Aspects of innate immunity in Sjögren's syndrome

Abstract

Previously, a dominant role of the adaptive immune system in the pathogenesis of Sjögren's syndrome was suspected. Recent advances, however, have revealed a major role of the type I IFN pathway, documented by an increased circulating type I IFN activity and an IFN 'signature' in peripheral blood mononuclear cells and minor salivary gland biopsies from the patients. Polymorphisms in the genes IRF5 and STAT4 leading to increased IFN activation are associated with disease susceptibility. In the pathogenesis of Sjögren's syndrome, the activation of salivary gland epithelial cells appears to be the initial event. Once intrinsically activated, they express costimulatory and Toll-like receptors (TLRs) and MHC class I and II molecules, can present autoantigens and produce proinflammatory cytokines. The subsequent activation of plasmacytoid dendritic cells induces the production of high levels of proinflammatory cytokines in individuals with the risk alleles of the susceptibility genes IRF5 and STAT4. Under the influence of the high IFN concentration in the glands and through TLR ligation, B-cell activating factor is produced by epithelial cells and, together with autoantigen presentation on salivary gland epithelial cells, stimulates the adaptive immune system. In view of the central role of IFNalpha in at least the initiation of the pathogenesis of Sjögren's syndrome, blockade of this cytokine may be a rational therapeutic approach.

Innate immunity in Sjögren's syndrome

“…Initially, it was thought that PRRs were important only in pathogen defense [14]; however, host-derived molecules can also activate innate immunity, and this is an established disease mechanism in autoimmunity [15–18]. While the innate immune system plays an important role in SS pathogenesis [19–22], the way in which it is activated is poorly understood. This review will provide an overview of the role of innate immunity in disease initiation and the specific cells and pathways that contribute to innate activation in SS.…”

The Potential Role for Early Biomarker Testing as Part of a Modern, Multidisciplinary Approach to Sjögren’s Syndrome Diagnosis

“…These new biomarkers are auto-antibodies to salivary protein-1 (SP-1), parotid secretory protein (PSP), and carbonic anhydrase VI (CA-6) [58,59]. An emerging hypothesis regarding SS pathogenesis includes a major role of the innate immune system [60]. These proteins (SP-1, PSP, CA-6) have various physiologic activities, including roles in the adherence and/or clearance of various infections [59].…”

Ocular Mucosal Immunity

“…There is increasing evidence that environmental factors such as viral infection or hypoestrogenism trigger Sjögren's syndrome in persons carrying susceptibility genes that predispose enhanced innate immunity via type 1 IFN pathway proteins, leading to activation of lacrimal and salivary gland epithelial cells. Subsequent autoantigen presentation by the epithelial cells leads to T cell activation and overproduction of B cell activating factor, induced by IFN, and stimulates B cell activation and initiation of adaptive immunity as well as the production of autoantibodies (Manoussakis and Kapsogeorgou, 2010;Mavragani and Crow, 2010;Low and Witte, 2011).…”