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Ulcerative Colitis - before and after Hurst

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.

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Ulcerative Colitis - before and after Hurst

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

  2. Samuel Wilks

  3. The LondonTeaching 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 BacteriaCD 30 - 40% FoodUC 10 - 15% Drugs Appendicitis

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

  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 betweenE. 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 • Lamina propria cells from IBD, but nothealthy subjects, proliferate toautologous 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 receptorsTLR-2 - lipoteichoic acidTLR-4 - lipopolysaccharideTLR-5 - flagellinTLR-9 - CpG DNA Caterpillar proteins (NACHT - LRRs)NOD1 - diaminopimelic acid of peptidoglycan from Gram -ve organismsNOD2 - muramyl dipeptide of PGN from Gram +ve and Gram -ve organisms

  16. Beutler 2004

  17. Polymorphisms in TLR2 and TLR4 TLR-2Functional polymorphism (rs 543708) associated with colectomy in UC (McGovern et al 2006) TLR-4 - Asp 299gly299G 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.

  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 + 32656 p<0.07NDI/ND3 haplotype p = 0.00007 Case control (UC 306, CD358 Controls 335)IBD p = 0.017CD p = 0.003UC 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

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