The role of intrinsic epithelial activation in the pathogenesis of Sjögren’s syndrome
Introduction
Impaired function and/or architectural destruction of epithelial tissues is encountered in several organ-specific and systemic autoimmune diseases, such as primary biliary cirrhosis, psoriasis, thyroiditis, inflammatory bowel disorders, Sjögren’s syndrome and type-1 diabetes. Such changes are thought to be primarily the result of injurious insults induced by humoral and/or cellular autoimmune reactions against epithelial tissues. However, several lines of evidence indicate that epithelia are not solely the innocent bystander targets of autoimmune responses but probably have their role as initiators or amplifiers of the inflammatory reactions. In fact, accumulating evidence in the recent decade indicates that epithelia and probably other types of non-immunologic tissues (e.g. endothelia) are inherently active participants in immune defenses [1], [2]. Beyond their crucial role in creating physical barriers to infection, epithelial cells are critical in the initiation and regulation of both innate and adaptive immune responses [3], [4]. Toll-like receptors (TLRs) expressed by epithelial cells recognize distinct pathogen-associated molecular patterns (PAMPs) and evoke diverse responses including the release of anti-microbial peptides and cytokines [5]. Epithelial cells are also capable to express a wide range of proteins associated with the immune response, including major histocompatibility complex (MHC) class I and II, costimulatory molecules, chemokines, cytokines, and prostaglandins, which together coordinate a strong adaptive immune response [6], [7]. Epithelial immune responses to infection appear finely regulated to preserve the balance between the induction of effector immune functions and their potential to cause injuries to healthy tissue. Disturbance of this delicate balance may have devastating consequences to the infected host, such as tissue damages due to an inappropriate immune response or to an immune response that is insufficient to clear the pathogen [8]. On the other hand, epithelia appear to be also crucially involved in the initiation and maintenance of immunologic tolerance to self-antigens, whereas the disruption of this function may play a role in the development of chronic autoimmune reactions [9], [10]. In this context, defective epithelial immunologic functions may be an essential contributory factor for the development of autoimmune reactivities during chronic infection of epithelial tissues by various pathogenic organisms [11], [12]. Despite the apparent key role of epithelial cells in safeguarding the homeostasis of host immunologic reactions, the study of immune responses triggered by epithelial cells is still only at its beginning.
Sjögren’s syndrome (SS) is a chronic autoimmune disorder that is characterized by dysfunction and destruction of exocrine glands, mainly of the salivary and lacrimal glands. SS is relatively common (encountered in approximately 3% of general population) and may affect both sexes and all ages; however, the disorder has a strong predilection for women (9:1 female to male ratio) at their fourth or fifth decade of life. SS is placed centrally in the taxonomy of autoimmune diseases, as it can be found alone (primary SS) or in the context of almost every other autoimmune disease (secondary SS). Patients may manifest a broad spectrum of clinical symptoms that extend from disease confined to the exocrine glands (organ-specific exocrinopathy) to various extraglandular manifestations (systemic disease) and the development of B-cell lymphoma [13]. SS exocrinopathy is associated with the presence of periductal infiltrates consisting of activated T and B cells, macrophages, and dendritic cells [13], [14], as well as polyclonal B-cell hyperreactivity illustrated by profound hypergammaglobulinemia, multiple autoantibodies (such as antinuclear antibodies, antibodies to Ro/SSA, and La/SSB ribonucleoproteins, to histones and to single-stranded DNA, rheumatoid factors, and cryoglobulins), and complement consumption [13]. The precise etiology of the disorder remains unclear. Although the implication of an infectious agent has long been suspected for the induction of SS, no study has been conclusive so far. Based on the involvement of various epithelial tissues, epithelial cells have been considered as important players in the pathogenesis of the disorder [13], [15]. Altogether, the clinical, laboratory, and histologic features render SS an excellent model not only for the study of autoimmunity but also for the investigation of the role of epithelial tissues in the development of autoimmune responses.
Section snippets
In-situ activation of epithelial cells in Sjögren’s syndrome
The presence of lymphoid cell infiltrations of the exocrine glands (the so-called benign lymphoepithelial sialadenitis) is the histopathologic hallmark of primary SS. These lymphoid proliferations are reactive-type lesions with characteristic periductal location and associate with deformation of affected epithelial structures, atrophy and destruction of acini. In fact, lymphocytic infiltrates occur in close proximity to and frequently invade the ductal epithelia [13], a fact that strongly
Phenotypic and functional properties of salivary gland epithelial cells
Approximately 15 years ago, we have developed a simple and reproducible protocol for the establishment of long-term cultured non-neoplastic SGEC lines (of ductal type) from minute amounts of minor salivary gland tissues obtained from patients with sicca complaints during their routine diagnostic work-up for SS [35]. The application of this methodology has permitted the analysis of various aspects of phenotypic and functional properties of SGEC. In fact, from these studies, insight into two
Evidence for intrinsic activation of epithelial cells in Sjögren’s syndrome
The inflammatory microenvironment of exocrine glands of SS patients is rich in various types of proinflammatory cytokines and other factors that are capable to induce an activation status to the surrounding epithelia [46]. Evidently, such local production of proinflammatory agents appears directly responsible for the high in-situ expression of immunoactive factors that is observed by the glandular epithelia of the patients. Nevertheless, in a previous study, the careful analysis of the
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