Molecular Mechanisms Linking Inflammation to Autoimmunity in Sjögren's Syndrome: Identification of New Targets

Abstract

Sjögren's syndrome (SS) is a systemic autoimmune rheumatic disorder characterized by the lymphocytic infiltration of exocrine glands and the production of autoantibodies to self-antigens. The involvement of the exocrine glands drives the pathognomonic manifestations of dry eyes (keratoconjunctivitis sicca) and dry mouth (xerostomia) that define sicca syndrome. To date, the molecular mechanisms mediating pathological salivary gland dysfunction in SS remain to be elucidated, despite extensive studies investigating the underlying cause of this disease, hampering the development of novel therapeutic strategies. Many researchers have identified a multifactorial pathogenesis of SS, including environmental, genetic, neuroendocrine, and immune factors. In this review, we explore the latest developments in understanding the molecular mechanisms involved in the pathogenesis of SS, which have attracted increasing interest in recent years.

Keywords: EMT; Sjögren’s syndrome; angiogenesis; apoptosis; aquaporin; autoimmunity.

Figure 1

Scheme that clarifies the hypothetical onset of SS.

Figure 2

Schematic representation of recently identified apoptotic events in SS. B-cell lymphoma protein 2 antagonist killer 1 (BAK); B-cell lymphoma protein-2-associated X protein (BAX); cytochrome c (Cyt c); death-inducing signaling complex (DISC); Epstein–Barr virus (EBV); fatty acid synthetase ligand (FASL); Fas-associated protein with death domain (FADD); human immunodeficiency virus (HIV); human T-cell leukemia virus type 1 (HTLV-1); lysosome-associated membrane protein 3 (LAMP3); nucleotide-binding domain (NOD)-like receptor protein 3 (NLRP3); tumor necrosis factor receptor type 1-associated DEATH domain (TRADD); TNF-related apoptosis-inducing ligand (TRAIL) retinoblastoma-associated protein 48 (RBAp48).

Figure 3

Role of angiogenesis in SS and SS-related diseases. Cluster of differentiation 3 (CD3); cluster of differentiation 31 (CD31); chemokine receptor type 4 (CXCR4); intercellular adhesion molecule 1 (ICAM-1); nuclear factor kappa B (NF-kB); vascular cell adhesion molecule 1 (VCAM-1); vascular endothelial growth factor A (VEGFA); vascular endothelial growth factor receptor 2 (VEGFR).

Figure 4

Advances in AQP research in SS (aquaporin, AQP).

Figure 5

Possible mechanisms of EMT activation in SS. Bone Morphogenetic Protein (BMP); ETS Proto-Oncogene 1, Transcription Factor (ETS); Follistatin-Like Protein 1 (FSTL1); Interleukin-6 (IL-6); Interleukin-17 (IL-17); Interleukin-22 (IL-22); mothers against decapentaplegic homolog 2 (SMAD2), mothers against decapentaplegic homolog 3 (SMAD3); mothers against decapentaplegic homolog 4 (SMAD4); zinc finger protein SNAI (SNAIL); transforming growth factor beta (TGF-β); transforming growth factor-β type I receptor (TGF-β RI/I).