Bone Marrow Transplantation | 2021
Autoantibodies against the plakin family proteins as a novel marker for chronic graft-versus-host disease of the lung
Abstract
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 immunoprecipitationimmunoblotting (IP-IB) were analyzed following * Nozomu Kawashima [email protected]