Immuno pathogenic mechanisms of IBD Flashcards
ulcerative colitis
characterized by chronic inflammation and ulcers in the innermost lining of the colon and/or rectum
crohn’s disease
characterized by inflammation of the lining of the GI which often spreads deep into affected tissues and may occur in any part of the GI tract
IBD
an inappropriate and exaggerated mucosal immunity to normal flora
UC/ CD is the rectum spared?
UC = not spared CD = spared 40% of the time
dysbiosis
condition in which there is disequilibrium of the microbial communities that constitute the microbiota at a given body site
What type of IBD shows string sign on barium x-ray?
crohn’s disease
what type of IBD shows lead pipe sign on barium x-ray?
ulcerative colitis
What type of IBD has a positive ASCA test?
Crohn’s disease
what type of IBD has a positive pANCA test?
ulcerative colitis
what type of IBD has cobblestone appearance on endoscopy?
Crohn’s disease
What type of gene editing is associated with IBD?
Single nucleotide polymorphisms (SNPs): loci variants with alleles that differ at a single base
Susceptibility locus for IBD and where is it found?
IBD-1 on chromosome 16
What does susceptibility gene for IBD contain?
CARD15/NOD2 genes
where is CARD15 expressed? What does it do?
in macrophages and dendritic cells; it is a pattern recognition receptor that triggers NF-kB
Mechanism for IBD susceptibility with CARD15/NOD2
1) defective macrophage function (chronic T cell activation)
2) defective epithelial cell responses (loss of barrier function)
3) defective conditioning of APCs (inappropriate activation)
What phyla is the gut microbiome mainly composed of?
Bacteroides (bacteroides or prevotella) and Firmicutes (clostridium and lactobacillus)
What bacteria is increased in UC patients?
proteobacteria
what bacteria is increased in CD patients?
firmicutes and actinobacteria
What happens when mice raised in a germ free environment are colonized with commensal bacteria?
spontaneous colitis develops rapidly
Explain the microbiota of babies born to women with IBD
lower bacterial diversity and altered bacterial composition
What happens to the microbiota with a high fat diet?
dysbiosis with a decrease in bacteriodetes, firmicutes, proteobacteria
infections (3) implicated in the development of IBD
1) M. paratuberculosis
2) Measles virus (paramyxovirus)
3) listeria monocytogenes
Populations where IBD is uncommon
Asia, Africa
role of anti-inflammatory microbiota (bacteroides) in homeostasis
beneficial bacteria upregulates Treg cells and IL-10 which, along with commensal bacteria, suppress pathobionts
important commensal bacteria product (from fiber)
- commensal bacteria ferment nondigestable polysaccharides to produce SCFAs
Roles (2) of SCFAs
- anti-inflammatory properties in macrophages, dendritic cells, CD4+ T cells and intestinal epithelial cells
- induction of IgA and mucus secretion into the lumen
what happens when intestine is colonized with Bacteroides fragilis and clostridium species?
induction of Treg cells in the lamina propria
What type of bacteria are bacteroides fragilis and clostridium species?
segmented filamentous bacteria (SFB)
What type of maintenance are segmented filamentous bacteria (SFB) involved in?
maintenance of the basal activation level of Th17 cells –> which is important for the integrity of the epithelial barrier
How is GALT developed properly?
Microbiota is required for GALT to develop properly.
What helps to form active secondary forms of bile acids?
microbiota
NF-kB relationship to commensal microbiota
commensal microbiota suppresses NF-kB pathway (tolerance to microflora)
How does bacteroides inactivate NF-kB directly?
induction of Peroxisome Proliferation Activated Receptor (PPAR) exports activated NF-kB from nucleus
General immune response in IBD dysbiosis
- increased Th17 and Th1 response
- decreased Treg and IL-10 response
What immune responses are up regulated in Crohn’s disease?
Th1 and Th17
cytokine(s) activating Th1 cells
IL-12
cytokine(s) produced by Th1 cells
IFN-gamma
cytokine(s) activating Th17 cells
IL-6
IL-23
TGF-beta
cytokine(s) produced by Th17 cells
IL-17
immune response upregulated in ulcerative colitis
Th2
cytokine(s) activating Th2
IL-4
cytokine(s) produced by Th2 cells
IL-4
IL-5
IL-13
What cytokine is produced by antigen presenting cells and is closely related to IL-12, but activates Th17 response?
IL-23
Result LOSS OF FUNCTION SNP in IL-10 and TGF-beta?
predisposition to IBD
Result LOSS OF FUNCTION SNP in TNF, IFN, IL-1, IL-6, IL-17, IL-22 (cell mediated inflammation)?
protection from Crohns
Result LOSS OF FUNCTION sNP in IL-4, IL-5, and IL-13 (Ab mediated inflammation) ?
protect from UC
Theory: IBD is a result of…
breakdown of tolerance to resident enteric bacteria (loss of Treg function)
Cytokines for maintenance of tolerance
IL-10 and TGF-beta
How are Treg cells activated?
APCs presenting auto-Ag
Receptors Tregs express (2)
CTLA-4 and CD25 (IL-2 receptor)
How do Treg cells suppress APCs?
cell-to-cell interactions and inhibitory cytokines
How do Treg cells act on activated T cells?
CTLA-4 and IL-2 deprivation
** deprive through their high affinity IL-2R receptor
Immuno-therapeutic treatment option for IBD
TNF-blockers for moderate to severe UC and CD
Future therapy IBD
fecal microbiota transplantation
