糖鎖異常ＩｇＡ１免疫複合体および扁桃細胞のＩｇＡ腎症における病態解明

2014 Fiscal Year Annual Research Report

• Project/Area Number: 24591213
• Research Institution: Juntendo University
• Principal Investigator: 鈴木 仁 順天堂大学, 医学部, 助教 (10468572)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Keywords: IgA腎症 / 糖鎖 / 免疫複合体 / 粘膜免疫 / 扁桃

Outline of Annual Research Achievements

IgA腎症の病態における糖鎖異常IgA1産生と免疫複合体形成機序を解明するために、IgA腎症患者の末梢血および摘出された扁桃よりB細胞を抽出し、EBウイルスで不死化し、IgA1-およびIgG産生細胞株を樹立した。これらの細胞株に対し、各種サイトカインの刺激によって、IgA1の糖鎖構造・糖鎖修飾酵素の活性化を検証した。IL-6により、ガラクトース欠損型、およびシアル酸過付加型の糖鎖異常IgA1の産生が亢進することが明らかとなり国際誌に発表した（J Biol Chem. 21: 5330-5339, 2014）。またIL-6の刺激によって免疫複合体形成を亢進させるようなIgGの産生も亢進されることも示唆された。
次に、本症における扁桃B細胞の役割を解明するため、2012年から2014年までに当院にて扁摘およびステロイドパルス療法が施行されたIgA腎症患者36名を対象とし、扁摘前・扁摘後・ステロイドパルス療法経過中の血中のバイオマーカー（糖鎖異常IgA1、糖鎖異常IgA1特異的IgG、およびIgG-IgA免疫複合体）を測定した。また、摘出された扁桃細胞を48時間培養し、培養上清中の糖鎖異常IgA1および糖鎖異常IgA1特異的IgGの産生量を測定した。尿所見異常の改善に伴い、血中糖鎖異常IgA1・糖鎖異常IgA1特異的IgG ・IgA1-IgG ICの有意な低下が認められ、扁摘パルス療法の治療効果が高い患者群での扁桃細胞では、toll-like receptor (TLR) 9の発現量が高く、糖鎖異常IgA1特異的IgGの産生量が有意に高値であった。以上より、IgA腎症の病態において重要な役割を担う糖鎖異常IgA1や糖鎖異常IgA1特異的抗体の一部は、口蓋扁桃由来であることが明らかとなった。扁桃B細胞におけるa proliferation-inducing ligand（APRIL）の発現がIgA腎症患者で亢進していることも明らかとなり、APRILの発現によって糖鎖異常IgA1および糖鎖異常IgA1特異的抗体の産生が亢進するものと考えられた。

