1. Ulcerative Colitis - before and after Hurst
D.P. Jewell
University of Oxford

2. Samuel Wilks

3. The London Teaching Hospitals Experience
300 cases
Aetiology debated:-
- bacterial (Hawkins)
- tinned foods / preservatives (Phillips)
- psychosomatic (Claye-Shaw)
Allchin 1909

4. Sir Arthur Hurst

5. 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

6. Ulcerative colitis - the Early Days
Treatment:
bed rest
low-fibre diet
soured milk
colonic irrigation - albargin (silver nucleinate) - tannic acid
antidysenteric serum
Hurst 1921

7. 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

8. Aetiopathogenesis of UC and CD
Genetic v Environment
Polygenic Childhood
Heritability Bacteria CD % Food UC % Drugs
Appendicitis

9. IBD Linkage regions 2005 12 1 3 4 5 6 7 10 IBD2 IBD5 IBD3 IBD7 X IBD9
DLG5 19
IBD6 16
IBD1
NOD2
IBD8 14
IBD4 17 ‘
Crohn’s disease
Linkage areas
Loci studied
Other linkage
areas

10. The Gut Flora 1010-1012/G in the colon
At least 500 species using 16S rRNA techniques
No specific pathogen detected for UC but 5-10% with bacillary dysentery may progress to UC
Prebiotics and probiotics (E. coli Nissle, VSL#3, Lactobacilli) may benefit UC and pouchitis.

11. The Hygiene Hypothesis
Increased allergy results from decreased exposure to infections in early life (small family size, clean environment) (Strachan 1989)
Some support for better living conditions in childhood associated with increased risk of IBD later in life (Gent et al)
Mechanisms include altering TH1/TH2 balance, induction of T reg cells
Basis of using ova of Trichuis suis as therapy to stimulate a down-regulating TH2 response.

12. Immune Responses to bacteria
Cross-reacting antibodies between E. Coli 014 and colonic epithelium (Perlmann et al)
1992 pANCA associated with UC % - Antigen may be a histone and may cross-react with gut flora
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

13. Bacterial Host Interaction
Adaptive immune response Presentation to T cells by dendritic cells through HLA-Class 2 and co-stimulating molecules
Innate immune response Pathogen-associated molecular patterns (PAMPs) interact with pattern recognition receptors.

14. HLA Class 2 and UC
HLA DR103:- Healthy controls <3% Severe UC 11-15% Colonic CD 15% Type 1 arthropathy 37%
HLA DR2 - UC in Japan Conflicting data in Europe
HLA DR4 - negative association

15. 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

16. Beutler 2004

17. Polymorphisms in TLR2 and TLR4
TLR-2 Functional polymorphism (rs ) 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
No association in Scotland, Hungary - higher allele frequency in controls.

18. Dr Charles Elson, Challenges in IBD 2nd Edition

19. 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 case-control studies
McGovern et al 2005

20. NOD1
Family association study (UC n = 252) NDI p<0.07 NDI/ND3 haplotype p =
Case control (UC 306, CD358 Controls 335) IBD p = CD p = UC p = 0.055
McGovern et al 2005

21. Lessons from Animal Models
Immune-manipulated mice do not develop colitis when germ-free
Certain strains induce colitis more than others
No single strain will induce colitis consistently in all models
Host genetic background influences disease severity.

22. Adoptive T cell transfer model - germ-free and SPF
Courtesy of Fiona Powrie

23. Sir Arthur Hurst

24. Conclusions
UC probably represents an interaction between host genetic susceptibility and the commensal flora
Genetic susceptibility mediated via adaptive (HLA Class 2) and the innate (NOD1, TLRs) immune response
Manipulating the gut flora as a therapeutic endeavor may provide further insights into pathogenesis
Factors influencing anatomical distribution of disease remain obscure - could relate to known antigenic, mucin and transport differences between R and L colon