new i nsight in the pathogenesis of sjogren’s syndrome
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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. - PowerPoint PPT PresentationTRANSCRIPT
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New Insight in the Pathogenesis of Sjogren’s syndrome
Sittichai Ukritchon , MD.Division of Rheumatology , Department of Medicine
Faculty of Medicine, Chulalongkorn UniversityBangkok ,Thailand
1 September 2013
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A systemic autoimmune disease
Sjogren’s syndrome (SS)
Clinical features
Hypergammaglobulinemia
Anti-Ro, anti-La, atypical autoAb
Cryoglobulinemic vasculitis
Anti-CA II , anti-M3R Ab
Pneumonitis, nephritis
Lymphoma
Dry mouth
Dry eye
+ monoclonality
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
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Pathogenesis of Sjogren’s syndrome (SS)Etiology : unknown
Pers JO, et al. Presse Med. 2012 ;41:e467-74.Nocturne G,et al. Nat Rev Rheumatol. 2013 Jul 16. doi: 10.1038
Multiple factors
- Genetics
- Epigenetics
- Environment : virus
- Hormone : estrogen deficiency
- Psychological factor
Activation of innate and adaptive immunity
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Genetics factor
HLA association with SS
Cobb BL, et al. Rheum Dis Clin N Am.2008;34:847–68.
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Genetics factor
Polymorphic genes associated
with SS
Nocturne G,et al. Nat Rev Rheumatol. 2013 Jul 16. doi: 10.1038
HLA-DQB1 : most sig. ass. in GWAS
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Epigenetic study in SSDistinct microRNA expression patterns are associated with salivary gland inflammationand dysfunction in patients with SS.
Alevizos I, et al. Arthritis Rheum. 2011;63(2):535-44.
N =8N =8 N =8 N =6
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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.)
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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. Iwakiri D,et al. J Exp Med 2009;206:2091–2099.
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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 Natl Acad Sci 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.
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Neuropsychological factors in the pathogenesis of SS
Before disease onset :
- Severe psychological stress
- Defective coping-stress strategies
- Lack of social support
Karaiskos D, et al. Ann Rheum Dis. 2009 ;68(1):40-6.
Association with primary SS.
Primary SS (N=47) vs Lymphoma (N=35) vs Healthy control (N=120)
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Epithelial cells are active participants in the induction and maintenace of the inflammatory process
pDCs
Resting epithelium Dysregulated epithelium
Chemokine
BAFF/BlySRo,La
Type I IFNs
virus
AutoAb
IC1. 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
IL-1b, IFN-g,TNF-a
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Ectopic germinal center (GC)-like structure in SS
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Ectopic germinal center (GC)-like structure in SS
Salivary gland
CXCL13 (BCA-1)
CXCR-5
IL-21
FH
FH
GC-like structure
FH
CXCR-5
- Somatic hypermutation- BCR editing- Ig class switching- Chronic B cell stimulation- Auto Ab production- risk of lymphoma
Nocturne G,et al. Nat Rev Rheumatol. 2013 Jul 16. doi: 10.1038
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Lymphomagenesis in SSPrevalence and relative risk of lymphoma in primary SS
Nocturne G,et al. Nat Rev Rheumatol. 2013 Jul 16. doi: 10.1038.
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Lymphomagenesis in SS
GC-like structure 1
CXCR-5 polymorphism 2
Continuous stimulation of autoreactive B cell
AutoAg stimulation
BAFF/BLyS 3
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.
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
Lymphoma
Monoclonality
Sustain NF-kB activation
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Pathogenesis of Sjogren’s syndrome (SS)Conclusion
Genetics and Epigenetics
Environment (eg. virus)
Hormone
NeuropsychologyInnate
Immunity
Adaptive Immunity
Tissue Damage- Lymphocytic infiltration- Cytokines- Inflammatory mediators- Pathogenic autoAb- Immune complex
Lymphoma
Salivary gland
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