Mechanisms of biliary epithelial cell destruction in primary sclerosing cholangitis

1
Mechanisms of biliary epithelial cell destruction
in primary sclerosing cholangitis

• Suchitra Sumitran-Holgersson
• Karolinska University Hospital
• Dept. of Transplantation Surgery
• Sweden

2
(No Transcript)
3
PSC A cholestatic Liver disease
4
Some immune factors in ALD
PSC PBC AIH
No. of PBL
Functional capacity of PBL
5
PSC PBC AIH
No. of LDL
Functional capacity of LDL
6
Functional capacity of liver-derived
lymphocytes and blood-derived lymphocytes from
patients with Primary sclerosing cholangitis
(PSC) Primary biliary cirrhosis
(PBC) and Autoimmune hepatitis (AIH)
GUT 2001
7
(No Transcript)
8
Liver-derived lymphocytes
Blood-derived lymphocytes
9
(No Transcript)
10
Cytokine production in supernatants of mitogen
stimulated lymphocytes in ALD
IL-2 (pg/ml) IFN-? (pg/ml) IL-1? (pg/ml) TNF-? (pg/ml)
Normals 5200 10200 40 lt40
PSC lt70 1900 gt3000 gt10000
PBC 3500 6500 2500 400
AIH 5200 9500 50 2400
11
(No Transcript)
12
Gut 2002
13
(No Transcript)
14
Binding of autoantibodies to biliary epithelial
cells
15
(No Transcript)
16
(No Transcript)
17
(No Transcript)
18
Signalling pathway used by anti-BEC antibodies
We purified immunglobulin (IgG) fractions from 33
PSC patients known to have anti-BEC antibodies
Freshly isolated biliary epithelial cells from a
normal healthy liver donor
19
(No Transcript)
20
(No Transcript)
21
A
C
B
22
(No Transcript)
23
BEC
24
(No Transcript)
25
(No Transcript)
26
(No Transcript)
27
Number of patients positive for expression of TLR
4 or 9 in the bile ducts in liver biopsy sections
28
Conclusions
Anti-BEC antibodies induce in BEC specific
phosphorylation of ERK 1/2 ELK-1 and
NFKB expression of TLR-4 and 9 Production of
several inflammatory cytokines and chemokines
29
Conclusions Cont
58 of liver specimens from PSC patients with
BEC abs. stained positively for TLR4 and/or 9
Anti-BEC abs. may be a major link between
adaptive and innate immunity in PSC
30
In PSC, BEC not only targets but also active
participants and mediators of their own
destruction
31
(No Transcript)
32
(No Transcript)
33
Acknowledgements
Ulrika Broomé Xu Bo, PhD student Azza Karrar,
PhD student Marie Jaksch, Post-doc Mehmet Uzunel,
Post-doc