Research Products

• [Journal Article] IgA腎症早期発見のための新規バイオマーカーを用いた血尿の2次スクリーニングの試み (2015)
  • Author(s): 鈴木 仁、鈴木祐介
  • Journal Title: 腎・高血圧の最新治療 Volume: 4 Pages: 28, 33
• [Journal Article] A panel of serum biomarkers differentiates IgA nephropathy from other renal diseases. (2014)
  • Author(s): Yanagawa H, Suzuki H, Suzuki Y, Kiryluk K, Gharavi AG, Matsuoka K, Makita Y, Julian BA, Novak J, Tomino Y.
  • Journal Title: PLoS One Volume: 23 Pages: e98081
  • DOI: 10.1371/journal.pone.0098081
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Proposal of remission criteria for IgA nephropathy. (2014)
  • Author(s): Suzuki Y, Matsuzaki K, Suzuki H, Sakamoto N, Joh K, Kawamura T, Tomino Y, Matsuo S.
  • Journal Title: Clin Exp Nephrol Volume: 18 Pages: 481, 486
  • DOI: 10.1007/s10157-013-0849-x
  • Peer Reviewed
• [Journal Article] Serum levels of galactose-deficient immunoglobulin (Ig) A1 and related immune complex are associated with disease activity of IgA nephropathy. (2014)
  • Author(s): Suzuki Y, Matsuzaki K, Suzuki H, Okazaki K, Yanagawa H, Ieiri N, Sato M, Sato T, Taguma Y, Matsuoka J, Horikoshi S, Novak J, Hotta O, Tomino Y.
  • Journal Title: Clin Exp Nephrol Volume: 18 Pages: 770, 777
  • DOI: 10.1007/s10157-013-0921-6
  • Peer Reviewed
• [Journal Article] Dietary zinc is a key environmental modifier in the progression of IgA nephropathy. (2014)
  • Author(s): Maiguma M, Suzuki Y, Suzuki H, Okazaki K, Aizawa M, Muto M, Tomino Y
  • Journal Title: PLoS One Volume: 28 Pages: e90558
  • DOI: 10.1371/journal.pone.0090558
  • Peer Reviewed
• [Journal Article] Changes in Nephritogenic Serum Galactose-Deficient IgA1 in IgA Nephropathy following Tonsillectomy and Steroid Therapy. (2014)
  • Author(s): Nakata J, Suzuki Y, Suzuki H, Sato D, Kano T, Yanagawa H, Matsuzaki K, Horikoshi S, Novak J, Tomino Y.
  • Journal Title: PLoS One Volume: 21 Pages: e89707
  • DOI: 10.1371/journal.pone.0089707
  • Peer Reviewed / Open Access
• [Journal Article] Uncoupling of glomerular IgA deposition and disease progression in alymphoplasia mice with IgA nephropathy. (2014)
  • Author(s): Aizawa M, Suzuki Y, Suzuki H, Pang H, Kihara M, Nakata J, Yamaji K, Horikoshi S, Tomino Y.
  • Journal Title: PLoS One Volume: 17 Pages: e95365
  • DOI: 10.1371/journal.pone.0095365
  • Peer Reviewed / Open Access
• [Journal Article] Serum under-O-glycosylated IgA1 level is not correlated with glomerular IgA deposition based upon heterogeneity in the composition of immune complexes in IgA nephropathy (2014)
  • Author(s): Satake K, Shimizu Y, Sasaki Y, Yanagawa H, Suzuki H, Suzuki Y, Horikoshi S, Honda S, Shibuya K, Shibuya A, Tomino Y
  • Journal Title: BMC Nephrol Volume: 15 Pages: 89
  • DOI: 10.1186/1471-2369-15-89
  • Peer Reviewed / Open Access
• [Journal Article] Discovery of new risk loci for IgA nephropathy implicates genes involved in immunity against intestinal pathogens. (2014)
  • Author(s): Kiryluk K, , Suzuki H, Wyatt RJ, Novak J, Julian BA, Feehally J, Lifton RP, Gharavi AG, et al.
  • Journal Title: Nat Genet Volume: 46 Pages: 1187, 1196
  • DOI: 10.1038/ng.3118
  • Peer Reviewed
• [Journal Article] Cytokines alter IgA1 O-glycosylation by dysregulating C1GalT1 and ST6GalNAc-II enzymes. (2014)
  • Author(s): Suzuki H, Raska M, Yamada K, Moldoveanu Z, Julian BA, Wyatt RJ, Tomino Y, Gharavi AG, Novak J.
