BL - Chronic Frustrated Immune Response

Question 1

Factors regulating Th0 differentiation in Peyer’s patches

Answer 1

Cytokine TGFb (pervasive in gut/submucosal Peyer's patches) favors differentiation of Th0 into Treg. Resident DCs also make IL-10 which favors Treg development. 
Combination of TGFb and IL-6 downregulates Treg and upregulates Th1, Th2, Th17 (defensive). IL-6 is produced by epithelial cells in response to stress or damage - so this favors the development of Th0s into defensive Th1/Th2/Th17 in cases of damage

Question 2

Relative influence of environment and genetics on risk for inflammatory bowel disease

Answer 2

IBD: dysregulated immune responses to commensal bacteria - intestinal wall becomes a “battlefield” of chronic inflammation
Epithelial barrier: something slightly leaky - defensins secreted and maybe they get back in (pro-inflammatory)
Concordance in monozygotic twins only 30-35% for CD and 10-15% for UC so environment and “bad luck” play a significant role.

Question 3

Pathogenesis of celiac disease

Answer 3

Peptides from gliadin (wheat protein) presented to Th cells. T-cell immunity to gliadin peptides responsible for chronic inflammation
90% of people with celiac are HLA-DQ2, most of rest are HLA-DQ8. But most people with those HLA alleles don’t get celiac, which means there are genetic/environmental factors contributing
Gold standard for diagnosis: endoscopic biopsy

Question 4

Chronic beryllium disease

Answer 4

Pulmonary inflammatory/fibrotic disease caused by exposure to inhaled beryllium dust. Seen in miners and machinists especially in nuclear industry.
Inhaled Be covalently linked to various peptides, thought to create novel epitopes to which a Th1/Th17 response is made and later scarring Th2 response.
Be cannot be removed by macrophages, so condition becomes established and chronic even after single inhalation exposure
Strongly linked to HLA-DP alleles that have glutamic acid at position 69 of b chain.

Question 5

Hygiene/Old Friends hypothesis

Answer 5

Certain harmless microorganisms (Mycobacteria non-tuberculosis, Lactobacilli, helminth worms) have been in humans so long we use them to develop a balance between activation and regulation, driven by right number of Treg.
But if you don’t have enough exposure to those bacteria, you might have too few Treg and make too strong a Th1, Th2, Th17 response to bacteria like gut flora or pollen

Question 6

Switching Th1/Th2/Th17 responses to Treg

Answer 6

Administration of whipworm ova increases Treg production in gut, which suppresses Th1/Th2/Th17 responses. Effect of suppression is not antigen-specific, so nearby activated T cells are downregulated or do not differentiate into effectors