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INFLAMMATORY BOWEL DISEASE

INFLAMMATORY BOWEL DISEASE. Dr Ramadas Nayak Professor & HOD Pathology Yenepoya Medical College Mangaluru. NFLAMMATORY BOWEL DISEASE. Inflammatory bowel disease (IBD) is an immune-mediated chronic intestinal inflammatory condition .

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INFLAMMATORY BOWEL DISEASE

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  1. INFLAMMATORY BOWEL DISEASE DrRamadasNayak Professor & HOD Pathology Yenepoya Medical College Mangaluru

  2. NFLAMMATORY BOWEL DISEASE • Inflammatory bowel disease (IBD) is an immune-mediated chronic intestinal inflammatory condition. • It results from inappropriate mucosal immune activation. • Major types of IBD • 1) Ulcerative colitis (UC) and • 2) Crohn disease (CD).

  3. Epidemiology • Age of onset • Both UC and CD occurs between 15 and 30 years of age. • A second peak is between the ages of 60 and 80 years. • Sex: Male to female ratio in • Crohn disease is 1.1–1.8:1 • Ulcerative colitis is 1:1.

  4. Epidemiology • Prevalence of IBD is higher in urban than rural areas, • Higher prevalence in high socioeconomic classes than lower socioeconomic classes. • Cigarette smoking • Risk of UC in smokers is 40% more than that of nonsmokers. • Smoking is associated with two-fold increased risk of CD.

  5. Epidemiology • Oral contraceptives use: Increased risk of CD. • Appendectomy • is protective against UC • but is associated with a higher risk of CD.

  6. Etiology and Pathogenesis • IBD is an idiopathic disorder. • The exact trigger for inflammatory bowel disease is not known.

  7. Etiology and Pathogenesis • Present evidences suggest that IBD represents the outcome of three main interactive factors: • Genetic • Environmental and • Host factors

  8. Genetic Factors • Genetic predisposition/susceptibility contributes to IBD.

  9. Genetic Factors • Susceptibility Genes • Genes associated with innate immunity and autophagy (e.g. NOD2/CARD15, ATG16L1 and IRGM): • They respond to infection and clear the infective agents such as bacteria, mycobacteria and viruses.

  10. Genetic FactorsSusceptibility Genes • NOD2/CARD15 is the first Crohn disease susceptibility gene • It was originally known as NOD2 (nucleotide oligomerization binding domain 2) • But subsequently renamed as CARD15.

  11. Genetic FactorsSusceptibility Genes • NOD2/CARD15 gene codes for a NOD2/CARD15 protein • Which is required for normal recognition and response against microbes in the intestinal lumen.

  12. Genetic FactorsSusceptibility Genes Actions of NOD2/CARD15 protein are: • Prevents the entry of microbes into the wall of the intestine • Regulates innate immune responses • Preventsexcessive immune response againstluminal microbes.

  13. Genetic Factors • Defective NOD2/CARD15 • It is produced due to mutations and mutant forms • They are less effective at recognizing and combating luminal microbes. .

  14. Genetic Factors • Defective NOD2: • Allows the entry of luminal microbes into the lamina propria of the intestinal wall and stimulates inflammatory reactions.

  15. Genetic Factors • Two other genes namely • ATG16L1 (autophagy-related 16-like) and • IRGM (immunity-related GTPase M) are involved in the recognition and response to intracellular pathogens. .

  16. Environmental Factors • Intestinal microflora • Smoking.

  17. Environmental Factors 1. Intestinal Microflora/Microbiota • Hygiene hypothesis • The gut lumen contains abundant commensal bacteria and • its composition within individuals remains stable for several years.

  18. Environmental Factors 1. Intestinal Microflora/Microbiota • Hygiene hypothesis • This intestinal microflora can be modified by diet and disease. • IBD is associated with an alteration in the bacterial flora.

  19. Environmental Factors 1. Intestinal Microflora/Microbiota • Improved food storage conditions and decreased food contamination: • It has reduced frequency of enteric infections with ‘clean’ environment in the intestinal lumen

  20. Environmental Factors • Intestinal Microflora/Microbiota → the immune system may not be exposed to microorganisms (pathogenic or nonpathogenic) → inadequate development of regulatory processes to limit mucosal immune responses.

  21. Environmental Factors • Inadequate immune regulation • The ‘untrained’ immune system when exposed to the normal commensal bacterial antigens/infections • → inadequate immune regulation • → allows pathogens (which normally cause self-limited disease) to produce an over aggressive immune responses and uncontrolled chronic inflammatory response in a genetically susceptible individual .

  22. EnvironmentalFactors Smoking • CD patients are more likely to be smokers and smoking exacerbates CD. • In contrast, an increased risk of UC is observed in non- or ex-smokers.

  23. Host Factors in IBD • Epithelial defects • Defective mucosal immune response

  24. Host Factors • 1. Epithelial defects • A variety of epithelial defects can develop in IBD. • Impaired mucosal barrier function: • It is observed in IBD → can activate innate and adaptive mucosal immunity and sensitize individuals to disease.

  25. Host Factors • 1. Epithelial defects: A variety of epithelial defects can develop in IBD. • Abnormal intestinal defensins: • Panethcell granules contain antimicrobial peptides termed defensins, which normally protect the mucosa against adherent and invading bacteria. • Abnormal defensinsare found in Crohn disease patients carrying ATG16L1 mutations.

