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Clinical and epidemiological research
Extended report
Lesional CD4+ IFN-γ+ cytotoxic T lymphocytes in IgG4-related dacryoadenitis and sialoadenitis
  1. Takashi Maehara1,2,
  2. Hamid Mattoo1,
  3. Miho Ohta2,
  4. Vinay S Mahajan1,
  5. Masafumi Moriyama2,3,
  6. Masaki Yamauchi2,
  7. Jefte Drijvers1,
  8. Seiji Nakamura2,
  9. John H Stone1,
  10. Shiv S Pillai1
  1. 1Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
  2. 2Section of Oral and Maxillofacial Oncology, Division of Maxillofacial Diagnostic and Surgical Sciences, Faculty of Dental Science, Kyushu University, Fukuoka, Japan
  3. 3Faculty of Dental Science, OBT Research Center, Kyushu University, Fukuoka, Japan
  1. Correspondence to Dr Shiv S Pillai, Ragon Institute of MGH, MIT and Harvard, 400 Tech Square, Cambridge, MA 02139, USA; pillai{at}helix.mgh.harvard.edu

Abstract

Objectives IgG4-related disease (IgG4-RD) is a chronic, systemic, inflammatory condition of unknown aetiology. We have recently described clonally expanded circulating CD4+ cytotoxic T lymphocytes (CTLs) in IgG4-RD that infiltrate affected tissues where they secrete interleukin (IL)-1β and transforming growth factor -β1 (TGF-β1). In this study, we sought to examine the role of CD4+ CTLs in the pathogenesis of IgG4-related dacryoadenitis and sialoadenitis (IgG4-DS) and to determine whether these cells secrete interferon-gamma (IFN-γ) at lesional sites.

Methods Salivary glands of 25 patients with IgG4-DS, 22 patients with Sjögren's syndrome (SS), 12 patients with chronic sialoadenitis (CS) and 12 healthy controls were analysed in this study. Gene expression analysis was performed on submandibular glands (SMGs) from five patients with IgG4-DS, three with CS and three healthy controls. Infiltrating CD4+ CTLs were examined by quantitative multicolour imaging in tissue samples from 20 patients with IgG4-DS, 22 patients with SS, 9 patients with CS and 9 healthy controls.

Results In IgG4-DS tissues, nine genes associated with CD4+ CTLs were overexpressed. The expression of granzyme A (GZMA) mRNA was significantly higher in samples from patients with IgG4-RD compared with corresponding tissues from SS and healthy controls. Quantitative imaging showed that infiltrating CD4+ GZMA+ CTLs were more abundant in patients with IgG4-DS than in the other groups. The ratio of CD4+GZMA+ CTLs in SMGs from patients with IgG4-DS correlated with serum IgG4 concentrations and the number of affected organs. A large fraction of CD4+GZMA+ CTLs in SMGs from patients with IgG4-DS secreted IFN-γ.

Conclusions The pathogenesis of IgG4-DS is associated with tissue infiltration by CD4+GZMA+ CTLs that secrete IFN-γ.

  • Inflammation
  • Sjøgren's Syndrome
  • T Cells

https://doi.org/10.1136/annrheumdis-2016-209139

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    Footnotes

    • Handling editor Tore K Kvien

    • TM and HM contributed equally.

    • Contributors Studies were performed by TM, HM, MO with contributions from JD, VSM, MM and MY. Studies were planned by TM, HM, VSM, SN, JHS and SSP. Manuscript was written by TM and SP.

    • Funding This study was funded by grants AI110495 and AI113163 from the NIH and supported by the Program for Advancing Strategic International Networks to Accelerate the Circulation of Talented Researchers (S2605) sponsored by the Japanese Society for the Promotion of Science (JSPS).

    • Competing interests None declared.

    • Ethics approval Ethics committee of Kyushu University, Japan (IRB serial number: 25-287).

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Data sharing statement All tissue quantification data were shared in TISSUE GNOSTICS SOFTWARE at Ragon Institute of MGH, MIT and Harvard.