膜性腎症の発症メカニズム 原因抗原とIgG4関連自己免疫疾患としての考察
要旨:膜性腎症は糸球体係蹄壁の上皮下に沈着する免疫複合物が，補体活性化などを介して濾過バリアを傷害し，高度蛋白尿をきたす免疫疾患である。最近，病理組織切片にレーザーマイクロダイセクション・液体クロマトグラフィー・質量分析法（LMD-LCMS/MS法）の技術が応用され，この疾患の原因抗原が次々と解明されている。その結果，膜性腎症のおよそ70%の原因抗原であるphospholipase A2 receptor（PLA2R）をはじめ，多くの原因抗原が糸球体足細胞（ポドサイト）に発現している蛋白であることが明らかとなった。また，血中に対応する自己抗体が検出されることから，膜性腎症はポドサイトに対する自...
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| Published in | 診断病理 Vol. 42; no. 2; pp. 93 - 102 |
|---|---|
| Main Authors | , , |
| Format | Journal Article |
| Language | Japanese |
| Published |
一般社団法人 日本病理学会
2025
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| Subjects | |
| Online Access | Get full text |
| ISSN | 1345-6431 2759-8128 |
| DOI | 10.69281/jspjjdp.2024_11_0045 |
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| Abstract | 要旨:膜性腎症は糸球体係蹄壁の上皮下に沈着する免疫複合物が，補体活性化などを介して濾過バリアを傷害し，高度蛋白尿をきたす免疫疾患である。最近，病理組織切片にレーザーマイクロダイセクション・液体クロマトグラフィー・質量分析法（LMD-LCMS/MS法）の技術が応用され，この疾患の原因抗原が次々と解明されている。その結果，膜性腎症のおよそ70%の原因抗原であるphospholipase A2 receptor（PLA2R）をはじめ，多くの原因抗原が糸球体足細胞（ポドサイト）に発現している蛋白であることが明らかとなった。また，血中に対応する自己抗体が検出されることから，膜性腎症はポドサイトに対する自己免疫疾患と理解されている。一方，自己抗体のサブクラスが主としてIgG4であることから，本疾患を IgG4関連自己免疫疾患の一つととらえることもできる。従来，特発性と続発性に分類されていた膜性腎症は，原因抗原を特定することが診断の要となり，原因抗原とIgG4免疫応答に基づいた病態の解明と治療の選択が始まっている。 |
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| AbstractList | 要旨:膜性腎症は糸球体係蹄壁の上皮下に沈着する免疫複合物が，補体活性化などを介して濾過バリアを傷害し，高度蛋白尿をきたす免疫疾患である。最近，病理組織切片にレーザーマイクロダイセクション・液体クロマトグラフィー・質量分析法（LMD-LCMS/MS法）の技術が応用され，この疾患の原因抗原が次々と解明されている。その結果，膜性腎症のおよそ70%の原因抗原であるphospholipase A2 receptor（PLA2R）をはじめ，多くの原因抗原が糸球体足細胞（ポドサイト）に発現している蛋白であることが明らかとなった。また，血中に対応する自己抗体が検出されることから，膜性腎症はポドサイトに対する自己免疫疾患と理解されている。一方，自己抗体のサブクラスが主としてIgG4であることから，本疾患を IgG4関連自己免疫疾患の一つととらえることもできる。従来，特発性と続発性に分類されていた膜性腎症は，原因抗原を特定することが診断の要となり，原因抗原とIgG4免疫応答に基づいた病態の解明と治療の選択が始まっている。 |
| Author | 康, 徳東 川西, 邦夫 本田, 一穂 |
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| Copyright | 2025 日本病理学会 |
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J Exp Med. 1987;166:109-128. 41) Murtas C, Bruschi M, Spinelli S, Kajana X, Verrina EE, Angeletti A, et al. Novel biomarkers and pathophysiology of membranous nephropathy: PLA2R and beyond. Clin Kidney J. 2024; 17:1-9. 2) Sethi S. New ‘Antigens’ in Membranous Nephropathy. J Am Soc Nephrol. 2021;32:268-278. 47) Haddad G, Lorenzen JM, Ma H, de Haan N, Seeger H, Zaghrini C, et al. Altered glycosylation of IgG4 promotes lectin complement pathway activation in anti-PLA2R1-associated membranous nephropathy. J Clin Invest. 2021;131:e140453. 29) Sethi S, Madden B, Casal Moura M, Singh RD, Nasr SH, Hou J, et al. Membranous Nephropathy in Syphilis is Associated with Neuron-Derived Neurotrophic Factor. J Am Soc Nephrol. 2023;34:374-384. 39) Prunotto M, Carnevali ML, Candiano G, Murtas C, Bruschi M, Corradini E, et al. Autoimmunity in membranous nephropathy targets aldose reductase and SOD2. J Am Soc Nephrol. 2010;21:507-519. 27) Hofstra JM, Beck LH Jr, Beck DM, Wetzels JF, Salant DJ. Anti-phospholipase A2 receptor antibodies correlate with clinical status in idiopathic membranous nephropathy. Clin J Am Soc Nephrol. 2011;6:1286-1291. |
| References_xml | – reference: 14) Ronco P, Debiec H. Advances in membranous nephropathy:success stories of a long journey. Clin Exp Pharmacol Physiol. 2011;38:460-466. – reference: 7) Couser WG. Membranous nephropathy:a long road but well traveled. J Am Soc Nephrol. 2005;16: 1184-1187. – reference: 20) Rodriguez FJ, Gamez JD, Vrana JA, Theis JD, Giannini C, Scheithauer BW, et al. Immunoglobulin derived depositions in the nervous system: novel mass spectrometry application for protein characterization in formalin-fixed tissues. Lab Invest. 2008;88:1024-1037. – reference: 19) Tomas NM, Beck LH Jr, Meyer-Schwesinger C, Seitz-Polski B, Ma H, Zahner G, Dolla G, et al. Thrombospondin type-1 domain-containing 7A in idiopathic membranous nephropathy. N Engl J Med. 2014;371:2277-2287. – reference: 10) Kerjaschki D, Neale TJ. Molecular mechanisms of glomerular injury in rat experimental membranous nephropathy （Heymann nephritis）. J Am Soc Nephrol. 