Crohn's disease
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Inflammatory bowel disease Ulcerative colitis Crohn's disease
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Crohn's disease
- 1. Crohn’s Disease By Ihab Muhammad Mahmoud Medical Research Institute- Alexandria
- 2. Normal Intestinal physiology • The key challenge of the intestinal immune system is balancing the need to respond to pathogens while coexisting with commensal bacteria and food antigens. • Immune tolerance (or at least controlled inflammation) to intestinal antigens, which is perturbed in IBD, is believed to be initially driven by commensal bacteria that reside in the intestinal lumen.
- 3. Crohn’s Disease is a chronic inflammatory bowel disease (IBD)
- 5. Inflammatory Bowel Disease • Crohn’s disease and ulcerative colitis have historically been studied together because they share common features: – Symptoms – Structural damage – Therapy • it is now clear that they represent two distinct pathophysiological entities.
- 6. Inflammatory bowel disease • Ulcerative colitis and Crohn’s disease are chronic inflammatory disorders of the gastrointestinal tract, with a tendency to remit and relapse. • Ulcerative colitis affects only the colon, and is confined to the mucosal layer. • Crohn’s disease, on the other hand, may affect any part of the gastrointestinal tract from mouth to anus, although the ileocaecal region is most frequently involved.
- 10. Geographic distribution of Crohn’s disease (epidemiology)
- 11. Etiology
- 12. Genetic susceptibility • NOD2 mutations. • Defects in autophagy . • Association with IL-23 receptor polymorphism. • IBD 5. • HLA region genes
- 13. Genetic susceptibility • NOD2 mutations. • Defects in autophagy . • Association with IL-23 receptor polymorphism . • IBD 5. • HLA region genes
- 15. Intestinal Immune system The innate and adaptive immune systems normally cooperate to limit inflammatory responses to intestinal bacteria through a combination of mechanisms: – a mucus layer produced by goblet cells; – tight junctions between the intestinal epithelial cells; – antimicrobial peptides released from epithelial cells and Paneth cells; – induction of Treg cells that inhibit effector CD4 T-cell development and promote the production of lgA antibodies that are transported into the intestinal lumen, where they inhibit translocation of intestinal bacteria.
- 17. Genetic susceptibility CARD15/NOD2 • Caspase recruitment domain family member 15. • Formerly NOD2 (Nucleotide binding oligomerization domain 2). • Intracellular Pattern recognition receptors (PRRs) recognize pathogen associated molecular patterns (PAMPs).
- 18. Genetic susceptibility CARD15/NOD2 • Leucine rich repeat region binds to MDP (biologically active moiety of peptidoglican; the cell wall polymer found in almost all bacteria). • MDP bind to dimerized CARD15 activates NFκB. • NFκB stimulate transcription of multiple genes that encode proinflammatory and protective molecules.
- 21. Genetic susceptibility • NOD2 mutations. • Defects in autophagy . • Association with IL-23 receptor polymorphism . • IBD 5. • HLA region genes
- 22. Genetic susceptibility Autophagy (ATG16L1) • Autophagy-related 16- like-1 gene. • Capturing organelles and cytoplasm within autophagosome. • Lysosome eradicates the invading microorganism.
- 23. Genetic susceptibility ATG16L1 mutation • Impairing intracellular bacterial handeling in macrophage (phagosome). • Prolonged immune response (inflammatory cytokines). • Altered exocytosis of AMP production from Paneth cells.
- 24. Genetic susceptibility • NOD2 mutations. • Defects in autophagy . • Association with IL-23 receptor polymorphism. • IBD 5. • HLA region genes
- 25. Genetic susceptibility IL-23 receptor • Chronic inflammation in CD contains cells that overproduce cytokines in the Th1 and Th17 pathways. • Th1 cells require IL-12 (p40 + p35 subunits). • Th17 cells require IL-23 (IL-12 p40 subunit + IL23p19). • IL23 contributes to the maintenance and development of TH17 cells.
