Glandular Epithelium: Innocent Bystander or Leading Actor?

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Introduction

Sjögren’s syndrome (SS) is an autoimmune disease with heterogeneous clinical pictures, which extend from benign local exocrinopathy that affects primarily the salivary and lachrymal glands to systemic disorder, and in approximately 5% of patients evolves to B-cell malignancies. Furthermore, SS can be expressed as an isolated clinical entity or coexpressed with virtually every other systemic autoimmune rheumatic disorder. Most of these features are present at diagnosis and do not change during follow-up treatment, suggesting that SS is a slowly progressive disease. Studies have identified clinical, laboratory, and histopathologic features, which predict the patients that are at high risk to develop lymphoproliferative disorder. Thus purpura, cryoglobulinemia, leukopenia, C3 and C4 hypocomplementemia, as well as persistent salivary gland enlargement, have been recognized as adverse prognostic indicators. Most importantly, in the majority of SS patients who are at high risk of lymphoma development, palpable purpura, cryoglobulinemia, and C4 hypocomplementemia are present at the time of diagnosis and thus can be used as predicting factors of adverse outcome. All these features along with the fact that the histopathologic lesions in minor salivary glands (MSGs) are easily accessible render SS as an ideal model for the study of autoimmunity and associated malignancy.

The extensive study of MSG autoimmune lesions revealed that, in accordance with the clinical picture of the disease, the severity and the composition of the histopathologic lesions vary among SS patients and do not significantly change over time. In fact, T cells predominate in mild lesions and B cells in severe, whereas macrophages increase with lesion severity and high incidence has been linked to lymphoma development. Most importantly, the severity and the composition of inflammatory lesions is fully blown at diagnosis and does not significantly change thereafter, with the exception of development of lymphoma in predisposed patients, suggesting that distinct pathogenetic pathways and immune responses operate in SS patients with variable degree of infiltration. Furthermore, the association between the intense salivary gland inflammation and the occurrence of extraglandular systemic manifestations such as Raynaud phenomenon, vasculitis, lymph node/spleen enlargement, and leukopenia, as well as of various histopathological parameters such as formation of ectopic germinal centers, infiltration by certain types of immune cells, and production of cytokines (eg, B-cell activating factor [BAFF], interleukin [IL]18, etc.) with lymphoma development, suggest that the local immune responses in SS are linked to the systemic manifestations of the disorder.

The mechanisms mediating the development and perpetuation of lymphocytic infiltrates, their severity, and the predominance of certain types of immune responses (T- or B-cell driven), as well as the way these could affect the outcome of the disease, have not been fully understood. Emerging data during the past two decades indicate that epithelial cells, which are the major targets of autoimmune responses, are not innocent bystanders but active, key regulators of SS autoimmune responses. Herein we summarize the factors that have been implicated in epithelial cell dysfunction, as well as the findings supporting the significant role of glandular epithelium in the development and regulation of autoimmune responses.

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Dysfunction of Glandular Epithelia in Sjögren’s Syndrome: “Innocent Bystanders”?

Historically, glandular epithelia in SS were considered to be innocent bystanders experiencing the injurious effects of chronic inflammation and its byproducts, such as function-modulating cytokines and cytotoxic and apoptotic signals that lead to epithelial dysfunction and/or destruction with ultimate result the salivary gland hypofunction. Nevertheless, the severity of salivary gland dysfunction in SS does not necessarily correlate with the degree of lymphocytic infiltration and epithelial loss and destruction, suggesting that the SS secretory functional impairment is not completely dependent on inflammatory processes. On the contrary, oral dryness in SS seems to be a complex phenomenon possibly owing to the reduction and/or inhibition of water transport machinery, as well as an altered quality of the saliva produced by epithelia. Autoimmune responses seem to affect both epithelial secretory function by modulating the underlying pathways and epithelial survival by promoting apoptotic cell death.