Immuno-Pathogenic Mechanisms of IBD

Question 1

What is the pathological mechanism of Inflammatory Bowel Disease?

Answer 1

increased permeability due to impaired tight junction formation allows normal intestinal microbiota to cause self-sustained mucosal inflammation

• induces innate AND adaptive immune responses

Question 2

What are the differences in mechanisms leading to inflammation in Ulcerative Colitis vs Crohn Disease?

What is an antibody marker for each?

Answer 2

UC = disruption of barrier function (pANCA +)
CD = dysfunction of microbe sensing (ASCA +)

environmental factors VERY important in development of disease states

Question 3

What bacteria are found mainly in the proximal GI tracts vs distal small intestine (ileum) and colon?

Answer 3

Proximal: aerobic and facultative anaerobic bacteria
Distal: obligate anaerobic (SCFA production)

Question 4

What phyla of bacteria are normally found in the Large Intestine, and how does that change between Ulcerative Colitis and Crohn Disease

Answer 4

Normal: bacteroidetes, firmicutes, proteobacteria, actinobacteria

UC: INC. proteobacteria

CD: INC. firmicutes, INC. actinobacteria

Question 5

How do baby microbiotas change if born to IBD women?

What is the biggest predictor of diversity of infant microbiotas?

Answer 5

• babies had lower bacterial diversity and altered bacterial composition
• Maternal IBD is MAIN PREDICTOR of diversity of infant microbiota

Question 6

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?

Answer 6

1. M. paratuberculosis
2. persistent Measles (paromyxovirus)
3. Listeria monocytogenes

• inc. risk of developing IBD (salmonella and campylobacter)

Question 7

What is IBD inversely associated with?

Answer 7

helminth colonization

• inc. helminths = dec. IBD risk

Question 8

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?

Answer 8

• UC and CD very uncommon in Asians and Africans
• risk inc. among FIRST-degree relatives
• monozygotic twins have higher risk rates than dizygotic twins

Question 9

What genetic alterations is IBD caused by?

Answer 9

SINGLE NUCLEOTIDE POLYMORPHISMS

• NOT caused by mutations

Question 10

What is CARD15/NOD2?

Answer 10

• 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

Question 11

How does normal Gut homeostasis occur?

Answer 11

• 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

Question 12

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?

Answer 12

• 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?

Question 13

What two microorganisms cause induction of Treg cells in the lamina propria of the gut? (BF/C)

Answer 13

bacteroides fragilis and Clostridium species

• segmented filamentous bacteria (SFB)
• also play a role in maintenance of basal activation lvl of Th17 cells

Question 14

What detoxifies the LPS of commensal bacteria in the gut microbiota?

Answer 14

IAP or intestinal alkaline phosphatase

Question 15

What are 4 things that SCFAs do for the microbiota?

Answer 15

induce IgA secretion, induce mucin secretion into lumen, promote barrier integrity, and prevent pathogen colonization

Question 16

What 5 entities make up the Bacterial Fire Wall of the gut?

Answer 16

epithelial barrier, mucus layer, IgA, dendritic cells, and T-cells

Question 17

How do commensal Bacteroides block inflammation in the presence of other organisms, such as Salmonella enteritidis?

Answer 17

• 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

Question 18

What T-Cells are seen in Crohns Disease, what factors do they release, and what 3 molcules cause their induction?

Answer 18

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

Question 19

What T-Cells are seen in Ulcerative Colitis, what factors do they release, and what molecule causes their induction?

Answer 19

IL-4 –> Th2 –> IL-4/5/13

NKT Cell –> IL13

Question 20

How do LOF and GOF mutations differ between normal microbiota tolerance and CD (cell-mediated)/UC (Ab-mediated) inflammation?

Answer 20

normal: LOF predisposes to IBD while GOF protects from IBD

CD/UC: LOF PROTECTS from CD/UC and GOF PREDISPOSES to CD/UC

Question 21

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?

Answer 21

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)