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Immunopathological analysis of the expression of glomerular exostosin 1 and exostosin 2 in Japanese patients with lupus nephritis

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Abstract

Exostosin 1 and exostosin 2 (EXT1/EXT2) on glomerular basement membrane (GBM) were recently reported as novel putative antigens in secondary membranous nephropathy with autoimmune disease. However, the clinical significance of glomerular EXT1/EXT2 remains elusive in patients with lupus nephritis (LN). The immunofluorescence staining pattern of glomerular EXT1/EXT2 is also undetermined in membranous LN (MLN) or proliferative LN (PLN). We cross-sectionally analyzed patients with MLN (pure class V, n = 11) and PLN (class III, IV, and mixed class III/IV + V, n = 22) who underwent renal biopsies between 2010 and 2020 at Showa University Hospital. Glomerular EXT1/EXT2 expressions were evaluated by immunofluorescence. T-helper (Th) cell-related serum inflammatory cytokines were measured using enzyme-linked immunosorbent assay. The positivity for both EXT1/EXT2 was higher in patients with MLN than PLN (90.9% vs 63.6%, P = 0.212). MLN showed global and bright granular EXT1/EXT2 expressions along GBM, while PLN showed segmental and moderate expressions on GBM. Additionally, glomerular EXT1/EXT2 positivity was not associated with the degree of proteinuria or renal function in MLN and PLN patients, but the levels of serum anti-dsDNA antibody and circulating immune complexes were lower in patients with EXT1/EXT2-positive MLN than EXT1/EXT2-negative PLN. Moreover, serum complement levels and IL-4/IFN-γ ratios were elevated in EXT1/EXT2-positive MLN than EXT1/EXT2-negative PLN. Collectively, immunofluorescence staining for glomerular EXT1/EXT2 had characteristic patterns between MLN and PLN. Glomerular EXT1/EXT2 expressions tended to be high in Th2-dominant MLN patients without severe hypocomplementemia and elevated autoantibodies. Thus, EXT1/EXT2 might be involved in the unique developmental mechanism of MLN.

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Acknowledgements

We thank Ms. Tomoko Suzuki for her excellent technical assistance.

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Author notes

  1. Yukihiro Wada and Masayuki Iyoda contributed equally to this work.

Authors and Affiliations

  1. Department of Medicine, Division of Nephrology, Showa University School of Medicine, Tokyo, Japan

    Yukihiro Wada, Masayuki Iyoda, Taihei Suzuki, Shohei Tachibana, Nobuhiro Kanazawa & Hirokazu Honda

  2. Department of Microbiology and Immunology, Showa University School of Medicine, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo, 142-8555, Japan

    Masayuki Iyoda

  3. Department of Medicine, Division of Nephrology, Showa University Koto Toyosu Hospital, Tokyo, Japan

    Kei Matsumoto

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  1. Yukihiro Wada
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  2. Masayuki Iyoda
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Contributions

YW and MI were responsible for the conception and design of the study. YW, MI, TS, ST, NK, and KM collected and processed the data. YW, MI, TS, ST, NK, and KM evaluated the histological and immunohistochemical findings. YW, MI, TS, ST, NK, KM, and HH analyzed the data and interpreted the results. YW, MI, and HH drafted the manuscript. All authors provided comments on this article and approved the final version.

The Ethics Committee at Showa University Hospital approved the study protocol (No. 3373), and the study proceeded in accordance with the ethical standards of the Declaration of Helsinki.

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Correspondence to Masayuki Iyoda.

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Wada, Y., Iyoda, M., Suzuki, T. et al. Immunopathological analysis of the expression of glomerular exostosin 1 and exostosin 2 in Japanese patients with lupus nephritis . Virchows Arch 479, 997–1005 (2021). https://doi.org/10.1007/s00428-021-03164-9

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  • DOI: https://doi.org/10.1007/s00428-021-03164-9

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