Chronic Frustrated Immune Responses and Regulation (complete)

Question 1

Describe the normal situation in the gut. Talk about Peyer’s Patches, TGF-beta, and Tregs

Answer 1

• A lot of TGF-beta in Peyer’s Patches —» differentiation of Th0 to Treg
• DCs in PPs make IL-10 —» favors Treg development
• Large Treg presence is desirable b/c of constant exposure to bacteria/food (aka Ags) coming through gut epithelium
• Tfh also in PPs —» cause B cells to produce IgA

Question 2

Describe the situation in the gut when there is stress or damage. Talk about Il-6, Th1, Th2, Th17, and Tregs

Answer 2

• IL-6 produced as a response to stress/damage

- Combo of TGF-beta and IL-6 downregulates Treg and upregulate Th1/2/17

Question 3

Describe IBD

Answer 3

• Includes Crohn Disease and ulcerative colitis
• Both thought to involve dysregulated immune responses to bacteria

CD: affects large/small intestine, especially terminal ileum — microabcesses –» generalized inflammation

UC: usually more superficial in large intestine - can erode surface —» bleeding

Question 4

Discuss the relative influence of environment and genetics on the risk of IBD

Answer 4

• GWAS have identified 163 loci associated for increased risk of IBD —» strong genetic component
• HOWEVER, concordance in monozygotic twins is only 30-35% for CD and 10-15% for UC —» environmental factors

Question 5

What is tissue transglutaminase 2?

Answer 5

TG2

• The autoAg in celiac disease
• Normally makes protein crosslinks through glutamines

Question 6

Describe the pathogenesis of celiac disease

Answer 6

• TG2 couples to but can’t release wheat peptides —» becomes an autoAg —» B cell presents it via foreign + self hybrid to Tfh
• Tfh w/ HLA DQ2/8 recognize autoAg and stimulate Ab production in B cells
• Leads to: inflammation, gut becomes battleground —» flattening of villi and decreased absorption

OVERALL: Ab doesn’t cause the disease, but Ab is caused by disease

Question 7

Discuss the importance of HLA alleles in celiac disease

Answer 7

• 90% of those w/ celiac have HLA-DQ2, the rest DQ8 (but most of the people w/ these don’t get celiac)
• Only people w/ these surface receptors can respond to the autoAg presented by B cell
• Therefore autoAg can be presented, but w/o stimulation disease does not occur

Question 8

Describe the mechanism of chronic beryllium disease

Answer 8

• A pulmonary inflammatory and fibrotic disease – caused by inhaling beryllium dust
• Be become covalently linked to peptides —»> creates novel epitopes
• Th1/17 respond to these epitopes, and late Th2 responds w/ scarring
• Be can’t be removed by macros —» therefore disease is established and chronic after one exposure

Question 9

What is the Hygiene hypothesis? Which observations support it?

Answer 9

• Theorized that exposure to environmental dirt/infections helped immune system mature normally (Th2 dominated —> balanced btwn Th1 and Th2)
• Evidence: Poor/equatorial countries, large families all head less of an increase in asthma/allergies

BUT — rich, clean peeps have increased risk for Th1 disease like IBD, DM Type 1 (should be more susceptible to Th2)

Question 10

What is the Old Friends hypothesis? Which observations support it?

Answer 10

• Says certain harmless microorgs have been in humans so long that we rely on their presence to instruct our immune systems
• Adequate exposure to these “old friends” —» develop balance btwn activation (Th1/2/17) and regulation (Treg)
• W/o these “old friends”, there are too few Tregs and too many Th1/2/17 when there isn’t anything threatening to respond to —» attacks normal gut flora or pollen

Question 11

How might it be possible to switch the Th1/2/17 responses to Treg?

Answer 11

• Based on an experiment w/ persons w/ severe CD and UC
• Ingesting whipworms (only live a few days in gut, safe)
• Increased Treg production in gut —» suppresses Th1/2/17 responses
• But remember too much Treg —»> immunosuppression also (can’t have any responses via Th1/2/17)