Lesional CD4⁺ IFN-γ⁺ cytotoxic T lymphocytes in IgG4-related dacryoadenitis and sialoadenitis

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.

Immunoglobulin G4-Related Thyroid Diseases

“…The mechanisms by which CD4+ CTLs may cause disease remain speculative. Reproduced from Maehara et al [13] with permission. …”

“…A model for the pathogenesis of IgG4-RD was developed by Maehara et al [13]. According to the model, the pathogenic processes of IgG4-RD could be initiated by immune responses to infections, commensal microbes, food, and environmental allergens, with tissue damage leading to activation of CD4+ cytotoxic T lymphocytes, which infiltrate affected tissues and mediate inflammation and fibrosis.…”

“…It is not yet clear whether IgG4 plays a central role in the pathogenesis of IgG4-RD or is the result of the fibroinflammatory process, as IgG4 antibodies are unable to cross-link antigens to form immune complexes and activate the complement system [16]. Figure 2 illustrates the pathogenesis of IgG4-RD [13]. …”

“…The major function of IL-4 and IL-10 is to initiate class switching of autoreactive B lymphocytes to IgE and IgG4 production and to promote the differentiation of IgG4-positive plasma cells. IL-5, IL-13, and TGF-β play a major role in the recruitment of eosinophils as well as fibroblast activation, causing dense fibrosis and obliterative phlebitis [13] with tissue damage. IgG4 and IgE antibodies cross-react to self-antigens.…”

THU0033 Age-associated b cells in early drug-naÏve rheumatoid arthritis patients

“…1 Rheumatology; 2 Immunology; 3 orthopedics, Erasmus Medical Centre, Rotterdam, Netherlands; 4 Immunology, University of Washington; 5 Pediatrics, Center for Immunity and Immunotherapies, Seattle; 6 Centre for Neurologic Diseases, Harvard Institute of Medicine, Boston, USA Background: The IL-23/IL-17A immune pathway is important for the progression of T cell-mediated arthritis. However, it is not known where IL-23R + T cells locate during the different stages of arthritis and which IL-23R + T cells drive joint inflammation.…”