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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 University
Bangkok ,Thailand
1 September 2013
Sjogren’s syndrome (SS)
A systemic autoimmune disease
Chronic inflammation of exocrine glands
Clinical features
- Salivary gland (Chronic sialadenitis)
 Dry mouth
- Lacrimal gland (Chronic dacryoadenitis)
 Dry eye
B cell hyperactivity
- Polyclonal gammopathy
- Antinuclear antibody
 Hypergammaglobulinemia
 Anti-Ro, anti-La, atypical autoAb
- Rheumatoid factor
 Cryoglobulinemic vasculitis
- Other autoantibodies
 Anti-CA II , anti-M3R Ab
- Lymphocytic infiltration
 Pneumonitis, nephritis
- Ectopic GC
+ monoclonality
 Lymphoma
Pathogenesis of Sjogren’s syndrome (SS)
Etiology : unknown
Multiple factors
Activation of innate
and adaptive immunity
- Genetics
- Epigenetics
- Environment : virus
- Hormone : estrogen deficiency
- Psychological factor
Pers JO, et al. Presse Med. 2012 ;41:e467-74.
Nocturne G,et al. Nat Rev Rheumatol. 2013 Jul 16. doi: 10.1038
Genetics factor
HLA association
with SS
Cobb BL, et al. Rheum Dis Clin N
Am.2008;34:847–68.
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
Epigenetic study in SS
Distinct microRNA expression patterns are associated with salivary gland inflammation
and dysfunction in patients with SS.
N =8
N =8
Alevizos I, et al. Arthritis Rheum. 2011;63(2):535-44.
N =8
N =6
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.)
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.
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 estrogendeficient 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.
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
Karaiskos D, et al. Ann Rheum Dis. 2009 ;68(1):40-6.
Association with
primary SS.
Epithelial cells are active participants in the induction
and maintenace of the inflammatory process
virus
Resting epithelium
Chemokine
Dysregulated epithelium
Ro,La
BAFF/BlyS
Type I IFNs
pDCs
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
Ectopic germinal center (GC)-like structure in SS
Ectopic germinal center (GC)-like structure in SS
CXCR-5
 CXCL13 (BCA-1)
IL-21
FH
Salivary gland
-
Somatic hypermutation
BCR editing
Ig class switching
Chronic B cell stimulation
Auto Ab production
 risk of lymphoma
CXCR-5
FH
FH
GC-like structure
Nocturne G,et al. Nat Rev Rheumatol. 2013 Jul 16. doi: 10.1038
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.
Lymphomagenesis in SS
AutoAg
stimulation
GC-like structure 1
CXCR-5 polymorphism 2
Continuous stimulation of
autoreactive B cell
Sustain NF-kB activation
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
BAFF/BLyS 3
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
Pathogenesis of Sjogren’s syndrome (SS)
Conclusion
Salivary gland
Neuropsychology
Innate
Immunity
Environment
(eg. virus)
Genetics and
Epigenetics
Hormone
Adaptive
Immunity
Tissue Damage
-
Lymphocytic infiltration
Cytokines
Inflammatory mediators
Pathogenic autoAb
Immune complex
Lymphoma
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