- 26. Genetic susceptibility IL-23 receptor • The functional IL-23R is composed of IL-23R + IL-12B1R. • IL-12 and IL-23 expression is increased in lamina propria of individuals with CD. • STAT3 has central roles in the differentiation of Th17 and Th1 cells. • Polymorphism alters efficacy of IL-23R signalling.
- 28. • Blocking antibodies for p40 inhibit both IL-23 and IL-12-induced signalling • The administration of p40-specific antibodies has proved to be a promising approach for the treatment of CD.
- 29. Genetic susceptibility • NOD2 mutations. • Defects in autophagy . • Association with IL-23 receptor polymorphism. • IBD 5. • HLA region genes
- 30. Genetic susceptibility IBD5 • Genetic association between IBD5 locus with CD. • Loss of optimal barrier function : – Enhance uptake of injurious toxins to disrupt the epithelial layer. – Promote the bacterial transmigration. – Initiate inflammatory response within innate elements.
- 31. Genetic susceptibility • NOD2 mutations. • Defects in autophagy . • Association with IL-23 receptor polymorphism. • IBD 5. • HLA region genes
- 32. Genetic susceptibility HLA region genes • IBD3 contain HLA genes. • Mostly class II MHC. • eg:; HLA-DRB1 exhibit the strongest association in colonic CD. • specific HLA genes influence clinical outcomes such as tissue distribution and severity.
- 34. Etiology
- 35. Gut Microbiota and immunity • Microbial genes powerfully influence host gene expression. • The early gut microbial colonization is essential for the development and maturation of the immune system. • Symbiotic relationship of tolerance and protective immunity. • Certain microbes favour the growth of distinct T-cell subsets.
- 36. Gut microbiota in IBD • Relapse of CD occurs upon mucosal exposure to the luminal contents. • Some m.o. are potentially pathogenic. • The decrease of protective m.O. Like polysaccahride A supress IL-17 production. • Antibiotic exposure amplifies dysbiosis.
- 37. Gut microbiota and IBD immunopathogenesis. • The defect in MAMPs will result in impaired clearance of antigenic materials and trigger adaptive immune response → chronic inflammation. • Microbial alterations alone are insufficient to cause IBD.
- 39. Etiology
- 40. Environmental Trigger • Infection and NSAIDs – Initiate non- specific inflamation. – Break mucosal barrier – Activate innate immune response. • Dietary. – Stimulate bacterial virulance • Stress can alter – mucosal permeability – Mucosal blood flow – Expression of cytokineas and neuropeptides • Smoking – Nicotine, carbon monoxide and hypoxia.
- 41. Novel Pathogenic components • The inflamosomes. • Regularity RNA. • DAMPs.
- 44. Diagnosis Radiological Diagnosis – Bariam enema – X-ray
- 45. Diagnosis colonoscopy –Red, granular mucosa with mucopus and contact bleeding.
- 46. Colonic biopsy • showed a small area of ulceration of the surface epithilium with considered mucopus. • Many crypt abscesses were present. • The lamina propria contained a heavy infiltrate of lymphocytes, plasma cells and macrophages.
- 47. Colonic biopsy • Several non-caseating granulomas were present in the muscular layer. (Crohn’s)
- 48. Histology • Histologically Crohn’s disease and ulcerative colitis are distinct though the common finding is inflammation – as suggested in the term ‘inflammatory bowel disease’. • Transmural inflammation in Crohn’s disease involves lymphocytes, plasma cells and eosinophils, and there is granuloma formation . The mucosa in ulcerative colitis is infiltrated with neutrophils as well as plasma cells and osinophils.