  • Journal Title: J Biol Chem Volume: 21 Pages: 5330, 5339
  • DOI: 10.1074/jbc.M113.512277
  • Peer Reviewed
• [Journal Article] Diagnosis and activity assessment of immunoglobulin A nephropathy: current perspectives on noninvasive testing with aberrantly glycosylated immunoglobulin A-related biomarkers (2014)
  • Author(s): Suzuki Y, Suzuki H, Makita Y, Takahata A, Takahashi K, Muto M, Sasaki Y, Kelimu A, Matsuzaki K, Yanagawa H, Okazaki K, Tomino Y
  • Journal Title: Int J Nephrol Renovasc Dis Volume: 7 Pages: 409, 414
  • DOI: 10.2147/IJNRD.S50513
  • Peer Reviewed / Open Access
• [Journal Article] Development of Animal Models of Human IgA Nephropathy. (2014)
  • Author(s): Suzuki H, Suzuki Y, Novak J, Tomino Y
  • Journal Title: Drug Discov Today: Dis Model Volume: 11 Pages: 5, 11
  • DOI: 10.1016/j.ddmod.2014.07.002, 2014
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] The kinetics of glomerular deposition of nephritogenic IgA (2014)
  • Author(s): Yamaji K, Suzuki Y, Suzuki H, Satake K, Horikoshi S, Novak J, Tomino Y
  • Journal Title: PLoS One Volume: 9 Pages: e113005
  • DOI: 10.1371/journal.pone.0113005
  • Peer Reviewed / Open Access
• [Presentation] New insights into the pathogenesis of IgAN (2015)
  • Author(s): Hitoshi Suzuki
  • Organizer: 23rd The ISN World Congress of Nephrology
  • Place of Presentation: Cape Town, South Africa
  • Year and Date: 2015-03-13 – 2015-03-17
  • Invited
• [Presentation] Pathogenic Role of Aberrantly-glycosylated IgA1 and Corresponding Autoantibodies in Patients with Henoch-Schoenlein Purpura Nephritis. (2014)
  • Author(s): Hitoshi Suzuki, Zina Moldoveanu, Bruce A. Julian, Yasuhiko Tomino, Robert J. Wyatt, Jan Novak.
  • Organizer: The ASN (American Society of Nephrology) 47th Annual Meeting
  • Place of Presentation: Philadelphia, USA
  • Year and Date: 2014-11-13 – 2014-11-16
• [Presentation] An increase in the EPA/AA ratio is associated with reduction of proteinuria in CKD patients (2014)
  • Author(s): Hitoshi Suzuki, Chieko Nogi, Hiroaki Io, Yusuke Suzuki, Yasuhiko Tomino
  • Organizer: The ASN (American Society of Nephrology) 47th Annual Meeting
  • Place of Presentation: Philadelphia, USA
  • Year and Date: 2014-11-13 – 2014-11-16
• [Presentation] Serum galactose-deficient IgA1 detected by specific monoclonal antibody KM55 is increased in IgA nephropathy patients (2014)
  • Author(s): Yusuke Suzuki, Hitoshi Suzuki, Junichi Yasutake, Yasuhiko Tomino
  • Organizer: The ASN (American Society of Nephrology) 47th Annual Meeting
  • Place of Presentation: Philadelphia, USA
  • Year and Date: 2014-11-13 – 2014-11-16
• [Presentation] IgA腎症の病因における口蓋扁桃のAPRIL産生B細胞の役割 (2014)
  • Author(s): 武藤正浩、鈴木祐介、鈴木 仁、城 謙輔、井出章三、Bertral Juard、富野康日己
  • Organizer: 第57回日本腎臓学会総会
  • Place of Presentation: 東京
  • Year and Date: 2014-07-04 – 2014-07-06
• [Presentation] Novle diagnostic approach for IgA Nephropathy (2014)
  • Author(s): Suzuki H, Yanagawa H, Suzuki Y, Kiryluk K, Gharavi AG, Matsuoka K, Makita Y, Julian BA, Novak J, Tomino Y.
  • Organizer: The 14th Asian Pacific Congress of Nephrology
  • Place of Presentation: Tokyo
  • Year and Date: 2014-05-14 – 2014-05-17
• [Patent(Industrial Property Rights)] ＩｇＡ腎症検査法 (2015)
  • Inventor(s): 鈴木 仁
  • Industrial Property Rights Holder: 鈴木 仁
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 特願2015-051874
  • Filing Date: 2015-03-16