Elucidation of pathophysiology of fibrosis and sclerosis and establishment of treatment in IgG4-related disease using model mouse

2019 Fiscal Year Final Research Report

• Project/Area Number: 16K19597
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Collagenous pathology/Allergology
• Research Institution: Kanazawa University
• Principal Investigator: Mizushima Ichiro 金沢大学, 附属病院, 特任助教 (50645124)
• Project Period (FY): 2016-04-01 – 2020-03-31
• Keywords: IgG4関連疾患 / 線維化 / モデルマウス

Outline of Final Research Achievements

In this study, using human specimens from affected organs and LAT Y136F knock-in mouse as model mouse, we investigated pathophysiology of fibrosis and sclerosis in IgG4-related disease (IgG4-RD). We have clarified the differences of types of collagen according to the anatomical locations and increase of fibril-forming collagens (collagen I and III) in parallel with progression of fibrosis and sclerosis. We have also clarified that M2 macrophages, that are implicated in fibrosis in IgG4-RD, produce APRIL promoting activation, proliferation, and survival of B lymphocytes and plasma cells, and contribute to the formation of characteristic pathology. In LAT Y136F knock-in mouse, we have found an increase of fibrosis score as mouse got older and enhanced expression of APRIL in affected organs.

Free Research Field

リウマチ・膠原病

Academic Significance and Societal Importance of the Research Achievements

IgG4関連疾患は原因不明の全身性炎症性疾患であり、組織学的に特異な線維化・硬化を呈し、それに伴い長期的には不可逆的な機能障害を呈する。ヒトIgG4関連疾患組織検体において、同じ臓器内においても血管周囲や腎皮質などの解剖学的部位により線維化・硬化を形成するコラーゲンのタイプが異なること、また病態の進展により線維性コラーゲンが増加してくることから、病変、病期にあわせて線維化・硬化の治療標的が異なることが示唆された。また、モデルマウスであるLAT Y136変異マウスの病変局所において、線維化の進展、ヒトと共通するサイトカインの産生亢進が確認され、本マウスを用いた更なる検討の妥当性が示唆された。