Immune-Pathogenic Mechanisms of IBD (Shnyra) Flashcards
What disorders make up Inflammatory Bowel Disease
Chron’s Disease
Ulcerative Colitis
What are the major phases in the development of IBD
- Genetic and environmental factors induce impared barrier function
- Translocation of commensal bacteria which activate immune cells and cytokine production
- If an acute inflammation can’t be resolved it leads to chronic intestinal inflammation
- This can lead to complications such as fibrosis, stenosis, abscess, fistula, cancer, etc.
What are the characteristics of Chron’s Disease
Signs & Symptoms
GI involvement
Pathology
Diagnosis
Cancer Risk
Management & Treatment
Lab
Signs & Symptoms - Abdominal pain, obstruction & fever
GI involvement - Mouth to Anus (rectum spared)
Pathology - Abscesses, fistuals, strictures, granulomas, transmural inflammation
Diagnosis -“string sign” on barium x-ray, Skip lesions, Cobblestone appearance on endoscopy
Cancer Risk - Increased after 15 years
Management & Treatment - Medical surgery not curative
Lab - ASCA positive (80% of pts)
What are the characteristics of Chron’s Disease
Signs & Symptoms
GI involvement
Pathology
Diagnosis
Cancer Risk
Management & Treatment
Lab
Signs & Symptoms - Bloody diarrhea, Urgency
GI involvement - Colon and/or rectum
Pathology - Pseudopolyps, Toxic megacolon, Mucosal or submucosal inflammation
Diagnosis - Ulcerations, Edema, Erythema & erythema of colonic mucosa, Negative stool cultures, Continuos Disease
Cancer Risk - Increased after 10 yrs
Management & Treatment - Medical surgery can be curative
Lab - Positive pANCA
What factors have a major effect on Gut Microbiota
Diet
Environment
Genetics
What type of triggers are necessary to initiate or reactivate IBD
Environmental triggers
What areas does IBD typically develop
Areas of high bacterial concentrations
What major phyla contribute to the human microbiome
Firmicutes
Bacteroidetes
Actinobacteria
Proteobacteria
What are the major Phyla in:
Normal large intestine microbiome
Ulcerative Colitis
Chron’s Disease
Normal large intestine microbiome - Bacteroidetes & Firmicutes
Ulcerative Colitis - Proteobacteria > other phyla
Chron’s Disease - Firmicutes > Actinobacteria > Other phyla
The prevalence of IBD is inversely associated with the prevalence of what?
Helminth colonization
Helminths are thought to play an important immunoregulatory role with the intestinal flora
What is the main genetic predisposition for developing IBD
Single Nucleotide Polymorphisms (SNPs) - loci variants with alleles that differ at a single base
What SNP mutation found in chromosome 16 is associated with CD
IBD-1 mutation
What gene does IBD-1 locus contain
CARD15/NOD2 gene
What is the normal function of CARD15/NOD2 gene
A pattern recognition receptor expressed in macrophages and dendritic cells that recognizes MDP (a peptidoglycan found on bacteria) which triggers activation of NF-kB
How does mutations in CARD15/NOD2 contribute to CD
Defective function of macrophages
- Leads to persistent intracellular infection of macrophages and chronic stimulation of T cells by macrophage-infecting organisms
Defective epithelial-cell responses
- Lead to loss of barrier function and increased exposure to the mucosal microflora
Defective “conditioning” of APCs
- Leads to inappropriate activation of APCs and disruption of the homeostatic balance of effector and regulator cells
List the role of commensal anti-inflammatory microflora in GI tract homeostasis
- Induce development of GALT
- Influences permeability and intestinal immunity
- Mantains basal levels of Th17 & Th1 cell activity in the lamina propria
- Suppression of pathobionts via induction of Treg cells and stimulation of IL-10 production by immune cells
- Ferment nondigestible polysaccharides to produce SCFAs which have anti-inflammatory properties in macrophages, DCs, CD4+ & intestinal epithelial cells.
Colonization of the gut with segmented filamentous bacteria (SFB) results in what
- Induction of Treg cells in the lamina propria
- Maintenance of the basal activation level of Th17 cells which are important for the integrity of the epithelial barrier
What consist of the mucosal firewall & what is the function
Combination of the epithelial barrier, mucus layer, IgA, DCs and T cells.
Limit the passage and exposure of commensals to the gut-associated lymphoid tissure, preventing untoward activation and pathology
What is the relationship between immune tolerance & microbiota
Commensal microbiota suppress NF-KB pathway which promotes tolerance of DCs and macrophages to microflora and thus do not secrete pro-inflammatory cytokines. In IBD, tolerance is lost
Chronic inflammation in IBD involves what
Hyperactivation of TH1 and TH17 cells
Inhitbion of Treg cells producing IL-10
What is the pathogenesis of Chron’s disease
- Dendritic cells and macrophages secrete IL-12 which activate Th1 cells & secrete IL-6, IL-23 and TGF-B which activate Th17 cells
- Th1 cells secrete IL-2, INF-y and TNF while Th17 cells secrete IL-17
- These inflammatory cytokines lead to the development of Chron’s disease
What is the pathogenesis of Ulcerative Colitis
An atypical activation of Th2 cells and NKT cells which produce the following cytokines:
Th2 –> IL-5, IL-4 & IL-13
NKT cells –> IL-13
ROLE OF CYTOKINES IN IBD
Look at slide 52 and memorize it!
What cytokines & substance promotes differentiation of T cells into T reg cells
Il-2 & TGF-B
Retinoic acid
