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 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

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.

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.

Immune Responses to bacteria 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 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 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.

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

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 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 case-control studies McGovern et al 2005

NOD1 Family association study (UC n = 252) NDI + 32656 p<0.07 NDI/ND3 haplotype 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 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.

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

Sir Arthur Hurst

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