The Interferon-Signature of Sjögren's Syndrome: What Does It Say About the Etiopathology of Autoimmunity?

Introduction

Sjögren's syndrome (SS) is a chronic systemic human autoimmune disease, but one characterized primarily by an immune-mediated destruction of salivary and lacrimal gland function resulting, respectively, in dry mouth (stomatitis sicca/xerostomia) and dry eye (keratoconjunctivitis sicca/xerophthalmia) diseases. However, in addition to the apparent primary sites of autoimmunity in SS, multiple tissues may become involved including the GI tract, skin, lungs, vasculature, kidneys, bladder, and vagina. Interestingly, approximately 20% of SS patients exhibit various neuropathies, including sensory, peripheral, cranial, and myelopathic complications, plus various cognitive impairments such as dementia, lack of concentration, memory loss, and various psychiatric disorders (ranging from depression to anxiety) that are often noted in patients during clinic visits, referred to as “mental fogginess.” Involvement of the musculature can lead to fibromyalgia-like symptoms and chronic fatigue, the latter being one of the most prevalent complaints. Although SS is generally not considered a lethal disease in the absence of B cell lymphoma formation, patients have an increasingly diminished quality of life as the disease progresses.

Abstract

INTRODUCTION

Sjögren's syndrome (SS) of humans and SS-like (SjS-like) diseases in mouse models are characterized by chronic immune attacks against the salivary and lacrimal glands leading to exocrine dysfunction. One characteristic of SS is an upregulated expression of interferon (IFN) and IFN-responsive genes, designating SS as an “interferon-signature” disease.

OBJECTIVE

To determine if SjS-like disease of C57BL/6.NOD-Aec1Aec2 mice, a model of primary SjS, displays the interferon-signature of SS.

METHODS

Using oligonucleotide microarrays, temporal gene expression profiles were generated for salivary and lacrimal glands of 4–20 week old C57BL/6.NOD-Aec1Aec2 mice. Pair-wise analyses were used to identify differentially expressed IFN and IFN-responsive genes.

RESULTS

Temporal gene expression profiles of IFN genes indicated that only a single gene, Ifna5, showed an upregulated expression during development and onset of SjS-like disease. In contrast, a selective subset of IFNα/β- and/or IFNγ-responsive genes were highly upregulated, and the times at which they were maximally upregulated corresponded to the two time points defining either the innate response (8–12 weeks of age) or the adaptive immune response (16–20 weeks of age). Several upregulated IFN-responsive genes of C57BL/6.NOD-Aec1Aec2 mice overlapped significantly with genes reported to be upregulated in PBMCs and/or LSG biopsies of SS patients.

CONCLUSIONS

Although a variety of genes known to respond to the direct or indirect actions of an IFN are upregulated in SS/SjS-like disease, the genes differentially expressed represent select subsets. We hypothesize, therefore, that understanding the functions of these upregulated genes and how they interact molecularly and biologically should provide critical details of SS pathology.

Keywords

Sjögren's Syndrome, interferon-signature, interferon genes, interferon-responsive genes, Mda5/Mavs, microarray, NOD mouse