Sjögren's syndrome and the danger model

Abstract

This review seeks to cover the data on primary Sjogren’s syndrome (SS) that has accumulated especially during recent years, and that apparently fits into a common theme of cellular stress abnormalities. This includes demonstrations of hyperactivity of danger-sensing antigen-presenting cells (APC), and of a strong response to DNA damage in many different cell types. The relevance of these findings for the pathogenesis of SS will be addressed by applying them to the danger model of immune activation [1, 2]. This model has been put forward by Matzinger, stating that immune activation, including the innate system as well as the adaptive lymphocyte response, is initiated by danger in a broad sense rather than solely by the presence of infectious non-self material. By means of danger signals, tissue stress is postulated to activate the APC of the innate immune system, in turn influencing also the adaptive immune cells, i.e. T and B lymphocytes. Thus, a consequence of the danger model of immune activation is that danger signals can be assumed to be a primary determinant of autoimmunity. A number of factors that threaten the integrity of a tissue or the host may act as danger signals. These are produced by, for example, necrotic cells, hypoxia, low pH and mechanical damage to blood vessels. Danger signals from necrotic cells that strongly stimulate APC to up-regulate HLA and costimulatory molecule expression include heat shock proteins transferred upon cell death to the cell surface [3], and the release from dying cells of high concentrations of crystalline uric acid [4]. CD40L on activated extravasating platelets, hyaluron modified in traumatized tissue, reactive oxygen species (ROS) and non-self molecules such as bacterial cell wall lipopolysaccharides can also act as potent danger signals, by the mechanism of binding to Tolllike receptors and other surface markers on APC [1, 2, 5–8]. Interestingly, physiological cell death manifested as apoptosis, posing no threat to the tissues, has been found to have a relatively minor influence on APC, in accordance with the lack of inflammation being typical of apoptosis [9].