Inflammation and pathogenic fibrosis in human ocular chronic graft versus host disease

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  • Ogawa Yoko
    Department of Ophthalmology, Keio University, School of Medicine, Tokyo, Japan Division of Cellular Signaling, Institute for Advanced Medical Research, Keio University, School of Medicine, Tokyo, Japan
  • Shimmura Shigeto
    Department of Ophthalmology, Keio University, School of Medicine, Tokyo, Japan
  • Kuwana Masataka
    Department of Internal Medicine, Keio University, School of Medicine, Tokyo, Japan
  • Yamazaki Kazuto
    Department of Pathology, Keio University, School of Medicine, Tokyo, Japan
  • Kawakami Yutaka
    Division of Cellular Signaling, Institute for Advanced Medical Research, Keio University, School of Medicine, Tokyo, Japan
  • Tsubota Kazuo
    Department of Ophthalmology, Keio University, School of Medicine, Tokyo, Japan

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Abstract

Uncontrolled fibrosis due to the excessive accumulation of extracellular matrix proteins plays a primary role in the lacrimal gland dysfunction of patients with ocular chronic graft-versus-host disease (GVHD). To investigate the pathogenesis of this disease, lacrimal gland biopsies obtained from patients with chronic GVHD were analyzed and compared with those from Sjögren's syndrome (SS) patients, as controls. Increased numbers of CD34+ fibroblasts and excessive fibrosis in the affected area was prominent, indicating a significant role for stromal fibroblasts in ocular chronic GVHD. The periductal area was the primary site for T-cell and fibroblast activation. A subset of fibroblasts that had accumulated in the affected area expressed HLA-class II and costimulatory molecules; such fibroblasts were not observed in SS lacrimal glands. In addition, donor fibroblast chimerism, which may also contribute to the pathogenic processes of this disease, were detected in the pathogenic fibrotic area. Moreover, T cells interacted with the lacrimal gland myoepithelia, which become HSP47-expressing cells under inflammatory stress. This mini-review will focus on recent researches on the immune response and pathogenic fibrosis in human ocular chronic GVHD, in which we examined the lacrimal gland as one of the targeted exocrine glands. These findings may help elucidate the pathogenesis of lacrimal gland as well as systemic chronic GVHD fibrosis and facilitate the development of novel anti-fibrotic interventions.

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