Sjogrens syndrome--the non-apoptotic model of glandular hypofunction.

The ‘classical’ model to explain glandular hypofunction in Sjögrens syndrome (SS) is tissue loss secondary to immune attack mediated by a combination of apoptosis and cytotoxic cell death (reviewed recently by Ramos-Casals and Font [1]). In this model, the process of glandular destruction is made self-sustaining by the continued production of novel ‘self ’ antigens, secondary to apoptotic bleb formation or cell-death [2]. Failure of the organ is thought to follow directly from tissue loss. For over six decades, research into SS has been directed towards understanding the mechanisms of destruction of salivary and lacrimal acinar tissue. Over this time, the only role envisaged for salivary glands themselves in the pathological process, has been that of a ‘reactor’ for infiltrating lymphocytes. Three recent observations cast a serious doubt on the principles upon which the classical model for salivary gland hypofunction in SS is based. Firstly, apoptosis of the epithelial cells in the salivary glands has been shown to be a rare event [3]. Secondly, many patients with SS who have little or no glandular function (as evidenced by markedly diminished or absent saliva output) nevertheless retain large amounts of normal-appearing acinar tissue in their salivary glands [4]. Thirdly, this residual tissue is functional in vitro [5, 6], but with a reduced sensitivity to muscarinic stimulation [5]. The latter is a crucial observation that is reflected in vivo, as many SS patients can be stimulated to secrete using systemic sialogogues [7]. According to the classical model, SS patients with no salivary flow should have no functional salivary tissue. This is clearly not the case. A ‘non-apoptotic’ model for glandular hypofunction in SS that may accommodate these findings has been proposed [4, 8–10]. In this model, glandular atrophy follows chronic immune-mediated inhibition of acinar secretory function. The many and varied mechanisms of glandular destruction, identified in association with the ‘classical’ model apply equally well to the ‘non-apoptotic’ model. What is different is that the atrophy is a consequence of salivary gland hypofunction and not the cause of it. What is most significant from any clinical perspective is that glandular destruction is clearly an irreversible process, but immune-mediated glandular hypofunction may not be. Within a ‘non-apoptotic’, ‘non-classical’ model of glandular hypofunction in SS, there is a fresh hope for both patients and clinicians because identification of the mechanisms responsible for inhibition of the secretory process may lead to the development of simplified and more sensitive diagnostic tools and ultimately to disease-modifying treatments.