TLR7 Signaling Drives the Development of Sjögren's Syndrome.

Yawen Wang,Andrianos Nezos,Clio Mavragani,Noël Hanna Kazazian,Lionel Chasson,Laetitia Marcadet,Michael H Sieweke,Lena Alexopoulou,Annie Roussel-Queval

doi:10.3389/fimmu.2021.676010

Abstract

Sjögren’s syndrome (SS) is a chronic systemic autoimmune disease that affects predominately salivary and lacrimal glands. SS can occur alone or in combination with another autoimmune disease like systemic lupus erythematosus (SLE). Here we report that TLR7 signaling drives the development of SS since TLR8-deficient (TLR8ko) mice that develop lupus due to increased TLR7 signaling by dendritic cells, also develop an age-dependent secondary pathology similar to associated SS. The SS phenotype in TLR8ko mice is manifested by sialadenitis, increased anti-SSA and anti-SSB autoantibody production, immune complex deposition and increased cytokine production in salivary glands, as well as lung inflammation. Moreover, ectopic lymphoid structures characterized by B/T aggregates, formation of high endothelial venules and the presence of dendritic cells are formed in the salivary glands of TLR8ko mice. Interestingly, all these phenotypes are abrogated in double TLR7/8-deficient mice, suggesting that the SS phenotype in TLR8-deficient mice is TLR7-dependent. In addition, evaluation of TLR7 and inflammatory markers in the salivary glands of primary SS patients revealed significantly increased TLR7 expression levels compared to healthy individuals, that were positively correlated to TNF, LT-α, CXCL13 and CXCR5 expression. These findings establish an important role of TLR7 signaling for local and systemic SS disease manifestations, and inhibition of such will likely have therapeutic value.

Highlights

Sjögren’s syndrome (SS) is a chronic systemic autoimmune disease characterized by infiltration and destruction of exocrine glands, predominantly the salivary and lacrimal glands, that leads to xerostomia and keratoconjunctivitis sicca [1]
We demonstrate a critical role for TLR7 signaling in the pathogenesis of associated SS in TLR8-deficient mice that is characterized by sialadenitis, increased SSA and SSB autoantibody production, immune complex deposition, increased cytokine production and development of ectopic lymphoid structures (ELS) in salivary glands, as well as lung inflammation
Since current data suggest that TLR7 might be involved in SS we examined the phenotype of TLR8ko mice, which as we reported previously, by the age of 8 months develop spontaneous systemic lupus erythematosus (SLE)-like disease due to increased TLR7 signaling by dendritic cells (DCs) [10, 11]

Summary

Introduction

Sjögren’s syndrome (SS) is a chronic systemic autoimmune disease characterized by infiltration and destruction of exocrine glands, predominantly the salivary and lacrimal glands, that leads to xerostomia (dry mouth) and keratoconjunctivitis sicca (dry eyes) [1]. SS can develop as Increased TLR7 Prompts Sjögren’s Syndrome an entity alone, termed “primary” SS or it can occur together with another autoimmune disease, like systemic lupus erythematosus (SLE), rheumatoid arthritis or systemic sclerosis, termed “secondary” or “associated” SS [3]. The etiology of SS is multifactorial, where genetic, epigenetic, hormonal and environmental factors are thought to interact [4, 5]. Microbial infections, by viruses such as Epstein-Barr virus, cytomegalovirus, hepatitis C virus and retroviruses are considered as an important trigger for SS [4]

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