1996;7:2518-2526. – reference: 8) Cybulsky AV. Membranous nephropathy. Contrib Nephrol. 2011;169:107-125. – reference: 31) Hoxha E, Beck LH Jr, Wiech T, Tomas NM, Probst C, Mindorf S, et al. An Indirect Immunofluorescence Method Facilitates Detection of Thrombospondin Type 1 Domain-Containing 7A-Specific Antibodies in Membranous Nephropathy. J Am Soc Nephrol. 2017;28:520-531. – reference: 45) Ellebrecht CT, Mukherjee EM, Zheng Q, Choi EJ, Reddy SG, Mao X, Payne AS. Autoreactive IgG and IgA B Cells Evolve through Distinct Subclass Switch Pathways in the Autoimmune Disease Pemphigus Vulgaris. Cell Rep. 2018;24:2370-2380. – reference: 9) Couser WG, Steinmuller DR, Stilmant MM, Salant DJ, Lowenstein LM. Experimental glomerulonephritis in the isolated perfused rat kidney. J Clin Invest. 1978;62:1275-1287. – reference: 42) Ghiggeri GM, Seitz-Polski B, Justino J, Zaghrini C, Payré C, Brglez V, et al. Multi-Autoantibody Signature and Clinical Outcome in Membranous Nephropathy. Clin J Am Soc Nephrol. 2020; 15:1762-1776. – reference: 24) Sethi S, Debiec H, Madden B, Vivarelli M, Charlesworth MC, Ravindran A, et al Semaphorin 3B-associated membranous nephropathy is a distinct type of disease predominantly present in pediatric patients. Kidney Int. 2020;98:1253-1264. – reference: 47) Haddad G, Lorenzen JM, Ma H, de Haan N, Seeger H, Zaghrini C, et al. Altered glycosylation of IgG4 promotes lectin complement pathway activation in anti-PLA2R1-associated membranous nephropathy. J Clin Invest. 2021;131:e140453. – reference: 46) Motta RV, Culver EL. IgG4 autoantibodies and autoantigens in the context of IgG4-autoimmune disease and IgG4-related disease. Front Immunol. 2024;15:1272084. – reference: 34) Zhang P, Huang W, Zheng Q, Tang J, Dong Z, Jiang Y, et al. A Novel Insight into the Role of PLA2R and THSD7A in Membranous Nephropathy. J Immunol Res. 2021;2021:8163298. – reference: 36) Fresquet M, Lockhart-Cairns MP, Rhoden SJ, Jowitt TA, Briggs DC, Baldock C, et al. Structure of PLA2R reveals presentation of the dominant membranous nephropathy epitope and an immunogenic patch. Proc Natl Acad Sci U S A. 2022; 119: e2202209119. – reference: 16) Iwaoka T, Umeda T, Nakayama M, Shimada T, Fujii Y, Miura F, et al. A case of membranous nephropathy associated with thyroid antigens. Jpn J Med. 1982;21:29-34. – reference: 41) Murtas C, Bruschi M, Spinelli S, Kajana X, Verrina EE, Angeletti A, et al. Novel biomarkers and pathophysiology of membranous nephropathy: PLA2R and beyond. Clin Kidney J. 2024; 17:1-9. – reference: 17) Neves PDMM, Muniz MPR, Morgantetti GF, Cutrim ÉMM, Macieira CA, Salgado-Filho N, et al. Membranous Nephropathy Secondary to Graves’ Disease: A Case Report. Front Immunol. 2022;13:824124. – reference: 32) Caza TN, Hassen SI, Dvanajscak Z, Kuperman M, Edmondson R, Herzog C, et al. NELL1 is a target antigen in malignancy-associated membranous nephropathy. Kidney Int. 2021;99:967-976. – reference: 22) Sethi S, Theis JD. Pathology and diagnosis of renal non-AL amyloidosis. J Nephrol. 2018;31:343-350. – reference: 15) Wang R, Wu Y, Zheng B, Zhang X, An D, Guo N, et al. Clinicopathological characteristics and prognosis of hepatitis B associated membranous nephropathy and idiopathic membranous nephropathy complicated with hepatitis B virus infection. Sci Rep. 2021;11:18407. – reference: 4) Ünlü S, Sánchez Navarro BG, Cakan E, Berchtold D, Meleka Hanna R, Vural S, Vural A, Meisel A, Fichtner ML. Exploring the depths of IgG4:insights into autoimmunity and novel treatments. Front Immunol. 2024;15:1346671. – reference: 3) Sethi S, Fervenza FC. Membranous nephropathy-diagnosis and identification of target antigens. Nephrol Dial Transplant. 2024;39:600-606. – reference: 29) Sethi S, Madden B, Casal Moura M, Singh RD, Nasr SH, Hou J, et al. 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| Title | 膜性腎症の発症メカニズム |
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