Innate immunity in Sjögren's syndrome
Introduction
Sjögren's syndrome (SS) is a debilitating autoimmune disease in which the immune system targets exocrine gland tissue. Like many other autoimmune diseases, SS displays a strong female predilection [1]. The disease occurs in two forms: primary (pSS) and secondary (sSS). Patients with pSS often experience loss of salivary and lacrimal flow, and exhibit serious systemic disease manifestations as well [2]. In sSS, patients have a diagnosis of SS as well as another autoimmune connective tissue disease, such as lupus erythematosus (SLE) or rheumatoid arthritis (RA) [1]. Most patients with SS experience salivary hypofunction, and this can lead to rampant dental decay and difficulty in chewing and swallowing [3]. Currently, there are no approved therapies that address disease etiology and patient management is palliative.
Although the cause of SS remains poorly understood, it is characterized by exaggerated innate and adaptive immune responses. The adaptive immune system is comprised of B and T cells and has been studied extensively in SS [4], [5]. B and T cells are activated pathogenically, and abnormalities in both populations are seen in glandular tissue and systemically in SS mouse models and patients [6]. Specifically, alterations in normal CD4 + T helper subset ratios are observed [7], [8]. Activated T cells produce inflammatory cytokines that drive B cell differentiation and class switching. Numerous B cells abnormalities are found in SS patients. For example, SS patients have autoantibodies with diverse specificities and are at high risk of developing B cell lymphomas [4], [9], [10], [11]. Thus, the adaptive immune system is a key contributor to SS pathology.
The adaptive immune system is often activated by signals generated by the innate immune response. Innate immunity provides the “first line” of defense, and serves to recognize Pathogen-Associated Molecular Patterns (PAMPs). These microbial components are capable of eliciting rapid and robust inflammatory responses [12]. There are many different types of receptors that bind PAMPs, termed pattern recognition receptors (PRRs). Toll-like receptors (TLRs) and nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs) are examples of PRRs that are activated by PAMPs [13]. 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], [16], [17], [18]. While the innate immune system plays an important role in SS pathogenesis [19], [20], [21], [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. In addition, we will discuss current therapeutic approaches to mitigate activation of innate immunity.
Section snippets
Innate immune activation in salivary tissue precedes the adaptive in SS mouse models
Since markers of early SS disease in humans are not well defined, mouse models are instrumental in establishing early events that mediate exocrine gland dysfunction in SS [23]. Microarray studies performed on the C57BL/6.NOD-Aec1Aec2 pSS mouse model prior to lymphocytic infiltration of the submandibular gland (SMG) and lacrimal tissue identified differential expression of numerous genes associated with innate immunity [24], [25], [26]. Studies in SMG tissue from these animals revealed
Genetic studies in pSS patients identify polymorphisms in innate immune genes
Although there is a need for continued genetic studies in SS patients, polymorphisms in genes associated with innate immunity are identified by several groups [28], [29], [30], [31], [32]. There are > 15 robust susceptibility loci identified for SS and many of these are shared with SLE [33]. Similar to SLE, patients with SS display increased expression of type I and type II IFN-regulated genes in both salivary tissue and peripheral blood [19], [30], [34], [35], [36], [37], [38]. While the
Evidence for activation of innate immunity by environmental stimuli
The innate immune system is activated by environmental insults and these likely play an important role in the initiation and progression of disease. Studies in SS patients suggest viral infection may contribute to disease initiation and chronicity, as cytomegalovirus (CMV), Epstein Barr virus (EBV), and hepatitis C virus (HCV) are implicated in SS pathogenesis [42], [43], [44], [45]. Corroborating work shows that some SS patients display an IFN gene signature (vide supra), and IFNα is secreted
Innate immune cells in SS disease
Many types of innate cells are implicated in SS. Inappropriate activation of innate immune pathways occurs within exocrine tissue as well as systemically [19], [27], [53]. DCs, macrophages, salivary epithelial gland cells (SGECs) and natural killer (NK) cells are among the best characterized innate cells in SS, and the role of these cells in disease is discussed below.
Toll-like receptors
TLRs are crucial for innate immune activation [14]. TLRs are upregulated in salivary tissue and peripheral blood from SS patients and mouse models [25], [77], [83], [84], [85], [86], [87]. Therefore, signals transduced by TLR ligation may represent a sustained event in SS pathogenesis. While several TLRs are dysregulated in SS, we will limit our discussion to those that are best characterized in this disease.
Therapeutic approaches targeting innate immunity may be efficacious
Many therapeutics that reduce activation of the innate immune response are currently in clinical trials for the treatment of RA, SLE, and inflammatory bowel disease (IBD) [95], [108], [143], [144], [145]. A summary of emerging innate immune drug targets, effects and study phase is provided in Table 1 [95], [144], [146], [147], [148], [149], [150], [151], [152], [153], [154], [155], [156], [157], [158]. Given the centrality of innate-driven inflammation in SS, inhibition of receptors and
Conclusion
In summary, the innate immune response is crucial for SS pathogenesis, as it is implicated in disease initiation, chronicity, and likely contributes to the development of B cell lymphomas. Numerous cell types in peripheral blood as well as in exocrine tissue participate in the hyperactive innate immune response in SS. Emerging data suggest that noncoding RNAs also mediate innate immune dysfunction in the context of SS. Therefore, therapeutics that target innate immune inflammation will likely
Acknowledgements
Funding for this study was provided by the University at Buffalo School of Dental Medicine Start-up Funds (JMK).
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