An Overview of the Dry Eye Disease in Sjögren's Syndrome Using Our Current Molecular Understanding

Abstract

Sjögren's syndrome is a chronic and insidious auto-immune disease characterized by lymphocyte infiltration of exocrine glands. The patients typically present with ocular surface diseases related to dry eye and other systemic manifestations. However, due to the high prevalence of dry eye disease and the lack of objective and clinically reliable diagnostic tools, discriminating Sjögren's syndrome dry eye (SSDE) from non-Sjögren's syndrome dry eye (NSSDE) remains a challenge for clinicians. Diagnosing SS is important to improve the quality of life of patients through timely referral for systemic workups, as SS is associated with serious systemic complications such as lymphoma and other autoimmune diseases. The purpose of this article is to describe the current molecular understanding of Sjögren's syndrome and its implications for novel diagnostic modalities on the horizon. A literature review of the pre-clinical and clinical studies published between 2016 and 2022 was conducted. The SSDE pathophysiology and immunology pathways have become better understood in recent years. Novel diagnostic modalities, such as tear and saliva proteomics as well as exosomal biomarkers, provide hope on the horizon.

Keywords: Sjögren syndrome; basic research; biomarkers; diagnosis; dry eye; exosomes; immune pathway; ocular surface; pathophysiology; proteomics.

Figure 1

The 4 steps in the pathogenesis of Sjögren’s syndrome dry eye.

Figure 2

Schematic representation of Sjogren’s syndrome pathogenesis. Environmental triggers, such as viruses, are known to activate innate immunity cells (e.g., macrophages) through pathogen-associated molecular patterns (PAMPs) and pathogen recognition receptors (i.e., toll-like receptors (TLRs)). The activation of TLRs induces a pro-inflammatory microenvironment, marked by the production of type 1 interferons (IFNs). IFNs enhance pro-inflammatory cytokine production by activating the JAK-STAT pathway in salivary gland epithelial cells (SGECs). Ultimately, the pro-inflammating environment leads to the formation of germinal center (GC)-like structures, composed of a tremendous number of activated B and T cells. (The Figure was partly generated using Servier Medical Art, provided by Servier, licensed under a Creative Commons Attribution 3.0 unported license).

Figure 3

Overview of the American College of Rheumatology/European League Against Rheumatism criteria for primary Sjögren’s syndrome 2016. This classification criteria applies to an individual who meets one of the inclusion criteria and does not have any of the exclusion criteria. A score of 4 or above confirms the diagnosis of pSS.

Figure 4

Main steps involved in exosomal biogenesis. Exosome formation is initiated by the endocytic pathway. Endocytosis of cell membrane components and lipids leads to the formation of early endosomes in the cytosol. Endosome sorting by ESCRT and CHMP proteins leads to the formation of multivesicular bodies composed of intraluminal vesicles (ILVs). Cell trafficking processes transfer late endosomes to the cell membrane, where the exocytic pathway expels exosomes in the extracellular space. (The Figure was partly generated using Servier Medical Art, provided by Servier, licensed under a Creative Commons Attribution 3.0 unported license).