Th17 cells in primary Sjögren's syndrome: Pathogenicity and plasticity

Abstract

Th17 cells play an important physiological role at mucosal barriers, and are involved in inflammatory responses to pathogens. Th17 cells and their signature cytokine IL-17 are also present in salivary gland lesions of primary Sjögren's syndrome (pSS) patients and can be elevated in their peripheral blood. In pSS patients, clear correlations between increased Th17 cell activity and symptoms of the disease have not been found, but Th17 cells may contribute to disease progression, for example by supporting autoreactive B cell responses. In mouse models of pSS, Th17 cells play an important role in pathogenesis, particularly at disease onset, when there is a disturbed balance between T effector and T regulatory cells. Studying the pathogenicity of Th17 cells in humans is complicated due to the plasticity of this cell subset, allowing them to obtain different effector functions depending on the local environment. Th17 cells can develop towards Th17.1 cells, producing both IL-17 and IFN-γ, or even towards Th1-like cells producing IFN-γ in the absence of IL-17. These effector subsets may be more pathogenic than bona fide Th17 cells. Co-expression of IFN-γ by Th17 cells has been shown to promote chronic inflammation in several autoimmune diseases and may also contribute to pSS pathogenesis. In line with the noticeable role of IL-17 in pSS mouse models, interference with Th17 cell generation, recruitment or effector functions (e.g. IL-17 inhibition) can prevent or ameliorate disease in these models. Therapies targeting Th17 cells or IL-17 have not been tested so far in pSS patients, although treatment with rituximab seems to lower local and systemic IL-17 protein levels, and to a lesser extent also chemokine receptor-defined Th17 cells. In this review we discuss current knowledge of pathogenicity and plasticity of Th17 cells in human pSS and murine models of pSS. We postulate that plasticity towards Th17.1 cells in pSS may enhance pathogenicity of Th17 cells at the main target sites of the disease, i.e. salivary and lacrimal glands.

Impaired Interleukin‐27–Mediated Control of CD4+ T Cell Function Impact on Ectopic Lymphoid Structure Formation in Patients With Sjögren's Syndrome

“…Thus, in SS patients, despite an increased expression of IL‐27 during active disease, impaired IL‐27 responsiveness leading to an aberrant control of IL‐17 and an excessive IFNγ response may contribute to the higher degree of SG immunopathology and ELS development observed. Consistent with this hypothesis, Th17 overactivation has been associated with the early phases of SG inflammation and the formation of ectopic GCs , while hyperactivation of type II IFN has been advocated as a biomarker of lymphoma development in SS .…”

Gut dysbiosis is prevailing in Sjögren’s syndrome and is related to dry eye severity

“…Regarding patients with environmental dry eye syndrome, the compositional changes of gut microbiota was somewhere between those of Sjögren's syndrome and controls. It suggests that pathogenesis of environmental dry eye syndrome would be different from the immunedysregulation in Sjögren's syndrome [40], although many studies revealed the culprit role of Th17 cells in environmental dry eyes [41][42][43]. Interestingly, Subdoligranulum genus was significantly decreased in environmental dry eye syndrome compared to controls and Sjögren's syndrome.…”

Modulation of Apoptosis by Cytotoxic Mediators and Cell-Survival Molecules in Sjögren’s Syndrome

“…With regard to SS patients’ genetic backgrounds, genome-wide association studies (GWAS) for SS patients showed susceptible loci in major histocompatibility complex and in regions for GTF21, along with differences among ethnic groups [10,11]. Although interferon-γ and Th2 cytokines are pathologically major factors for T cell-related immunological dysfunction in SS [12,13], a recent study showed the importance of the involvement of Th17 cells in SS [14]. …”