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Inflammatory-bowel-disease-pathogenesis.ppt
- 1. CHRONIC INFLAMMATORY BOWEL DISEASE- PATHOGENESIS
- 2. INFLAMMATORY BOWEL DISEASE Definition : • IBD is a chronic condition resulting from inappropriate mucosal immune activation • Two disorders comprising IBD are •Ulcerative colitis (UC) •Crohns disease (CD)
- 3. INFLAMMATORY BOWEL DISEASE • Distinction between Ulcerative colitis and Crohns disease depends upon the distribution of affected sites • Crohn’s Disease : Most often distal small intestine & colon • Ulcerative Colitis : Colon & Rectum CROHNS DISEASE ULCERATIVE COLITIS
- 4. INFLAMMATORY BOWEL DISEASE • Ulcerative Colitis is limited to the mucosa and submucosa. • In contrast Crohns Disease referred to as regional enteritis is typically transmural CROHNS DISEASE ULCERATIVE COLITIS
- 5. INFLAMMATORY BOWEL DISEASE • Increased incidence world wide – explained by hygiene hypothesis Improved food storage condition, decreased food contamination Changes in gut microbiome composition Inadequate development of regulatory immune response Triggers persistent chronic inflammation in susceptible hosts
- 6. INFLAMMATORY BOWEL DISEASE PATHOGENESIS •Results from unregulated & exaggerated local immune responses to commensal microbes in the gut, in genetically susceptible individuals •Factors which play important role in pathogenesis are • Genetic susceptibility • Mucosal immune response • Enteric microflora • Environmental triggers
- 7. INFLAMMATORY BOWEL DISEASE Genetic factors • Risk of the disease is increased when there is an affected family member with IBD • Monozygotic twin concordance for CD is 30%-50% where as for UC is 15% • Genes associated with Crohns disease are • NOD2 (Nucleotide oligomerization binding domain 2) • ATG16L1 (Autophagy Related 16 Like 1) • IRGM (Immunity Related GTPase M)
- 8. NOD2 (NUCLEOTIDE OLIGOMERIZATION BINDING DOMAIN 2) NOD2 Bacterial peptidoglycans Activates signaling pathways Cytokines Chemokines Antimicrobial products Proliferative mediators ATG16L1 Attack the microbes and destroys the microbial products Produces inflammatory reaction Proliferation of cells as reparative process NOD2 gene is located on the long arm of chromosome 16 at band 21
- 9. CROHNS DISEASE NOD 2 polymorphism Abnormal protein Fails to recognize the microbes and allows them to grow in gut Over reaction to bacteria by adaptive immune system Defective NOD2 function in intestinal epithelial cells and Paneth cells Abnormal immunologic response to normal commensal bacteria with in gut Excessive immune response Excessive cytokines and chemokines Proliferative mediators COLITIS TUMORIGENESIS
- 10. INFLAMMATORY BOWEL DISEASE • ATG16L1 and IRGM – are part of autophagy pathways • Autophagy is involved in intracellular homeostasis, contributing to the degradation and recycling of cytosolic contents and organelles as well as removal of intracellular microbes. • In Crohns disease - ATG16L1 and IRGM mutations result in protein which adversely affect the normal autophagy and does not allow repair of worn out cell parts and defense against microbes
- 11. ATG16L-1 AND IRGM ATG16L1 NOD2 Autophagosome Lysosome Autophagolysosome IRGM Degradation and antigen presentation Bacterial peptidoglycans Activating signaling pathways Phagophore ATG16L-1 - Autophagy Related 16 Like 1 protein IRGM - Immunity-related GTP ase family M protein
- 12. INFLAMMATORY BOWEL DISEASE Immune response • Two main types of IBD represent clearly distinct forms of gut inflammation. • CD has been considered to be driven by a Th1 response. • UC has been associated with Th2 response. • Newly described Th17 cells are also involved in the gut inflammatory response in IBD.
