Salivary gland tissue expression of interleukin‐23 and interleukin‐17 in Sjögren's syndrome: Findings in humans and mice

Abstract

Objective. Recently, the Th1/Th2 paradigm has been expanded by the discovery of Th17 cells, a subset of CD4؉ memory T cells characterized by their unique ability to secrete interleukin-17 (IL-17) family cytokines. Importantly, Th17 cells appear to be intimately involved in autoimmunity. We undertook the present study to investigate whether the Th17/IL-23 system is up-regulated in Sjögren's syndrome (SS).Methods. Sera, saliva, and salivary glands from C57BL/6.NOD-Aec1Aec2 mice (a model for primary SS), as well as sera, saliva, and salivary gland biopsy specimens obtained from patients with primary SS, were evaluated for IL-17 and IL-23 expression by immunohistochemistry, real-time polymerase chain reaction, and the Luminex system.Results. Immunohistochemical stainings of submandibular glands from C57BL/6.NOD-Aec1Aec2 mice and of salivary gland biopsy specimens from SS patients revealed strong positive staining for both IL-17 and IL-23 within lymphocytic foci and diffuse staining on epithelial tissues. Temporal expression of IL-17 and IL-23 in submandibular glands of C57BL/6.NODAec1Aec2 mice correlated with expression of retinoic acid-related orphan receptor ␥t, the Th17 cell master control gene. While IL-17 could not be detected in saliva from 4-20-week-old C57BL/6.NOD-Aec1Aec2 mice, this cytokine was present in the blood of mice up to age 16 weeks. This contrasted with sera and saliva from SS patients, in which IL-17 and IL-6 were present at varying levels.Conclusion. These results suggest that the Th17/ IL-23 system is up-regulated in C57BL/6.NOD-Aec1Aec2 mice and SS patients at the time of disease. A correlation between up-regulated IL-17/IL-23 expression and specific clinical manifestations of SS has yet to be identified.

Systemic and Local Interleukin-17 and Linked Cytokines Associated with Sjögren’s Syndrome Immunopathogenesis

“…In MSGs from patients with SS, inflammatory cell infiltrates are pronounced (median FS ϭ 7; range, 4.87-9.75; n ϭ 10) and contain large numbers of CD3 ϩ T cells of which the majority are CD4 ϩ , with fewer numbers of 21 that may account, in part, for the detection of IL-17 in association with this population, also seen in previous studies, 22 but does not exclude their ability to produce this cytokine. Because the widespread distribution of the IL-17R may confound quantification because of an inability to dissociate cells producing IL-17 and those binding/ responding to it and multiple cell types may be responsible for IL-17 secretion, the number of IL-17 ϩ cells may seem inflated.…”

“…Seventh, Th17 pathogenesis may be enabled by circumvention of Treg accumulation. Finally, in a larger cohort of patients, IL-17 and key lineage commitment cytokines were significantly up-regulated systemically, distinct from recent studies, 22 but correlative with clinical manifestations and further indicative of their contribution to exocrinopathy and, potentially, systemic manifestations of pSS, as well as candidate diagnostic and/or prognostic markers.…”

“…Second, at the local tissue level, pronounced expression of IL-17 protein in the locale of infiltrating CD3 ϩ CD4 ϩ T lymphocytes was evident by immunohistochemical analyses, similar to recent reports. 21,22 However, we also demonstrate by detailed quantitative analysis that the number of IL-17 ϩ cells escalated as the lymphoepithelial lesions progressed from mild to intermediate and advanced and significantly correlated with focus scores, along with IL-17R-bearing cells. Fourth, levels of glandular tissue IL-17 RNA increased in parallel to protein, being higher in advanced disease than in mild or early stages.…”

Aquaporin gene therapy corrects Sjögren’s syndrome phenotype in mice

“…Salivary gland epithelia are reported to play an immune regulatory role as nonprofessional antigen-presenting cells and directly produce proinflammatory cytokines, such as IFN-γ, IL-17, IL-23, and chemokines (43)(44)(45)(46)(47). It is possible that the restoration of immune homeostasis may result from the external effect of AQP1 on the restoration of flow.…”

Spontaneous Autoimmune Dacryoadenitis in Aged CD25KO Mice

“…25 Furthermore, IL-17A expression has been found in salivary gland ductal epithelial cells of SS patients and nonobese diabetic (NOD) mice. 26,27 Numerous animal models of SS have been proposed in an attempt to elucidate the pathogenesis of the disease. Some of the more studied murine models include MRL/ lpr, NOD, and NZB/NZW.…”