Sjögren's Syndrome: Epidemiology, Classification Criteria, Molecular Pathogenesis, Diagnosis, and Treatment

Abstract

Sjögren's syndrome (SS) is a chronic autoimmune disorder characterized by T-cell-mediated B-cell hyperactivity and cytokine production, clinically manifesting, dry mouth and eyes, accompanied by pain and fatigue. The disease may progress from asymptomatic glandular involvement to systemic manifestations or even lymphoma. The pathogenesis of SS is intricate, involving a multifaceted interplay of genetic, environmental, and immunological factors. There is still uncertainty regarding the effectiveness of SS-targeted treatments, due to the significant diversity in disease phenotypes and potentially varying responses to immunomodulatory therapies, stringent enrollment criteria and adoption of outcome metrics in clinical trials may partially explain the failure of many trials to achieve their primary outcomes. Despite the current lack of effective treatments, recent advancements have been made in epidemiology, the development of classification criteria, and the establishment of systems for assessing disease activity. Notably, enhanced insights into the pathogenesis have paved the way for the potential development of targeted therapies. This review aims to systematically synthesize the latest research advancements in the epidemiological characteristics, diagnostic criteria, molecular mechanisms, and clinical manifestations of SS, thereby providing a scientific foundation for the development of future therapeutic strategies.

Keywords: Sjögren's syndrome; classification criteria; diagnosis; epidemiology; molecular pathogenesis; treatment.

FIGURE 1

A brief view of possible etiologic events preceding the diagnosis of desiccation syndrome. Created with www.figdraw.com.

FIGURE 2

Sjögren syndrome pathogenetic model. In genetically susceptible individuals, viral infection is thought to trigger activation of SGECs, which leads to activation of the innate immune system and ultimately to interactions between innate and adaptive immune cells. Activated SGECs can act as antigen‐presenting cells and produce a specific cytokine milieu, including IL‐6 (dark green squares), IFN‐I (yellow circles), CXCL12 (purple triangles), and BAFF (light green hexagons). In addition, overexpression of IFN‐I by plasmacytoid dendritic cells promotes B‐cell differentiation and survival, sges injury triggered by exogenous triggers and sustained by activated CD8⁺ T cells and immune complexes, leading to chronic release of self‐antigens, which in turn stimulates innate immune activation in a vicious cycle. B cells, monocytes and macrophages, innate‐like lymphocytes and T helper 17 (TH17) cells, as well as a variety of cytokines and chemokines are involved in the development of the disease.

FIGURE 3

Nucleic acid sensors and downstream signaling pathways induce type I IFN production. Cytoplasmic sensors for RNA (RIG‐1) and DNA (cGAS) signal through the adapters MAVS and STING, respectively, and activate the kinases TBK1 and IKKε, as well as downstream IRF3 (left). IRF3 translocates to the nucleus, cooperates with NF‐κB, and drives IFN‐β transcription in a variety of cell types including macrophages and epithelial cells. In pDCs producing large amounts of IFN‐α, nucleic acid‐containing immune complexes are endocytosed and delivered to the nuclear endosomes via the Fc receptor (FcR), which then activates TLR sensors in RNA (TLR7, TLR8) or DNA (TLR9) (right). These endosomal TLRs signal through the junction MyD88 and activate the IKK kinase complex, which in turn activates downstream transcription factors, including IRF7 and the NF‐κB subunits p50 and p65. IRF5 is activated by an unknown mechanism. These transcription factors translocate to the nucleus and drive IFN‐α transcription.

FIGURE 4

The involvement of IFN‐I‐activated immune cells and salivary gland epithelial cells (SGECs) in the pathogenesis of SS.

FIGURE 5

Type I, type II, and type III interferon signaling and IFN‐I pathway‐related inhibitors. Type I, type III, and type II interferons activate different typical signaling pathways leading to downstream induction of interferon‐sensitive response element (ISRE)‐driven and IFN‐γ‐activation site (GAS)‐driven target genes. IFN‐I binds the IFNAR receptor complex (composed of IFNAR1 and IFNAR2); type II interferon binds the IFNGR receptor complex (IFNGR1 and IFNGR2); and type III interferon binding IFNLR receptor complex (composed of INFLR1 and IL‐10Rβ). Binding of interferons to specific receptors results in activation of the Janus kinase (JAK)‐signal transducer and activator of transcription (STAT) pathway. Transcriptional activation of the IFN‐I signaling pathway requires that STAT dimers bind interferon regulatory factors (IRFs), that is, IRF9, translocated into the nucleus, where they bind to interferon signaling genes (IFGs) promoters on the ISREs or GASs, and binding to these promoter elements leads to the transcription of hundreds of IFGs.

FIGURE 6

Biological and synthetic DMARDs that target BCR signaling. Targeting BCR signaling has emerged as a promising therapeutic strategy in SS, the BCR signaling cascade is remarkably complex, involving a ged as a promising therapeutic strategy in SS, the BCR signaling cascade is remarkably complex, inK signaling enzymes, ultimately driving diverse cellular outcomes ranging from survival, anergy, or apoptosis to proliferation and differentiation into antibody‐producing cells or memory B cells. Created with www.figdraw.com.