Toll-Like Receptor 7 Is Required for Lacrimal Gland Autoimmunity and Type 1 Diabetes Development in Male Nonobese Diabetic Mice.

Ivy L Debreceni,Michael S Chimenti,Yi-Guang Chen,Scott M Lieberman,Aron M Geurts,David V Serreze

doi:10.3390/ijms21249478

Abstract

Sjögren syndrome (SS) is an immunologically complex, chronic autoimmune disease targeting lacrimal and salivary glands. Nonobese diabetic (NOD) mice spontaneously develop inflammation of lacrimal and salivary glands with histopathological features similar to SS in humans including focal lymphocytic infiltrates in the affected glands. The innate immune signals driving lymphocytic infiltration of these glands are not well-defined. Here we evaluate the role of Toll-like receptor (TLR) 7 in the development of SS-like manifestations in NOD mice. We created a Tlr7 knockout NOD mouse strain and performed histological and gene expression studies to characterize the effects of TLR7 on autoimmunity development. TLR7 was required for male-specific lacrimal gland inflammation but not for female-specific salivary gland inflammation. Moreover, TLR7 was required for type 1 diabetes development in male but not female NOD mice. RNA sequencing demonstrated that TLR7 was associated with a type I interferon (IFN) response and a type I IFN-independent B cell response in the lacrimal glands. Together these studies identify a previously unappreciated pathogenic role for TLR7 in lacrimal gland autoimmunity and T1D development in male NOD mice adding to the growing body of evidence supporting sex differences in mechanisms of autoimmune disease in NOD mice.

Highlights

Sjögren syndrome (SS) is a chronic autoimmune disease that primarily targets lacrimal and salivary glands leading to progressive exocrine gland dysfunction and debilitating ocular and oral dryness [1]
We developed gene-edited Nonobese diabetic (NOD) mice lacking Tlr7 expression and found that male mice lacking TLR7 were protected from the spontaneous development of lacrimal gland inflammation, whereas females were not protected from spontaneous salivary gland inflammation
To evaluate the role of TLR7 in the development of autoimmunity in NOD mice, we developed Tlr7 knockout (KO) NOD mice through CRISPR/Cas9-mediated gene editing directly in NOD mouse embryos resulting in a 2 base-pair deletion in Tlr7 (Figure 1A)

Summary

Introduction

Sjögren syndrome (SS) is a chronic autoimmune disease that primarily targets lacrimal and salivary glands leading to progressive exocrine gland dysfunction and debilitating ocular and oral dryness [1]. The ensuing poor ocular and oral health may lead to defects in vision and difficulty with normal oral function such as talking and swallowing. Beyond these glandular manifestations, many individuals with SS develop autoimmunity affecting other organs, chronic musculoskeletal pain, and profound fatigue. Current treatments largely aim to replace or augment tears and saliva but fail to adequately halt or reverse the chronic inflammation to prevent damage or progressive exocrine gland dysfunction. The lack of well-established therapeutics to modulate the immune response may relate to the gap in understanding of the early immunopathogenic mechanisms driving the exocrine gland inflammation

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