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

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

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

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

Nocturne G,et al. Nat Rev Rheumatol. 2013 Jul 16. doi: 10.1038

HLA-DQB1 : most sig. ass. in GWAS

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

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 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.

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)

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

Ectopic germinal center (GC)-like structure in SS

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

Lymphomagenesis in SSPrevalence and relative risk of lymphoma in primary SS

Nocturne G,et al. Nat Rev Rheumatol. 2013 Jul 16. doi: 10.1038.

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

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

Thank You for Your Attention