Epithelial–immune cell interplay in primary Sjögren syndrome salivary gland pathogenesis

Abstract

In primary Sjögren syndrome (pSS), the function of the salivary glands is often considerably reduced. Multiple innate immune pathways are likely dysregulated in the salivary gland epithelium in pSS, including the nuclear factor-κB pathway, the inflammasome and interferon signalling. The ductal cells of the salivary gland in pSS are characteristically surrounded by a CD4+ T cell-rich and B cell-rich infiltrate, implying a degree of communication between epithelial cells and immune cells. B cell infiltrates within the ducts can initiate the development of lymphoepithelial lesions, including basal ductal cell hyperplasia. Vice versa, the epithelium provides chronic activation signals to the glandular B cell fraction. This continuous stimulation might ultimately drive the development of mucosa-associated lymphoid tissue lymphoma. This Review discusses changes in the cells of the salivary gland epithelium in pSS (including acinar, ductal and progenitor cells), and the proposed interplay of these cells with environmental stimuli and the immune system. Current therapeutic options are insufficient to address both lymphocytic infiltration and salivary gland dysfunction. Successful rescue of salivary gland function in pSS will probably demand a multimodal therapeutic approach and an appreciation of the complicity of the salivary gland epithelium in the development of pSS. Salivary gland dysfunction is an important characteristic of primary Sjögren syndrome (pSS). In this Review, the authors discuss various epithelial abnormalities in pSS and the mechanisms by which epithelial cell–immune cell interactions contribute to disease development and progression. Dysregulation of the functional machinery of acini, activation and apoptosis of ductal cells and defects in progenitor cell homeostasis all contribute to salivary gland dysfunction in primary Sjögren syndrome (pSS). Unknown trigger(s) in salivary gland epithelial cells might activate innate immune responses and result in adaptive immune responses towards self-antigens, making epithelial cells both mediators and targets of the response. Dysregulation of innate immune signalling pathways in salivary gland epithelial cells and consequent pro-inflammatory cytokine production by the epithelium probably contributes to salivary gland dysfunction. Direct or indirect interference of autoantibodies with innate immune responses could perpetuate type I interferon activity in salivary gland epithelial cells and immune cells. Increased activation of nuclear factor-κB and expression of pro-survival factors, together with enhanced proliferation, might predispose certain intraepithelial B cells to neoplastic changes, promoting mucosa-associated lymphoid lymphoma development. The restoration of salivary gland function in patients with pSS might require treatment tailored to glandular pathology and multimodal therapeutic approaches, for example, a combination of immunotherapy and cell therapy. Dysregulation of the functional machinery of acini, activation and apoptosis of ductal cells and defects in progenitor cell homeostasis all contribute to salivary gland dysfunction in primary Sjögren syndrome (pSS). Unknown trigger(s) in salivary gland epithelial cells might activate innate immune responses and result in adaptive immune responses towards self-antigens, making epithelial cells both mediators and targets of the response. Dysregulation of innate immune signalling pathways in salivary gland epithelial cells and consequent pro-inflammatory cytokine production by the epithelium probably contributes to salivary gland dysfunction. Direct or indirect interference of autoantibodies with innate immune responses could perpetuate type I interferon activity in salivary gland epithelial cells and immune cells. Increased activation of nuclear factor-κB and expression of pro-survival factors, together with enhanced proliferation, might predispose certain intraepithelial B cells to neoplastic changes, promoting mucosa-associated lymphoid lymphoma development. The restoration of salivary gland function in patients with pSS might require treatment tailored to glandular pathology and multimodal therapeutic approaches, for example, a combination of immunotherapy and cell therapy.