The complexity of Sjögren's syndrome: Novel aspects on pathogenesis

Abstract

In Sjögren's syndrome, like in most other autoimmune diseases, the enigma leading to a pathogenic attack against self has not yet been solved. By definition, the disease must be mediated by specific immune reactions against endogenous tissues to qualify as an autoimmune disease. In Sjögren's syndrome the autoimmune response is directed against the exocrine glands, which, as histopathological hallmark of the disease, display persistent and progressive focal mononuclear cell infiltrates. Clinically, the disease in most patients is manifested by two severe symptoms: dryness of the mouth (xerostomia) and the eyes (keratoconjunctivitis sicca). A number of systemic features have also been described and the presence of autoantibodies against the ubiquitously expressed ribonucleoprotein particles Ro (Sjögren's-syndrome-related antigen A – SSA) and La (SSB) further underline the systemic nature of Sjögren's syndrome. The original explanatory concept for the pathogenesis of Sjögren's syndrome proposed a specific, self-perpetuating, immune mediated loss of acinar and ductal cells as the principal cause of salivary gland hypofunction. Although straightforward and plausible, the hypothesis, however, falls short of accommodating several Sjögren's syndrome-related phenomena and experimental findings. Consequently, researchers considered immune-mediated salivary gland dysfunction prior to glandular destruction and atrophy as potential molecular mechanisms underlying the symptoms of dryness in Sjögren's syndrome. Accordingly, apoptosis, fibrosis and atrophy of the salivary glands would represent consequences of salivary gland hypofunction. The emergence of advanced bio-analytical platforms further enabled the identification of potential biomarkers with the intent to improve Sjögren's syndrome diagnosis, promote the development of prognostic tools for Sjögren's syndrome and the long-term goal to identify possible processes for therapeutic treatment interventions. In addition, such approaches allowed us to glimpse at the apparent complexity of Sjögren's syndrome.

Introduction

Sjögren's syndrome is a complex autoimmune rheumatic disease characterized by mononuclear cell infiltration of exocrine glands and the presence of autoantibodies against the ribonucleoprotein particles SSA/Ro and SSB/La. The salivary and lacrimal glands are the principal targets of a proposed T cell mediated chronic inflammation, with a resulting glandular atrophy and deficient function. The clinical consequences are dry eyes (keratoconjunctivitis sicca) and dry mouth (xerostomia). Due to affection of other organs there are a number of systemic features of Sjögren's syndrome.

One of the unsolved questions in this directed autoimmune attack has been the mechanism responsible for the formation of mononuclear cell accumulations in exocrine glands. It has been hypothesized that primary events (e.g. infections) may occur in the glands themselves, followed in a second phase by an autoimmune attack. Whether B cell activation is a primary cause or a secondary effect in Sjögren's syndrome is not known.

The etiology and many aspects of the pathogenesis of Sjögren's syndrome are still elusive. Several factors such as genetic predisposition and environmental triggers influence the development of Sjögren's syndrome, and only after irreversible organ damage has occurred become clinical symptoms evident. Moreover, diagnosis is hampered by the heterogeneity of manifestations leading to further delay of the correct diagnosis (Fig. 1). So far, there exists no cure for this disease, and the treatment is limited to ease the symptoms.

In this review we will, after giving some background information about Sjögren's syndrome, highlight recent and novel aspects on the pathogenesis.