Principles of GI Inflammation Disorders

Question 1

In general, which cells influence immune cells?

Answer 1

EPITHELIAL CELLS!

Question 2

Dynamic epithelial layer

Answer 2

thin, one cell layer thick, rapidly renewing the intestinal layer, which is good

goblet cells are protective

paneth cells produce proteins for defense against bacteria (i.e defensin)

Question 3

describe the barrier function and how it relates to development of specific inalmmatory diseases

Answer 3

Barrier function:

• mucus layer established by goblet cells
• when confronted by bacteria, endothelial cells produce cytokines
• cytokines affect immune cells and shape the T-cell response
• add genetic mutations in inflammatory path –> develop specific inflammatory diseases

Question 4

TLR - what is their role normally and in inflammatory diseases?

Answer 4

• epithelial cells sense bacteria by Pattern Recognition Receptors, such as Toll Like Receptors (TLRs)
• you want your TLRs to be tolerant and low (and not that sensitive)
• many inflammatory diseases are due to increased TLR

Question 5

Effects of increased expression of TL2 and TLR in patients with Crohn’s DIsease

Answer 5

• greater sensitivity to gut flora
• stimulation of PRO-inflammatory cytokines: IL-8 and TNF-alpha

(key to leukocyte infiltration)

Question 6

Target of Irritable Bowel Disorder therapy

Answer 6

TNF-alpha (inhibitors, to inhibit pro-inflammation signals)

Question 7

endothelial cells and the protection of immune tolerance

Answer 7

IEC influence maturation of dendritic cells, which regulate Th1 and Th2 responses

Question 8

Microbiome and Cancer (3)

Answer 8

1. Direct Tumor promoting effect / stimulation of TLR and inflammation
2. Indirect by Microorganism Associated Molecular Patterns
3. Pathogens (Helicobacter) or altered commensal bacteria (dysbiosis)

Question 9

“Cancer is the failure to clear cancer cells”

-provide 3 mechanisms that support this

Answer 9

1. Tumor cells block Th1 responses (clearing) by expression of COX2 and IL-10
2. COX2 expression associated with increased PGE-2 and suppression of cytoxoic lymphocytes
3. tumor cells secrete cell death ligand, inducing apoptosis in immune cells

**restoring immune recognition is the new clinical goal**

Question 10

broken barrier

Answer 10

broken epithelilal barrier = leaky barrier

too much exposure to bacteria, overwhelm the system

Question 11

3 different mechanisms by which bacteria may increase probability for cancer

`

Answer 11

1. translocated bacteria
   
   1. associated proteins that influence cells, particularly macrophages and myofibroblasts and shape the inflammatory cells –promote inflammation, prevent apoptosis, and produce carcinoma ‘
2. Genotoxins produced by bacteria
   
   1. Bacterial H2S and ROS production, damage to cells
   2. impair mitochondrial function and metabolism
3. Bacteria may convert ethanol to acetyladehyde , which may produce nitrosamine and carcinogen activation
   
   1. alter biometabolism, change energy requirements, FA’s etc.

SUM UP: bacteria can work directly, indirectly, and in concert with one another to induce lifestyle change.