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Ulcerative Colitis
- before and after Hurst
D.P. Jewell
University of Oxford
Samuel Wilks
The London
Teaching Hospitals Experience
300 cases
Aetiology debated:- bacterial (Hawkins)
- tinned foods / preservatives (Phillips)
- psychosomatic (Claye-Shaw)
Allchin 1909
Sir Arthur Hurst
Ulcerative colitis - the Early Days
Hurst (1921) described:• gradual onset
• limited distal disease tended to present
as constipation
• sigmoidoscopically identical to bacillary
dysentery but distinct from amoebiasis
Ulcerative colitis - the Early Days
Treatment: bed rest
low-fibre diet
soured milk
colonic irrigation
- albargin (silver nucleinate)
- tannic acid
antidysenteric serum
Hurst 1921
Anti-dysenteric antiserum for UC
IV antiserum: 20, 40, 60, 80 and 100mls on
consecutive days
Adrenaline for anaphylaxis
Relapse much less frequent if treatment
continued until mucosal healing
‘Dramatic effect’
Hurst 1935
‘Splendid results’
Crohn and Rosenak 1935
Aetiopathogenesis of UC and CD
Genetic
v
Environment
Polygenic
Childhood
Heritability
Bacteria
CD 30 - 40%
Food
UC 10 - 15%
Drugs
Appendicitis
IBD Linkage regions 2005
1
4
3
IBD7
5
6
7
10
IBD3
IBD9
DLG5
IBD5
Crohn’s disease
Linkage
areas
‘
Loci studied
Other linkage
areas
IBD4
IBD8
IBD1
IBD2
IBD6
NOD2
12
14
16
17
19
X
The Gut Flora
1.
1010-1012/G in the colon
2.
At least 500 species using 16S rRNA
techniques
3.
No specific pathogen detected for UC but 510% with bacillary dysentery may progress to
UC
4.
Prebiotics and probiotics (E. coli Nissle,
VSL#3, Lactobacilli) may benefit UC and
pouchitis.
The Hygiene Hypothesis
1. Increased allergy results from decreased exposure
to infections in early life (small family size, clean
environment)
(Strachan 1989)
2. Some support for better living conditions in
childhood associated with increased risk of IBD
later in life
(Gent et al)
3. Mechanisms include altering TH1/TH2 balance,
induction of T reg cells
4. Basis of using ova of Trichuis suis as therapy to
stimulate a down-regulating TH2 response.
Immune Responses to bacteria
1967
Cross-reacting antibodies between
E. Coli 014 and colonic epithelium
(Perlmann et al)
1992 pANCA associated with UC - 40-60%
- Antigen may be a histone and may
cross-react with gut flora
1995 Lamina propria cells from IBD, but not
healthy subjects, proliferate to
autologous gut bacterial antigens
(Duchmann et al)
Hypothesis:- UC represents a failure to regulate mucosal
immune responses to gut antigens
Bacterial Host Interaction
1. Adaptive immune response
Presentation to T cells by dendritic cells
through HLA-Class 2 and co-stimulating
molecules
2. Innate immune response
Pathogen-associated molecular patterns
(PAMPs) interact with pattern recognition
receptors.
HLA Class 2 and UC
1. HLA DR103:Healthy controls
Severe UC
Colonic CD
Type 1 arthropathy
<3%
11-15%
15%
37%
2. HLA DR2 - UC in Japan
Conflicting data in Europe
3. HLA DR4 - negative association
Pattern Recognition Receptors
Toll-like receptors
TLR-2- lipoteichoic acid
TLR-4- lipopolysaccharide
TLR-5- flagellin
TLR-9- CpG DNA
Caterpillar proteins (NACHT - LRRs)
NOD1 - diaminopimelic acid of peptidoglycan
from Gram -ve organisms
NOD2 - muramyl dipeptide of PGN
from Gram +ve and
Gram -ve organisms
Beutler 2004
Polymorphisms in TLR2 and TLR4
TLR-2
Functional polymorphism (rs 543708)
associated with colectomy in UC
(McGovern et al 2006)
TLR-4 - Asp 299gly
299G associated with UC and CD
(Franchimont et al 2004)
299G associated with colectomy in UC
(McGovern et al 2006)
No association in Scotland, Hungary - higher allele
frequency in controls.
Dr Charles Elson, Challenges in IBD 2nd Edition
NOD1 and IBD
• NOD1 is within a region of linkage on Chr 7
• Expressed in the intestine
• Insertion-deletion polymorphism associated with
UC and CD in family-association and casecontrol studies
McGovern et al 2005
NOD1
Family association study
NDI + 32656
NDI/ND3 haplotype
(UC n = 252)
p<0.07
p = 0.00007
Case control (UC 306, CD358 Controls 335)
IBD p = 0.017
CD p = 0.003
UC p = 0.055
McGovern et al 2005
Lessons from Animal Models
1. Immune-manipulated mice do not develop
colitis when germ-free
2. Certain strains induce colitis more than
others
3. No single strain will induce colitis
consistently in all models
4. Host genetic background influences disease
severity.
Adoptive T cell transfer model - germ-free and SPF
Courtesy of Fiona Powrie
Sir Arthur Hurst
Conclusions
1.
UC probably represents an interaction between host genetic
susceptibility and the commensal flora
2.
Genetic susceptibility mediated via adaptive (HLA Class 2) and the
innate (NOD1, TLRs) immune response
3.
Manipulating the gut flora as a therapeutic endeavor may provide
further insights into pathogenesis
4.
Factors influencing anatomical distribution of disease remain obscure
- could relate to known antigenic, mucin and transport differences
between R and L colon