Sjögren's syndrome pathophysiology
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Farbod Zahedi Tajrishi, M.D.
Overview
Sjögren's syndrome (SS) is a chronic auto-immune disorder that can affect several organ systems. Both genetic and immune factors contribute to the pathogenesis of the disease. In the most common presentation of the disease, lymphocytes infiltrate the lacrimal and salivary glands and impair their function, hence causing the main characteristic symptoms- dry mouth (keratoconjunctivitis sicca) and eyes (xerostomia). CD4+ T-cells are predominant in mild and moderate salivary gland infiltrations, while B cells play the major role in severe lesions.[1] The disease may also manifest itself with dryness of skin and other mucosal surfaces or even cause systemic extraglandular disturbances such as arthritis, vasculitis and renal, pulmonary, hematopoietic and neurologic involvement. In general, a combination of lymphocytic infiltration, B lymphocyte hyperreactivity, production of certain autoantibodies, genes mostly involved in the production of MHC molecules and certain viral infections are all linked to the pathogenesis of SS.
Pathophysiology
The pathogenesis of Sjögren's syndrome can be linked to both genetic and nongenetic components:[2]
Genetic components:
Multiple genes are found to be associated with Sjögren's syndrome. Evidence suggests genes that encode MHCs, particularly Human Leukocyte Antigens (HLA) genes, play an important role in the disease, although ethnicity seems to affect these roles.[3][4][5] Among non-HLA genes, TNIP1, IRF5, BLK, STAT4, IL12A, and CXCR5 are all reported to have a significant association.[6] These genes mainly contribute to the production and activation pathways of several immune signal molecules such as interferons and interleukins, therefore facilitating the immune injury to the susceptible tissues.
Viral infections:
Several studies have indicated an association between Sjögren's syndrome and some viral infections. Though the evidence is not definitive yet, both Epstein-Barr Virus (EBV) and Coxsackie Virus are thought to be having a role in causing primary SS. There are also certain types of viruses including HIV, HTLV-1 and Hepatitis C virus that cause SS-like syndromes.
Immune-mediated components:
- 1. Lymphocytic infiltration:
The basic mechanism underlying the symptoms of SS involves infiltration of lymphocytes into the exocrine glands. While the infiltrating B and T cells remain somehow resistant to apoptosis themselves, T cells induce apoptosis signals to the glandular epithelial cells, causing them to die and the gland to malfunction. The infiltrated T cells also produce several cytokines, all of which playing a part in tissue inflammation. T helper 17 (Th17) cells and the interleukin 17 (IL17) they produce, can boost local inflammation in SS along with a change in cytokine balance between T helper 1 and 2 cells (Th1 and Th2) in favor of Th1.[7]
- 2. Autoantibodies:
Anti-Ro/SSA and Anti-La/SSB are the most common autoantibodies (both from IgG subclass) found in patients with SS. Anti-Ro/SSA is found in more than 70-90 percent[8] of patients and is produced against an autoantigen consisting of a complex of two polypeptide (52 and 60 kDa) chains along with cytoplasmic RNAs. Anti-52 kD antibodies are more strongly associated with the primary form of SS, while anti-60 kD antibodies are common in SS associated with Systemic Lupus Erythematosus (SLE).[9]
References
- ↑ Christodoulou MI, Kapsogeorgou EK, Moutsopoulos HM (2010). "Characteristics of the minor salivary gland infiltrates in Sjögren's syndrome". J Autoimmun. 34 (4): 400–7. doi:10.1016/j.jaut.2009.10.004. PMID 19889514.
- ↑ Mavragani CP, Nezos A, Moutsopoulos HM (2013). "New advances in the classification, pathogenesis and treatment of Sjogren's syndrome". Curr Opin Rheumatol. 25 (5): 623–9. doi:10.1097/BOR.0b013e328363eaa5. PMID 23846338.
- ↑ Lessard CJ, Li H, Adrianto I, Ice JA, Rasmussen A, Grundahl KM; et al. (2013). "Variants at multiple loci implicated in both innate and adaptive immune responses are associated with Sjögren's syndrome". Nat Genet. 45 (11): 1284–92. doi:10.1038/ng.2792. PMC 3867192. PMID 24097067.
- ↑ Li Y, Zhang K, Chen H, Sun F, Xu J, Wu Z; et al. (2013). "A genome-wide association study in Han Chinese identifies a susceptibility locus for primary Sjögren's syndrome at 7q11.23". Nat Genet. 45 (11): 1361–5. doi:10.1038/ng.2779. PMID 24097066.
- ↑ Kang HI, Fei HM, Saito I, Sawada S, Chen SL, Yi D; et al. (1993). "Comparison of HLA class II genes in Caucasoid, Chinese, and Japanese patients with primary Sjögren's syndrome". J Immunol. 150 (8 Pt 1): 3615–23. PMID 8468491.
- ↑ Nocturne G, Mariette X (2013). "Advances in understanding the pathogenesis of primary Sjögren's syndrome". Nat Rev Rheumatol. 9 (9): 544–56. doi:10.1038/nrrheum.2013.110. PMID 23857130.
- ↑ Mitsias DI, Tzioufas AG, Veiopoulou C, Zintzaras E, Tassios IK, Kogopoulou O; et al. (2002). "The Th1/Th2 cytokine balance changes with the progress of the immunopathological lesion of Sjogren's syndrome". Clin Exp Immunol. 128 (3): 562–8. PMC 1906267. PMID 12067313.
- ↑ Gordon TP, Bolstad AI, Rischmueller M, Jonsson R, Waterman SA (2001). "Autoantibodies in primary Sjögren's syndrome: new insights into mechanisms of autoantibody diversification and disease pathogenesis". Autoimmunity. 34 (2): 123–32. doi:10.3109/08916930109001960. PMID 11905842.
- ↑ St Clair EW, Burch JA, Saitta M (1994). "Specificity of autoantibodies for recombinant 60-kd and 52-kd Ro autoantigens". Arthritis Rheum. 37 (9): 1373–9. PMID 7945502.