- 49. Therapy
- 52. Therapeutics • Conventional therapy – Salazopyrine (5-ASA) – Corticosteroids – Immunosupressants (methotrexate, cyclosporin) • Immunological therapy – Anti-TNF α – Anti-IL-12/23
Notes de l'éditeur
- Different responses to transient intestinal injury in genetically susceptible versus genetically resistant hosts. After nonspecific injury from an environmental trigger, such as an infection or exposure to a nonsteroidal anti-inflammatory drug (NSAID), normal hosts rapidly repair the mucosal defect and downregulate innate and T-cell immune responses with no residual tissue damage. By contrast, individuals in whom immunoregulation, epithelial barrier function or bacterial killing is defective, develop chronic inflammation that is mediated by aggressive T-cell responses to commensal bacterial antigens. Chronic inflammation is perpetuated by continued uptake of luminal antigens.
- Hygiene theory
- Interaction of various factors contributing to chronic intestinal inflammation in a genetically susceptible host. Genetic susceptibility is influenced by the luminal microbiota, which provide antigens and adjuvants that stimulate either pathogenic or protective immune responses. Environmental triggers are necessary to initiate or reactivate disease expression. Abbreviation: IBD, inflammatory bowel diseases.
- Most important mechanisms of defence in the intestinal epithelial barrier. Invasion of the mucosa is prevented by physical defences (mucus layer secreted by goblet cells, cellular barrier formed by epithelial cells) and by epithelial immune cells (Paneth cells and M cells). Recognition of pathogenic bacterial components is performed via TLR and NOD receptors. The inflammatory reaction involves mucosal immune system activation (mononuclear cells, lymphocytes and dendritic cells of the subepithelial dome). Inflammation is mediated by cytokines (TNF, IL) secreted by these different immune cells. EGF, epithelial growth factor; GM-CSF, granulocyte macrophage-colony stimulating factor; FAE, follicle-associated epithelium; ITF, intestinal trefoil factor; IL, interleukin; NOD2, nucleotide oligomerization domain 2; SED, subepithelial dome of the Peyer patch; Th, T helper lymphocyte; TLR, toll-like receptor; TNF, tumor necrosis factor.
- Key features of the intestinal immune system. The intestinal immune system is extensive and unique with respect to its close apposition to intraluminal bacteria, which are separated from the underlying lamina propria by only a single layer of epithelial cells. The epithelial-cell layer is comprised of absorptive and secretory cells, goblet cells and Paneth cells. Goblet cells contribute to the formation of the protective mucus layer. Microfold cells (M cells) and dendritic cells (DCs) sample intestinal luminal contents. The presence of either pathogenic bacteria or disruption of the epithelial-cell barrier results in activation and migration of DCs to the mesenteric lymph nodes, where they activate naive T cells, which then undergo differentiation under the influence of factors released by DCs and other stromal elements. A central challenge facing researchers of inflammatory bowel diseases is defining the mechanisms of crosstalk between components of the innate and adaptive immune systems in light of the multiple established genetic variants associated with Crohn’s disease. SED, subepithelial dome; TGFβ, transforming growth factor-β; TH, T helper; TReg, T regulatory.
- MDP: muramyl dipeptide
- Binding of microbial adjuvants to extracellular and intracellular pattern-recognition receptors. Toll-like receptors on the cell membrane selectively bind to various bacterial, viral or fungal components. This ligation activates conserved signaling pathways that activate NFκB and mitogen-activated protein kinases. These transcription factors stimulate the expression of a number of proinflammatory and antiinflammatory genes. Homologous intracellular receptors, CARD4 (formerly NOD1) and CARD15 (formerly NOD2), bind to diaminopimelic acid and muramyl dipeptide, respectively, to activate NFκB as discussed in the text. CARD15 can modulate NFκB activation following ligation of TLR2. Abbreviations: CARD, caspase recruitment domain family member; CpG DNA, DNA containing cytosine–guanine repeats linked by phosphodiester bonds; DAP, diaminopimelic acid; dsRNA, double-stranded RNA; ERK, extracellular signal regulated kinase; HSP60, heat shock protein 60; IL-1, interleukin-1, IL-1R, interleukin 1 receptor; JNK, c-Jun amino-terminal kinase; MAPK, mitogen-activated protein kinase; MDP, muramyl dipeptide; NFκB, nuclear factor κB; P38, mitogen-activated protein kinase 1; P50, subunit of NFκB that forms a heterodimer with P65; P65, NFκB subunit; TLR, Toll-like receptor; TLR4/MD2, complex of Toll-like receptor 4 and MD2, a molecule that confers responsiveness to lipopolysaccharide; TNF, tumor necrosis factor; TNFR, TNF receptor.
