ChronicFrustratedImmuneResp Flashcards
Describe the factors that regulate the differentiation of Th0 cells in the Peyer’s Patches to Treg cells.
○ Lots of cytokine TGFβ in Peyer’s Patches. This favors differentiation of Th0 cells →Treg.
○ DCs in the Patches make IL-10 →Treg development
Why are Tregs beneficial?
○ Super favorable to be rich in Treg cells because you are constantly bringing foreign material into the gut, and you don’t want all of that to cause an immune response
○Tregs can also easily differentiate into Tfh and vice versa, so you can drive B-cells to make IgA
Describe the factors that regulate the differentiation of Th0 cells in the Peyer’s Patches to Th1, Th2, or Th17
○ During infection - pathogens are aggressive and can start invading. The damage to tissues causes innate immune response. Characteristic cytokine is IL-6.
○ IL-6 is produced by epithelial and other cells in response to stress or damage
○ Combo of TGFβ and IL-6 →upregulation of Th1, Th2, and Th17
• Once you get rid of the IL-6 by eliminating the PAMPs, then you get to go back to Treg dominated system
○ During infection - pathogens are aggressive and can start invading. The damage to tissues causes innate immune response. Characteristic cytokine is IL-6.
○ IL-6 is produced by epithelial and other cells in response to stress or damage
○ Combo of TGFβ and IL-6 →upregulation of Th1, Th2, and Th17
• Once you get rid of the IL-6 by eliminating the PAMPs, then you get to go back to Treg dominated system
• So big picture here is that you live with your bugs in your gut by having a TGFβ-mediated system in which you normally have a bunch of Treg. When your innate response sees a threat, you make stress cytokines and switch from Th0 becoming Treg to Th0 becoming Th1, Th2, and Th17
Difference between Crohns disease and Ulcerative colitis (UC)
○ CD affects large & small intestine and the terminal ileum. Microabcesses form in the wall of the intestine and the “patchy” diseased areas spread. They eventually become granulomas.
○ UC is more superficial in the large intestine and erosion of the surface leads to bleeding
3 parts to etiology of chronic frustrated immune response:
- Genetics
- Environment
- Bad Luck (2/3rds) - no joke yo
pathogenesis of Celiac disease
Cause of the disease: Direct ability to respond to gluten! (make the Tfh cells that can help B-cells)
1. Indigestable fragments of gluten induces enterocytes to release zonulin protein, which loosens tight junctions
2. Gluten fragments cross the intestinal lining in abundance and accumulate under epithelial cells
3. Gluten induces enterocytes to secrete IL-15, which arouses lymphocytes against enterocytes
4. Tissue transglutaminase (TTG), are released by damaged cells –> modifies the gluten
5. APC of joins the modified gluten to HLA molecules and display to helper T cells
6. helper T cells cause Killer T cells to attack enterocytes
7. B cells release Ab targeted to gluten and TTG -> more damage
Cytogenetic marker of individuals with Celiac disease
§ 90% of people with Celiac are HLA-DQ2
§ Some are HLA-DQ8
Discuss the mechanism of chronic beryllium disease.
• Pulmonary inflammatory and fibrotic disease that comes from inhaling beryllium dust (mining).
• 1 million exposed, 15% are symptomatic
• Inhaled Beryllium covalently links to various peptides → create novel epitopes for Th1 and maybe Th17 to initiate a response
• Unfortunately, Be cannot be removed by macrophages, so even one exposure can lead to CFR
• Linked to HLA-DP alleles with a glutamic acid at position 69 (hehe). This makes a negatively charged pocket to bind Be+
Hygiene Hypothesis
• First proposed in 1989 to explain why allergy and asthma was increasing w/o clear cause
○ Less of an increase in poor countries vs rich ones
○ Less increase in equatorial vs northern
○ Less increase in rural vs. urban
○ Less increase in slums vs. rich neighborhoods
○ Less increase in children of large families vs single-child families
• Suggested that exposure to dirt and infections helped the immune system mature
○ Newborns start with a Th2-dominated system
○ Gradually balances to Th1
• Explains why Th2 diseases increased, but couldn’t explain Th1 (UC and CD). Too simple of a model
Old Friends Hypothesis
• Stuff like Mycobacteria, lactobacilli, and helminth worms have been around in our body for so long that we need them to teach our immune systems
• If they teach our immune systems about good bugs, then we won’t overreact to low-grade pathogens or commensals.
• Old friends teach balance between activation and regulation, driven by Treg numbers
○ If you have too few Tregs, then you can prematurely activate an immune response/make too strong of a response
○ Feed yo kids dirt
Discuss the idea that it may be possible to switch Th1/Th2/Th17 responses to Treg instead.
• Idea of “sibling rivalry” between the effects of Th1 and Th2 responses upon each other
○ Thought in CD and UC that Th2 opposed Th1 and could be good
• Led to a study with CD patients: feed them whipworm ova
○ Great improvement in patients
○ Th2 was not suppressing Th1, instead there was an increase in Treg
§ Treg suppressed all of the Th responses
§ Effect of suppression is not antigen-specific. Many nearby T-cells are down-regulated
