hitoshi
IKAWA Masato
SATO Yukoh
ALIEL-HUSSIEN Marwa
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| Project Period (FY) |
2016-04-01 – 2019-03-31
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| Project Status |
Completed (Fiscal Year 2018)
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| Budget Amount *help |
¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000)
Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2016: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
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| Keywords | 自己免疫疾患 / 自己抗体 / B細胞 / 全身性エリテマトーデス / 免疫寛容 / Ｂ細胞 / 免疫学 |
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| Outline of Final Research Achievements |
In acute systemic lupus erhthematosus (SLE), pathogenic autoantibodies are produced by self-reactive B cells that acquire somatic mutations to augment their reactivity. However, germline-encoded, low-affinity precursors for pathogenic autoantibody-producing cells have not been characterized. In this study, we generated site-directed knock-in mice of germline-encoded, low-affinity anti-DNA BCR and characterized the precursor B cells of pathogenic anti-DNA autoantibody-producing cells in vivo. Our analysis demonstrated that low-affinity anti-ssDNA B cells from the KI mice were not functionally anergic. Nonetheless, the KI B cells failed to differentiate into germinal center B cells, undergo somatic hypermutation and clonal expansion. Therefore, low-affinity anti-ssDNA B cells are suppressed by a tolerance checkpoint at germinal centers.
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| Academic Significance and Societal Importance of the Research Achievements |
全身性エリテマトーデス(SLE)に代表される自己免疫疾患の多くは根治が困難であり、解決すべき問題は多い。本研究で示されたように、胚中心反応には弱親和性抗ssDNA B細胞を抑制する免疫寛容機構がある。その一方で、多くのSLEモデルマウスでは自発的な胚中心形成が顕著であり、それに由来する自己抗体がSLE様症状を誘引する。従って、胚中心でのB細胞免疫寛容はさほど厳格ではなく、自己反応性B細胞をとりまく環境や状況によっては機能しないことが明確とななった。
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