Identification of molecular characteristics of pathogenic autoantibody-producing cells

2018 Fiscal Year Final Research Report

• Project/Area Number: 16H05201
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Immunology
• Research Institution: Tohoku University
• Principal Investigator: TAKAI Toshiyuki 東北大学, 加齢医学研究所, 教授 (20187917)
• Research Collaborator: Inui Masanori ; Itou Ari ; Endo Shota ; Su Mei-Tzu
• Project Period (FY): 2016-04-01 – 2019-03-31
• Keywords: 免疫抑制 / 免疫チェックポイント / レセプター / 自己免疫疾患 / 免疫寛容

Outline of Final Research Achievements

In this study, first we have found that expression of leukocyte immunoglobulin-like receptor (LILR)B4, an inhibitory member of the human LILR family, is augmented in autoantibody-producing plasmablasts/plasma cells (PCs) of systemic lupus erythematosus (SLE) patients. However, the mechanism behind the upregulation of LILRB4 upon pathogenic antibody-secreting cells is yet to be known. To clarify the mechanism, next we have examined if glycoprotein 49B (gp49B), the murine counterpart of human LILRB4, is also elevated in autoantibody-producing cells in several SLE mouse models. We have found that gp49B is indeed expressed on PC of SLE-prone models but not of healthy C57BL/6 mice, and the level was positively correlated to the autoantibody IgG titer in serum. Gp49B genetic deletion, however, did not abolish the serum autoantibodies or fully ameliorate the lethal glomerulonephritis, indicating that gp49B is not the sole regulator of lupus but a pathogenic element in the disease.

Free Research Field

免疫抑制性受容体による免疫寛容の維持およびその破綻による免疫疾患の発症機構の解明と創薬

Academic Significance and Societal Importance of the Research Achievements

SLEではステロイド剤と免疫抑制剤を併用することで短期生存率が著明に改善しているが特異性に乏しく，ステロイド長期投与による骨粗鬆症や感染症，動脈硬化性病変などは長期の生命予後，患者QOLを大きく低下させる。自己抗体のソースである汎B・活性化Bリンパ球を標的にした抗体療法の臨床試験が進められているが，リスク，ベネフィットのバランスに優れた薬剤の開発は成功していない。本研究は自己抗体を高産生するSLE病原性プラズマセル（PC）特異的に高発現する，リガンドが未同定のオーファン受容体LILRB4（B4）を見出した。これにより病原性PC特異的に治療する道筋が見えた。