A comprehensive review of Sjögren's syndrome: Classification criteria, risk factors, and signaling pathways

Abstract

Sjögren's syndrome (SS) is a chronic autoimmune disease that affects the exocrine glands and may lead to a range of systemic symptoms that impact various organs. Both innate and adaptive immune pathways might trigger the disease. Studying the signaling pathways underlying SS is crucial for enhancing diagnostic and therapeutic effectiveness. SS poses an ongoing challenge for medical professionals owing to the limited therapeutic options available. This review offers a comprehensive understanding of the intricate nature of SS, encompassing disease classification criteria, risk factors, and signaling pathways in immunity and inflammation. The advancements summarized herein have the potential to spark new avenues of research into SS.

Keywords: Immune; Inflammation; Signaling pathways; Sjögren's syndrome.

Fig. 1

General features, risk factors and systemic complications of Sjögren's syndrome Sjögren's syndrome is an incurable autoimmune disease that occurs most frequently in women, usually affecting the lacrimal and salivary glands, with systemic complications. Genetic, viral, and hormonal factors are essential in inducing SS. The extra-glandular manifestations mainly include active synovitis, severe leukocytopenia, interstitial pneumonia, autoimmune cytopenia, Raynaud's phenomenon, lymphadenopathy, cutaneous vasculitis, renal disease, neurological involvement, and myositis. Interstitial lung disease is the most common pulmonary complication in SS. Non-Hodgkin's lymphoma is a severe complication of SS and could worsen disease prognosis. In severe cases, the extra-glandular manifestations of SS may be life-threatening. Created with BioRender.com.

Fig. 2

Milestones in the history of research on Sjögren's syndrome SS has been studied for over a century, with research progressing from case reports to cellular and molecular studies. The history of SS research may be divided into three periods: clinical (1888–1950), immunologic (1950–1980), and molecular (1980–present). Over time, SS became recognized as a systemic disease by Sjögren in 1933 and auto-antibodies were subsequently discovered by various researchers. The development of lip gland biopsy and the recognition of auto-antibodies have led to notable improvements in the diagnosis and treatment of SS. Various classification standards for the diagnosis of SS have been successively formulated. The earliest of these was the Bloch criterion in 1965, which was followed by several regional standards. The 2002 European criteria, the 2012 Sjögren's International Collaborative Clinical Alliance classification standard, and the 2016 American College of Rheumatology/European League Against Rheumatism Classification Criteria are commonly used at present. Created with BioRender.com.

Fig. 3

The complex pathogenesis of Sjögren's syndrome (a) Altered glandular homeostasis precedes the onset of inflammation, contributing to secretory dysfunction in patients with SS. In individuals with SS, acinar cells tend to have multiple defects. The expression of different AQPs is altered, and the ability of these channels to respond to muscarinic stimuli is significantly impaired. Aberrant localization of fusion receptors involved in regulated exocytosis has been observed in the salivary glands of SS patients. The ductal epithelium may be affected during SS development because of various pathogenic events such as activation of innate immune pathways, epithelial cell apoptosis, and senescence. Multiple factors could cause chronic antigen exposure, leading to the formation of lymphoepithelial lesions. (b) During immune cell activation, pro-inflammatory factors are released, leading to sustained and persistent inflammatory responses, amplifying tissue damage, and causing progressive functional damage to affected organs. TFH cells secrete cytokines to drive B cell proliferation, leading to the differentiation of B cells into plasma cells and the production of numerous autoantibodies, thus further advancing the progression of SS. The activated infiltrated immune cells are considered to form a complex signaling network with salivary gland cells, leading to impaired secretion. Created with BioRender.com.