- 13. GUT MICROBIOTA Dendritic cells (conditioned) T Regulator cells T effector cells Suppression of Th1, Th2, Th17 Suppression of T cell migration Suppression of B cells Inhibition of effector cells like Basophils, eosinophils and mast cells Th1 cells Th2 cells Th17 cells LUMEN EPITHELIUM LAMINA PROPRIA Suppression Activation NORMAL IMMUNE MECHANISM IN GUT Anti inflammatory cytokines IL-10, TGF- β
- 14. INFLAMMATORY BOWEL DISEASE Mucosal immune response • Inflammatory cells • In IBD, activated CD4+Tcells are present in the lamina propria and in the peripheral blood • These cells either activate other inflammatory cells like macrophages, and B cells or recruit more inflammatory cells by stimulation of homing receptors on leukocytes and vascular endothelial cells
- 15. INFLAMMATORY BOWEL DISEASE - MUCOSAL IMMUNE RESPONSE GUT MICROBIOTA Dendritic cells CD4+T effector cells Th1 cells Proinflammatory cytokines IFN γ and TNF Granulomatous inflammation Th2 cells IL-4, IL-5 and IL-13 Superficial mucosal inflammation Th17 cells IL-17 Activates neutrophils CROHNS DISEASE ULCERATIVE COLITIS IL 12 IL -23
- 17. INFLAMMATORY BOWEL DISEASE - EPITHELIAL BARRIER DEFECTS CROHNS DISEASE NOD2 polymorphism Activates innate and adaptive mucosal immune response Activation of effector cytotoxic T lymphocytes Production of cytokines, metalloproteinases and enzymes Tissue destruction and epithelial barrier defect
- 18. ULCERATIVE COLITIS INFLAMMATORY BOWEL DISEASE - EPITHELIAL BARRIER DEFECTS Polymorphism of Hepatocyte Nuclear factor 4α Defects in epithelial tight junctions and intestinal permeability Normally HNF4α – controls the epithelial tight junction and intestinal permeability
- 19. INFLAMMATORY BOWEL DISEASE - ENTERIC MICROBIOTA Enteric microbiota Transepithelial influx of bacteria Activating innate and adaptive immune response Release of TNF and other cytokines Increase in the epithelial junction permeability
- 20. INFLAMMATORY BOWEL DISEASE - ENVIRONMENTAL FACTORS INFLAMMATORY BOWEL DISEASE SMOKING It increases the risk of CD Nicotine - inhibitory effect on Th2 lymphocytes – no UC VITAMIN D DEFICIENCY NSAID Due to COX -1 inhibitory effect which inhibits protective mucosal prostaglandin production and increased leukocyte migration and adherence USE OF ANTIBIOTICS effect on the microbiome STRESS
- 21. INFLAMMATORY BOWEL DISEASE • Autoantibodies • In UC mucosal B cells and plasma cells are increased • In addition in UC circulation of autoantibodies directed against human intestinal tropomyosin isoform as well anticolonocyte antibodies are found and are thought to represent a secondary phenomenon in clearing apoptotic cells • 49% to 86% of patients have circulating ANCA which may represent cross reacting Abs to antigenic target on E-coli and bacteroides bacterial strain
- 22. Genetic susceptibility: NOD2, ATG16L1, IRGM Epithelial barrier deficiency: NOD2, HNF 4α Microbial flora Environmental factors Antibiotics Smoking Stress Vit D deficiency NSAIDS Defective immune response or exaggerated immune response Activation of CD4+ T cells TH 1 cells TH 2 cells TH 17 cells CROHNS DISEASE ULCERATIVE COLITIS Activates neutrophils and exaggerates immune response SUMMARY Autoantibodies ULCERATIVE COLITIS
Editor's Notes
- NOD2 gene is located on the long arm of chromosome 16 at band 21 It encodes for NOD2 protein which is intracellular and binds to bacterial peptidoglycans and activates the signaling events including NF-κβ pathway leading to the production of inflammatory cytokines This protein is active in immune system cells like monocytes, macrophages and WBC’s and also in intestinal epithelial cells and Paneth cells
- In normal individuals there is lack of immune responsiveness to dietary antigens and commensal flora in intestinal lumen The mechanism responsible for this is by the activation of CD4+T cells secreting cytokines inhibitory to inflammation (IL-10, TGF-β) which suppress inflammation in the gut wall In the IBD, this immune mechanism of suppression of inflammation is defective and this results in uncontrolled inflammation.
- Main types of CD4+ T cells involved in IBD are Th1 cells secrete proinflammatory cytokines IFN γ and TNF which induces transmural granulomatous inflammation seen in CD. IL-12 initiates Th1 cytokine pathway Th2 cells secrete IL-4, IL-5 and IL-13 which induces superficial mucosal inflammation characteristically seen in UC Th17 cells contribute to pathogenesis by producing IL-17 which inturn activates neutrophils and contributes to disease pathogenesis
- Defects in intestinal epithelial tight junction barrier are present in CD In patients with CD and their relatives, barrier dysfunction associated with specific disease associated NOD2 polymorphism - can activate innate and adaptive mucosal immunity and sensitize subjects to disease Activation of effector cytotoxic T cells and cytokine release result in generation of activated matrix metalloproteinases, enzyme that are mediators of tissue destruction.
- Polymorphism in certain transcription factor like Hepatocyte Nuclear factor 4α are associated with reduced intestinal barrier function and are associated with UC and not with CD. HNF 4α that controls epithelial tight junctions and intestinal permeability is reduced (down regulated) in UC.
- The roles of intestinal microbiota, epithelial function and mucosal immunity suggests a cycle by which there is transepithelial influx of luminal bacterial components which activates innate and adaptive immune responses. In a genetically susceptible host, the subsequent release of TNF and other immune mediated signals direct epithelia to increase tight junction permeability which causes further increase in the influx of luminal material.
- Smoking has protective effect on the development of UC with lower rate of relapse. In contrary it increases the risk of CD and is associated with higher rate of post operative disease. Nicotine has been shown to have an inhibitory effect on Th2 lymphocytes but no effect on Th1 lymphocytes. Vitamin D deficiency has been associated with increasing risk of IBD High dose, prolonged using duration and frequent use of NSAID had been associated with an increased risk of CD and UC. NSAIDS has affect due to COX -1 inhibitory effect of drug which inhibits protective mucosal prostaglandin production and increased leukocyte migration and adherence. Use of antibiotics is an important environmental factor, influencing the risk of IBD through their effect on the microbiome Stress plays a role in pathogenesis of both CD and UC.