Abstract
Inflammation and impaired secretion by lacrimal and salivary glands are hallmarks of the autoimmune disease, Sjögren’s Syndrome. These changes in the lacrimal gland promote dryness and inflammation of the ocular surface, causing pain, irritation and corneal damage. The changes that initiate and sustain autoimmune inflammation in the lacrimal gland are not well-established. Here we demonstrate that interferon-γ (IFN-γ) is significantly elevated in lacrimal gland and tears of the male NOD mouse, a model of autoimmune dacryoadenitis which exhibits many ocular characteristics of Sjögren’s Syndrome, by 12 weeks of age early in lacrimal gland inflammation. Working either with primary cultured lacrimal gland acinar cells from BALB/c mice and/or rabbits, in vitro IFN-γ treatment for 48 hr decreased expression of Rab3D concurrent with increased expression of cathepsin S. Although total cellular cathepsin S activity was not commensurately increased, IFN-γ treated lacrimal gland acinar cells showed a significant increase in carbachol-stimulated secretion of cathepsin S similar to the lacrimal gland in disease. In vitro IFN-γ treatment did not increase the expression of most components of major histocompatibility complex (MHC) class II-mediated antigen presentation although antigen presentation was slightly but significantly stimulated in primary cultured lacrimal gland acinar cells. However, exposure of cultured human corneal epithelial cells to IFN-γ more robustly increased expression and activity of cathepsin S in parallel with increased expression and function of MHC class II-mediated antigen presentation. We propose that early elevations in IFN-γ contribute to specific features of ocular disease pathology in Sjögren’s Syndrome.
Highlights
Sjogren’s Syndrome (SS) is a chronic autoimmune disease that primarily affects lacrimal glands (LG) and salivary glands (SG), leading to reduced production and altered composition of tears and saliva and, respectively, ocular surface inflammation/corneal damage and compromised oral health [1]
We selected IFN-γ as our major focus since it increases expression of cathepsin S (CTSS) in different cells including macrophages, alveolar epithelial cells, hepatic stellate cells [29,30,31] and is a known inducer of CTSS expression associated with increases in other components of major histocompatibility complex (MHC) class II-mediated antigen presentation, each of which has been linked to autoimmune dacryoadenitis [9, 32]
By applying the same multiplex assay, we utilized in non-obese diabetic (NOD) mouse LG in Table 1 to tears, we found that IFN-γ levels were significantly higher in tears from male NOD mice compared to levels found in tears of the control strain, male BALB/c mice, which was below the limits of detection (Fig 5)
Summary
Sjogren’s Syndrome (SS) is a chronic autoimmune disease that primarily affects lacrimal glands (LG) and salivary glands (SG), leading to reduced production and altered composition of tears and saliva and, respectively, ocular surface inflammation/corneal damage and compromised oral health [1]. Pro-inflammatory cytokines such as IL-1α, IL-2, IFN-γ, IL-6, and TNF-α are increased in SG of SS patients [4], in parallel with increased major histocompatibility complex (MHC) class II molecules in SG acinar cells [5, 6]. Many studies have shown that MHC class II expression is upregulated in SG epithelial cells from SS patients compared to healthy controls, while a role for IFN-γ in increased expression of antigen-presenting molecules [6, 7] and ICAM1 [8] on SG acinar cell plasma membranes and induction of antigen presentation is supported [9]. In vitro studies have implicated increased MHC class II expression in the process of lymphocytic proliferation driven by LGAC [12]
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