- Variation in multiple genes in the IL ‑23R pathway is associated with Crohn’s disease. Functional IL‑23R (interleukin-23 receptor) signalling results from the engagement of a heterodimeric cytokine (comprised of p40 and p19 subunits) with a heterodimeric receptor (comprised of IL‑23R and IL‑12RB1 subunits). On engagement of IL‑23 with its receptor, Janus kinase 2 (JAK2) is activated, resulting in JAK2 autophosphorylation and tyrosine phosphorylation of IL‑23R. This in turn results in the recruitment, phosphorylation, homodimerization and nuclear translocation of signal transducer and activator of transcription 3 (STAT3). Asterisks denote genes proven to be associated with Crohn’s disease. TYK2, tyrosine kinase 2.
- Impact of CD mutations on mucosal host defenses. Shown are proposed mechanisms of known CD mutations and their effect on mucosal immune responses. Shown on the right are specific impacts of mutations on host defenses. Mutations associated with increased CD activity include: NOD2 (1), ATG16L1 (2), IBD5 Locus (4), and HLA region genes (5). Shown in the figure are locations where mutations impact mucosal host defenses. Mutations that are protective in CD include IL23R (3).
- Interaction of various factors contributing to chronic intestinal inflammation in a genetically susceptible host. Genetic susceptibility is influenced by the luminal microbiota, which provide antigens and adjuvants that stimulate either pathogenic or protective immune responses. Environmental triggers are necessary to initiate or reactivate disease expression. Abbreviation: IBD, inflammatory bowel diseases.
- Intestinal immune homeostasis and inflammation. a | In the presence of a balanced commensal microbiota (eubiosis), intestinal epithelial cells secrete mucins and AMPs, and microbe-associated molecular patterns (MAMPs) induce the secretion of epithelial cytokines (TSLP, IL‑33, IL‑25 and TGF‑β) that promote development of tolerogenic DCs and macrophages. DCs, in turn, induce the development of iTREG cells through processes dependent on TGF‑β and RA. In addition, TREG-cell-derived TGF‑β and epithelial-derived BAFF and APRIL promote generation of protective IgA plasma cells. Through additional mechanisms, including the secretion of TGF‑β and IL‑10 by iTREG cells and the secretion of IL‑10 by macrophages, a physiological state of intestinal inflammation (tolerance) is induced and maintained. b | In the presence of pathogenic bacteria and viruses (dysbiosis), injury or xenobiotics, MAMPs stimulate the production of proinflammatory cytokines (IL‑1, IL‑6 and IL‑18 from epithelial cells and IL‑6, IL‑12 and IL‑23 from DCs and macrophages) that induce development of the effector CD4+ T cells TH1 and TH17. Depending on the cytokine milieu, TH2 or TH9 cells are generated that mediate TH2‑type responses or impair epithelial barrier function, respectively. Intestinal innate lymphoid cells, including NK‑like cells, LTi cells, and γδ IELs, respond to proinflammatory cytokines upregulating IL‑22 (which protects the epithelial barrier) and IL‑17A and IL‑17F ( which recruit neutrophils to promote inflammation and IL‑22‑mediated epithelial proliferation). AMP, antimicrobial peptide; APRIL, a proliferation-inducing ligand; BAFF, B‑cell-activating factor of the TNF family; DC, dendritic cell; IEC, intraepithelial cell; IEL, intraepithelial lymphocyte; iTREG cell, induced regulatory T cell; LTi, lymphoid tissue inducer; NK cell, natural killer cell; RA, retinoic acid; sIgA, secretory IgA; TGF‑β, transforming growth factor β; TH, T helper cell; TSLP, thymic stromal lymphopoietin. Adapted with permission from Nature Publishing Group © Maynard, C. et al. Nature 480, 231–241 (2012).
