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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.

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ulcerative colitis before and after hurst
Ulcerative Colitis - before and after Hurst

D.P. Jewell

University of Oxford

slide3

The LondonTeaching Hospitals Experience

300 cases

Aetiology debated:-

- bacterial (Hawkins)

- tinned foods / preservatives (Phillips)

- psychosomatic (Claye-Shaw)

Allchin 1909

ulcerative colitis the early days
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
slide6

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
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

Aetiopathogenesis of UC and CD

Genetic v Environment

Polygenic Childhood

Heritability BacteriaCD 30 - 40% FoodUC 10 - 15% Drugs

Appendicitis

ibd linkage regions 2005

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
the gut flora
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
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
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

bacterial host interaction
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 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
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

polymorphisms in tlr2 and tlr4

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.

nod1 and ibd
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

slide20

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

lessons from animal models
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.
conclusions
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