Immuno-Pathogenic Mechanisms of IBD Flashcards
What is the pathological mechanism of Inflammatory Bowel Disease?
increased permeability due to impaired tight junction formation allows normal intestinal microbiota to cause self-sustained mucosal inflammation
- induces innate AND adaptive immune responses
What are the differences in mechanisms leading to inflammation in Ulcerative Colitis vs Crohn Disease?
What is an antibody marker for each?
UC = disruption of barrier function (pANCA +) CD = dysfunction of microbe sensing (ASCA +)
environmental factors VERY important in development of disease states
What bacteria are found mainly in the proximal GI tracts vs distal small intestine (ileum) and colon?
Proximal: aerobic and facultative anaerobic bacteria
Distal: obligate anaerobic (SCFA production)
What phyla of bacteria are normally found in the Large Intestine, and how does that change between Ulcerative Colitis and Crohn Disease
Normal: bacteroidetes, firmicutes, proteobacteria, actinobacteria
UC: INC. proteobacteria
CD: INC. firmicutes, INC. actinobacteria
How do baby microbiotas change if born to IBD women?
What is the biggest predictor of diversity of infant microbiotas?
- babies had lower bacterial diversity and altered bacterial composition
- Maternal IBD is MAIN PREDICTOR of diversity of infant microbiota
What 3 infections organisms are potentially indicated as contributing to IBD? (MP/M/LM)
What do pts. with gastroenteritis have an inc. risk of developing?
- M. paratuberculosis
- persistent Measles (paromyxovirus)
- Listeria monocytogenes
- inc. risk of developing IBD (salmonella and campylobacter)
What is IBD inversely associated with?
helminth colonization
- inc. helminths = dec. IBD risk
What two ethnicities is IBD less common in, what relatives are at inc. risk of development, and which set of twins has a higher risk of IBD development?
- UC and CD very uncommon in Asians and Africans
- risk inc. among FIRST-degree relatives
- monozygotic twins have higher risk rates than dizygotic twins
What genetic alterations is IBD caused by?
SINGLE NUCLEOTIDE POLYMORPHISMS
- NOT caused by mutations
What is CARD15/NOD2?
- genes found on IBD-1 susceptibility locus on chromosome 16 (expressed in macrophages/dendritic cells)
- people homozygous for SNP variant have 20x inc. risk of CD (found in 17-27% of CD)
- CARD15 is PPR that recognizes MDP (peptidoglycan on Gram (+)/(-) bacteria) and triggers NF-kB
How does normal Gut homeostasis occur?
- bacterial colonization induces GALT (gut-associated lymphoid tissue) development and helps induce basal levels of Th17 and Th1 activity in lamina propria
- beneficial bacterial inc. development of Treg cells and IL-10, both of which help protect from pathobionts
Why are SCFAs important to homeostasis and what are they created by?
What are three common SCFAs (A/B/P) and how do they interact with Treg cells?
- created by fermentation of nondigestible polysaccharides (CELLULOSE) by commensal bacteria to produces SCFAs
- actetate, butyrate, propionate (SCFAs) bind to GPR43 on Treg cells, causing them to release IL-10, which blocks the inflammatory response?
What two microorganisms cause induction of Treg cells in the lamina propria of the gut? (BF/C)
bacteroides fragilis and Clostridium species
- segmented filamentous bacteria (SFB)
- also play a role in maintenance of basal activation lvl of Th17 cells
What detoxifies the LPS of commensal bacteria in the gut microbiota?
IAP or intestinal alkaline phosphatase
What are 4 things that SCFAs do for the microbiota?
induce IgA secretion, induce mucin secretion into lumen, promote barrier integrity, and prevent pathogen colonization
What 5 entities make up the Bacterial Fire Wall of the gut?
epithelial barrier, mucus layer, IgA, dendritic cells, and T-cells
How do commensal Bacteroides block inflammation in the presence of other organisms, such as Salmonella enteritidis?
- Salmonella flagellin alone binds TLR5 causing IkB kinase to dissociate from p50/RelA –> proinflammatory gene transcription
- Bacteroides induce Peroxisome Proliferation Activated Receptor (PPAR) that can export activated NF-kB from nucleus
What T-Cells are seen in Crohns Disease, what factors do they release, and what 3 molcules cause their induction?
IL-12 –> Th1 –> IL-2/IFN-y/TNF
- IFN-y causes macrophage activation
- MO released IL-23 = Th17 indcution
IL-6/23/TGF-b –> Th17 –> IL17
What T-Cells are seen in Ulcerative Colitis, what factors do they release, and what molecule causes their induction?
IL-4 –> Th2 –> IL-4/5/13
NKT Cell –> IL13
How do LOF and GOF mutations differ between normal microbiota tolerance and CD (cell-mediated)/UC (Ab-mediated) inflammation?
normal: LOF predisposes to IBD while GOF protects from IBD
CD/UC: LOF PROTECTS from CD/UC and GOF PREDISPOSES to CD/UC
What two molecules induce activated T-Cells to become Treg cells, what two molecules do they produce, and what do they produce that blocks Th17 induction?
IL-2/TGF-b induce Treg cell differentiation
- Treg cells produce IL-10 and TGF-b
Treg cells also release Retinoic Acid that BLOCKS Th17 differentiation
- have CTLA-4 that is constitutively expressed (activated T Cells blocker) and a-subunit IL-2R which has INC. affinity for IL-2 (deprive T-cells)