- Interaction of various factors contributing to chronic intestinal inflammation in a genetically susceptible host. Genetic susceptibility is influenced by the luminal microbiota, which provide antigens and adjuvants that stimulate either pathogenic or protective immune responses. Environmental triggers are necessary to initiate or reactivate disease expression. Abbreviation: IBD, inflammatory bowel diseases.
- Chronic intestinal inflammation induced by multiple exogenous and endogenous signals and mediated by multiple immune and nonimmune cells. The epithelial translocation of exogenous substances, including dietary antigens, gut microbiota-derived MAMPs, pathogens or xenobiotics, or a combination of them, can trigger an initial response mediated primarily by immune cells that initiates mucosal inflammation. This primary inflammatory response induces proliferation of endothelial and mesenchymal cells, tissue damage and cell death resulting in the release of endogenous DAMPs, which trigger a secondary inflammatory response mediated by immune and nonimmune cells (endothelial, mesenchymal and other cells) that amplifies inflammation and stimulates angiogenesis, fibrogenesis and structural changes; continuous inflammation induces further tissue damage, cell death, and additional release of DAMPs acting on both immune and nonimmune cells, eventually resulting in a self-sustaining cyclic of chronic inflammation associated with angiogenesis, lymphangiogenesis and fibrosis. DAMP, damage-associated molecular pattern; MAMP, microbe-associated molecular pattern.
- The intricate universe of immune and nonimmune components involved in IBD immunopathogenesis. When considering IBD comprehensively, the immune system is only one contributor and its role in disease pathogenesis must be considered in light of the other major components, that is, the environment, the genetic make-up and the gut microbiota. Together, all four components must be functionally integrated before they can trigger disease, as no single component alone can initiate or mediate IBD. A dysregulated immune response represents the effector arm of the inflammatory response, which includes a number of diverse cell types of immune and nonimmune (myeloid, lymphoid, epithelial, endothelial, mesenchymal, neurogenic) origin as well as their products (cytokines, chemokines, neuropeptides, ROS, AMPs, DAMPs, etc.), in addition to regulatory and mediator elements (regulatory RNAs, inflammasome, etc.). A large number of specific and nonspecific stimuli (diet, microbes, infectious agents, xenobiotics) can activate the mucosal immune system, but at present the temporal sequence of downstream events leading to chronic inflammation is still uncertain, making it impossible to distinguish primary from secondary abnormalities in IBD immunopathogenesis. AMP, antimicrobial peptide; DAMP, damage-associated molecular pattern; DC, dendritic cell; ECM, extracellular matrix; HMGB1, high mobility group box chromosomal protein 1; ILC, innate lymphoid cell; NK cell, natural killer cell; NKT cell, natural killer T cell; ROS, reactive oxygen species; TH, T helper; TREG cell, regulatory T cell
- Initiating events increase intestinal permeability, and subsequently luminal bacteria or bacterial products disseminate in the mucosal compartment. In normal individuals these small inflamatory events reside subclinically; inflammation is controlled via tolerogenic immune responses that finally result in healing. The pattern recognition receptor NOD2, which is involved in the recognition of bacterial components and initiation of innate- and adaptive immune responses, is crucial in this process. Mutations within the Nod2 gene are associated with uncontrolled gastrointestinal immune responses that finally result in signs of chronic inflammation. Currently many therapies for induction of remission are interfering with processes late in the inflammatory cascade, and the challenge of contemporary research is to develop maintenance strategies that are aimed at early intervention in this cascade.
- 5-ASA = 5- amino salysilic acid