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Autoantibodies against the plakin family proteins as a novel marker for chronic graft-versus-host disease of the lung

Bone Marrow Transplantation volume 56, pages 2291–2294 (2021)Cite this article

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Prompt diagnosis of bronchiolitis obliterans syndrome (BOS) is challenging after allogenic hematopoietic stem cell transplant (HSCT) because its pathophysiology is yet to be fully clarified and no specific disease markers have been established [1, 2]. The diagnosis relies upon pulmonary impairment evidenced using pulmonary function test (PFT) in the absence of other etiologies, but performing PFT in young individuals is difficult. Treatments for BOS have been developed recently [3]; however, a disease-specific treatment remains to be established [2], and lung transplantation is needed once BOS progresses to end-stage respiratory disease. Thus, a better understanding of the pathophysiology and identification of biomarkers for BOS is required. BOS is also observed in non-HSCT settings [1, 4], wherein 20–30% of patients with paraneoplastic pemphigus (PNP), a rare autoimmune skin disease characterized by chronic GVHD-like blistering skin lesions and mucositis, reportedly develop BOS [5]. PNP might be caused by neoplasm-induced abnormalities in humoral and cell-mediated immunity; the former is characterized by circulating autoantibodies primarily targeted against desmogleins and plakin family proteins. Considering that chronic GVHD and PNP share a common underlying pathophysiology, we hypothesized that patients with PNP and chronic GVHD developing BOS might have the same aberrant B-cell immunity.

Of consecutive 344 patients aged 0–26 years who underwent allogeneic HSCT between January 1988 and December 2015 at the Department of Pediatrics, Nagoya University Hospital (21 patients received allogeneic HSCT twice and 1 patient received it three times), 21 patients developed chronic GVHD and were included in this study. Sera were collected weekly during hospitalization and stored at −80 °C until further use. The patient characteristics are listed in Table S1. Diagnosis, evaluation of organ involvement, and therapeutic response were re-evaluated according to the 2014 NIH consensus [6]. PFT was performed at least twice before preconditioning and before discharge. Detailed transplant settings are described in the Supplementary Methods. BOS was defined according to the literature (Table S2) [6]. For children who did not understand PFT instructions, BOS was defined by progressive hypoxemia with the presence of bronchiectasis and/or a mosaic pattern defined as segmental lobular areas of hypoattenuation that are associated with narrowing of the caliber of the pulmonary vessels which was observed on high-resolution computed tomography. Enzyme-linked immunosorbent assays (ELISA) and immunoprecipitation-immunoblotting (IP-IB) were analyzed following institutional approval. Anti-EVPL and PPL antibodies in patient sera were quantified using ELISA [7]. IP-IB using a KU-8 cell lysate containing the plakin family proteins was performed according to the protocol described elsewhere [8] with some modifications (see Supplementary Methods). Data were retrospectively reviewed and analyzed as of September 2019. Statistical analysis is detailed in the Supplementary Methods. All patients provided informed consent for storing sera in accordance with the Declaration of Helsinki. This retrospective analysis was approved by the ethics committee of Nagoya University Graduate School of Medicine.

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Acknowledgements

The authors thank Yoshie Miura for her professional assistance. This work was supported by the Japan Society for the Promotion of Science, KAKENHI (grant number: 18K12273) and the Morinaga Foundation for Health & Nutrition, Japan.

Funding

JSPS KAKENHI (grant number: 18K12273).

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Authors and Affiliations

  1. Department of Pediatrics, Nagoya University Graduate School of Medicine, Nagoya, Japan

    Nozomu Kawashima, Eri Nishikawa, Yusuke Okuno, Motoharu Hamada, Daisuke Ichikawa, Atsushi Narita, Hideki Muramatsu, Nobuhiro Nishio, Seiji Kojima & Yoshiyuki Takahashi

  2. Department of Dermatology, Kurume University School of Medicine, Kurume, Japan

    Atsunari Tsuchisaka

  3. Department of Dermatology, Osaka City University Graduate School of Medicine, Osaka, Japan

    Takashi Hashimoto

  4. Genome Medical Center, Nagoya University Hospital, Nagoya, Japan

    Yusuke Okuno

  5. Center for Advanced Medicine and Clinical Research, Department of Advanced Medicine, Nagoya University Hospital, Nagoya, Japan

    Nobuhiro Nishio

  6. Department of Dermatology, Nagoya University Graduate School of Medicine, Nagoya, Japan

    Yoshinao Muro

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  1. Nozomu Kawashima
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Contributions

NK, TH, and YM conceived the study and designed the experiments. NK, EN, and YM performed the experiments and analyzed the data. AT provided critical reagents and analyzed the data. MH, DI, AN, HM, NN, and YT analyzed the clinical data. NK, TH, SK, and YM wrote the manuscript. All authors read and approved the manuscript.

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Correspondence to Nozomu Kawashima or Yoshiyuki Takahashi.

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The authors declare no competing interests.

Ethics approval

This retrospective analysis was approved by the ethics committee of Nagoya University Graduate School of Medicine (2020-0089).

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Kawashima, N., Nishikawa, E., Tsuchisaka, A. et al. Autoantibodies against the plakin family proteins as a novel marker for chronic graft-versus-host disease of the lung. Bone Marrow Transplant 56, 2291–2294 (2021). https://doi.org/10.1038/s41409-021-01335-5

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