  26. Host Factors • 2. Defective mucosal immune responses (immune dysregulation): • Immunological abnormality have been observed in both innate (macrophage and neutrophil) and acquired (T- and B-cell) immunity.

  27. Host Factors • 2. Defective mucosal immune responses (immune dysregulation): • Normal regulatory immune response of gut mucosa: • It is very powerful and prevents immunologic/ inflammatory response against the dietary antigens and the commensal microbiota.

  28. Host Factors • 2. Defective mucosal immune responses (immune dysregulation): • Defective regulatory immune response: • In a genetically predisposed individual, the regulatory immune suppression is defective

  29. Host Factors • 2. Defective mucosal immune responses (immune dysregulation): • → leads to abnormal immune response to nonpathogenic commensal bacteria within the gut • → activates CD4+ T-cells in the lamina propria • → secretes excess of inflammatory cytokines relative to anti-inflammatory cytokines • → imbalance between the proinflammatory and anti-inflammatory mediators • → uncontrolled inflammation.

  30. Host Factors • IBD: • Imbalance between proinflammatory and anti-inflammatory mediators → uncontrolled inflammation • Crohndisease: Abnormal defensins in patients with ATG16L1 mutations.

  31. Host Factors • Psychosocial Factors • It can contribute to worsening of symptoms in IBD. • Major life events (e.g. illness or death in the family, divorce or separation) are associated with an increase in symptoms such as pain, bowel dysfunction and bleeding.

  32. Hypothesis for Pathogenesis of IBD • The IBD is characterized by • abnormal mucosal immunological response and • shows lymphocytes, macrophages and other cells of the immune system infiltrating the lamina propria.

  33. Hypothesis for Pathogenesis of IBD • However, the antigens that trigger the immune response are not yet identified. • Whatever the antigenic trigger, • activated T-cells in the lamina propria are involved in the pathogenesis of IBD.

  34. Hypothesis for Pathogenesis of IBD • IBD: Three types of TH T-cells involved— • 1. TH1T-cell • 2. TH2T-cell • 3. TH17T-cell.

  35. Hypothesis for Pathogenesis of IBD • One hypothesis signifies the • roles of intestinal microbiota, • epithelial function and • mucosal immunity in the pathogenesis of IBD. • The various events are:

  36. Hypothesis for Pathogenesis of IBD • Transepithelialflux of luminal bacterial components: • .

  37. Hypothesis for Pathogenesis of IBD • Bacterial components/antigens within the intestinal microbiota • pass between leaky epithelial cells or • enter the lamina propria through ulcerated mucosa.

  38. Hypothesis for Pathogenesis of IBD • Processing of bacterial antigens: • Antigens from the lumen of the bowel are transported by M (microfold) and dendritic cells in the specialized (follicle associated epithelium (FAE).

  39. Hypothesis for Pathogenesis of IBD • Processing of bacterial antigens: • Antigen-presenting cells (APC) in the lamina propria process these bacterial antigens and present to CD4+ T helper (TH) cells.

  40. Hypothesis for Pathogenesis of IBD • T-cell activation and differentiation: • CD4+ T-cells are activated and undergo differentiation by the cytokines secreted by APCs.

  41. Hypothesis for Pathogenesis of IBD • T-cell activation and differentiation: • Major cytokines involved in IBD include: IL-12, IL-23, IL-1 and IL-6.

  42. Hypothesis for Pathogenesis of IBD • Role of CD4+ T helper (TH) cells: • They promote inflammation by secreting excess of cytokines and contribute to the pathogenesis of IBD.

  43. Hypothesis for Pathogenesis of IBD • Role of CD4+ T helper (TH) cells: • TH1cells secretes interferon gamma (IFNγ) which is the most powerful cytokine that activates macrophages; and also TNF.

  44. Hypothesis for Pathogenesis of IBD • Role of CD4+ T helper (TH) cells: • In a genetically susceptible individual, the release of TNF and other immune-mediated signals increases the tight junction permeability of epithelial cells.

  45. Hypothesis for Pathogenesis of IBD • Role of CD4+ T helper (TH) cells: • This causes further increase in the entry of bacterial components into the lamina propria. • These events may result in a self-amplifying cycle which may be sufficient to initiate IBD.

  46. Hypothesis for Pathogenesis of IBD • Role of CD4+ T helper (TH) cells: • TH2cells secretes IL-4, IL-5 and IL-17. IL-13 induces superficial inflammation of mucosa.

  47. Hypothesis for Pathogenesis of IBD • Role of CD4+ T helper (TH) cells: • TH17cells secrete IL-17, IL-21 and are responsible for neutrophilic recruitment. • IL-23 secreted by APCs is essential for the development and maintenance of TH17cells.

  48. Hypothesis for Pathogenesis of IBD • •Differentiation of CD4+ T-cells: • Cytokines secreted by APCs causes differentiation of CD4+ T-cells into three major types of CD4+ T helper effector cells, namely: • ––TH1type by IL-12 • ––TH2type by IL-4 • ––TH17type by IL-23

  49. Hypothesis for Pathogenesis of IBD • TH1T-cell secretion: • T-cells continue the inflammatory process with activation of non-immune cells and release of other important cytokines, e.g. interleukin (IL)-12, IL- 23, IL-1, IL-6 and tumor necrosis factor (TNF).

  50. Hypothesis for Pathogenesis of IBD • The above mentioned pathways occur in all normal individuals exposed to an inflammatory insult. • These processes are self-limiting in healthy subjects.

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