Update on Pathogenesis of Sjogren's Syndrome

Abstract

Sjogren's syndrome is a common autoimmune disease that presents with sicca symptoms and extraglandular features. Sjogren's syndrome is presumably as common as RA; yet it is poorly understood, underdiagnosed and undertreated. From the usual identity as an autoimmune exocrinopathy to its most recent designate as an autoimmune epithelitis - the journey of SS is complex. We herein review some of the most important milestones that have shed light on different aspects of pathogenesis of this enigmatic disease. This includes role of salivary gland epithelial cells, and their interaction with cells of the innate and adaptive immune system. Non-immune factors acting in concert or in parallel with immune factors may also be important. The risk genes identified so far have only weak association, nevertheless advances in genetics have enhanced understanding of disease mechanisms. Role of epigenetic and environmental role factors is also being explored. SS has also some unique features such as congenital heart block and high incidence of lymphoma; disease mechanisms accounting for these manifestations are also reviewed.

Keywords: Aetiology; Sjogren's syndrome; epigenetics; genetics; immunological factors; non-immunological factors; pathogenesis.

Figure 1. Role of SGEC and Immune cells in Pathogenesis of Sjogren’s Syndrome

SGEC express a) MHC class II and costimulatory factors CD40 and CD80/86 that enhances interaction with T cells, and B7-H6, a ligand for NK cell receptor NCR30 b) chemokines CCL17,CCL19, CCL21, CCL22 that recruits T cells and dendritic cells; and CXCL13 that causes B cell homing, c)cytokines like TNFα, IL1, IL6, IL7,IL18,IL22, IFNα, BAFF d) IL33R e) adhesion molecules-ICAM,VCAM and selectin; and TLR3 f)FAS-FASL expression resulting in apoptosis g) SGEC also releases exosomes. Autoantigens Ro and La are contained in exosome bodies and apoptotic bodies. Immune cells –pDC are most important sources of IFNα. pDCs are believed to be activated by virus or endogenous nucleic acid containing immune complexes bound to TLRS. DCs interact closely with T cells and NK cells. DC, T cells as well as NK cells produce IFN γ which contributes to the IFN signature which acts as link between innate and adaptive immunity. IFN signature mediates lymphocytic infiltration and lymphocyte activation and stimulate BAFF production. Th1 pathway and Th17 pathway and their cytokines are important players in pathogenesis. IL 12, 1l21, IFNγ drives stimulates Th1 specific transcription factors and results in stimulation of TH1 pathway and its cytokines that is IFN γ, TNF. Th 17 cells produce il-17 and IL22 that augment the inflammatory response BAFF plays a crucial role in B cell maturation and proliferation. CXCL13 directs B cell homing into the salivary gland. CXCL13 binds to its receptor CXCR5 that is present on TFH cells and B cells, TFH and its cytokine IL21 induce B cell activation and formation of germinal centre. BAFF along with IFN also promotes autoantibody production by B cells. Immune complexes formed between antibodies and autoantigens further activates pDC enhancing and perpetuating inflammation. SGEC - Salivary gland epithelial cell, MHC-Major histocompatibility complex, NK-Natural killer, NCR-Natural-cytotoxicity-triggering receptor 3, IFN-Interferon, BAFF- B-cell activating factor, ICAM-Intercellular adhesion molecule, VCAM- vascular cell adhesion molecule 1,DC-Dendritic cell, pDC-plasmacytoid dendritic cell,

Figure 2

Interplay of immune and non-immune factors in pathophysiology of SS EC - Epithelial cell, DC - Dendritic cell, CHB - Congenital Heart Block.