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New I nsight in the Pathogenesis of Sjogren’s syndrome

New I nsight in the Pathogenesis of Sjogren’s syndrome. Sittichai Ukritchon , MD. Division of Rheumatology , Department of Medicine Faculty of Medicine, Chulalongkorn University Bangkok ,Thailand. 1 September 2013. Sjogren’s syndrome (SS). A systemic autoimmune disease.

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New I nsight in the Pathogenesis of Sjogren’s syndrome

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  1. New Insight in the Pathogenesis of Sjogren’s syndrome SittichaiUkritchon , MD. Division of Rheumatology , Department of Medicine Faculty of Medicine, ChulalongkornUniversity Bangkok ,Thailand 1 September 2013

  2. Sjogren’s syndrome (SS) A systemic autoimmune disease Chronic inflammation of exocrine glands - Salivary gland (Chronic sialadenitis) - Lacrimal gland (Chronic dacryoadenitis) B cell hyperactivity - Polyclonal gammopathy - Antinuclear antibody - Rheumatoid factor - Other autoantibodies - Lymphocytic infiltration - Ectopic GC Clinical features  Dry mouth  Dry eye Hypergammaglobulinemia  Anti-Ro, anti-La, atypical autoAb  Cryoglobulinemicvasculitis  Anti-CA II , anti-M3R Ab  Pneumonitis, nephritis  Lymphoma + monoclonality

  3. Pathogenesis of Sjogren’s syndrome (SS) Etiology : unknown Multiple factors - Genetics - Epigenetics - Environment : virus - Hormone : estrogen deficiency - Psychological factor Activation of innate and adaptive immunity Pers JO, et al. Presse Med. 2012 ;41:e467-74. Nocturne G,et al. Nat Rev Rheumatol. 2013 Jul 16. doi: 10.1038

  4. Genetics factor HLA association with SS Cobb BL, et al. Rheum DisClin N Am.2008;34:847–68.

  5. Genetics factor Polymorphic genes associated with SS HLA-DQB1 : most sig. ass. in GWAS Nocturne G,et al. Nat Rev Rheumatol. 2013 Jul 16. doi: 10.1038

  6. Epigenetic study in SS Distinct microRNA expression patterns are associated with salivary gland inflammation and dysfunction in patients with SS. N =8 N =8 N =8 N =6 Alevizos I, et al. Arthritis Rheum. 2011;63(2):535-44.

  7. The ten most statistically significant biological functions generated by Ingenuity Pathways Analysis for the genes targeted by the A) decreased salivary flow associated and B) inflammatory group of microRNAs. (Alevizos I, et al. Arthritis Rheum. 2011;63(2):535-44.)

  8. Environmental factors in the pathogenesis of SS Viral infection - Epstein Barr virus (EBV) : DNA can be detected in blood and salivary gland in SS 1,2 : a common virus that infects both salivary epithelial cell and B cell 3 : promote release of Ro and La ribonucleoprotein complexes through epithelial cell apoptosis 4 : EBV-encoded small RNA (EBER) can form complex with La, and activate type I IFN through TLR-3 4 1. Saito I. et al. J Exp Med. 1989; 169:2191-2198. 2. Mariette X, et al. Am J Med 1991;90:286–294. 3. Yamaoka K, et al. Arthritis Rheum 1988:31;1014–1021. 4. IwakiriD,et al. J Exp Med 2009;206:2091–2099.

  9. Hormonal factor in the pathogenesis of SS Role of estrogen deficiency in SS - Human : predominant of SS in postmenopausal women compared with men - Animal models : estrogen-deficient mice can develop SS-like syndrome. 1,2 : RBBP4 -transgenic mice can develop SS-like syndrome through p53-mediated apoptosis of epithelial cells in estrogen-deficient state. 3 1. Shim GJ, et al. Proc NatlAcadSci USA.2004;101:12628–12633. 2. Ishimaru N, et al. Am J Pathol. 2003;163(4):1481-90. 3. Ishimaru N, et al. Mol Cell Biol. 2006;26(8):2924-35.

  10. Neuropsychological factors in the pathogenesis of SS Primary SS (N=47) vs Lymphoma (N=35) vs Healthy control (N=120) • Before disease onset : • Severe psychological stress • Defective coping-stress strategies • Lack of social support Association with primary SS. Karaiskos D, et al. Ann Rheum Dis. 2009 ;68(1):40-6.

  11. Epithelial cells are active participants in the induction and maintenace of the inflammatory process virus Chemokine IL-1b, IFN-g,TNF-a Resting epithelium Dysregulated epithelium Ro,La pDCs BAFF/BlyS Type I IFNs AutoAb 1. Voulgarelis M, et al. Nat Rev Rheumatol.2010;101:529-537. 2. Jonsson R, et al. Immunol Lett. 2011;141:1-9. 3. Nocturne G,et al. Nat Rev Rheumatol. 2013 Jul 16. doi: 10.1038 IC

  12. Ectopic germinal center (GC)-like structure in SS

  13. Ectopic germinal center (GC)-like structure in SS  CXCL13 (BCA-1) CXCR-5 IL-21 FH FH FH Salivary gland - Somatic hypermutation - BCR editing - Ig class switching - Chronic B cell stimulation - Auto Ab production -  risk of lymphoma CXCR-5 GC-like structure Nocturne G,et al. Nat Rev Rheumatol. 2013 Jul 16. doi: 10.1038

  14. Lymphomagenesis in SS Prevalence and relative risk of lymphoma in primary SS Nocturne G,et al. Nat Rev Rheumatol. 2013 Jul 16. doi: 10.1038.

  15. Lymphomagenesis in SS Sustain NF-kB activation AutoAg stimulation Mutation of TNFAIP3 (TNF-a-induced protein 3, A20) - Inhibit NF-kB activation - TNF-a mediated apoptosis :  A20 protein and  TNFAIP3 in MSG4 : rs2230926 SNP is associated with pSS complicated by lymphoma5 GC-like structure 1 CXCR-5 polymorphism 2 Continuous stimulation of autoreactive B cell BAFF/BLyS3 Monoclonality 1 Theander E, et al. Ann Rheum Dis 2011;70:1363–1368. 2 Lessard CJ, et al. Ann Rheum Dis 2013;72 (Suppl. 3):54. 3 Quartuccio L, et al. Rheumatology 2013;52:276–281. 4 Sisto M, et al. Cell Biol 2011;135:615–625 . 5 Mariette X, et al. Arthritis Rheum 2011;63 (Suppl. 10)161. Lymphoma

  16. Pathogenesis of Sjogren’s syndrome (SS) Conclusion Salivary gland Genetics and Epigenetics Environment (eg. virus) Hormone Neuropsychology Innate Immunity Tissue Damage - Lymphocytic infiltration - Cytokines - Inflammatory mediators - Pathogenic autoAb - Immune complex Adaptive Immunity Lymphoma

  17. Thank You for Your Attention

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