7 BL Chronic frustrated immune response 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 in the gut??
○ 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
Big picture of Th0 switching from Treg to Th1,2, or 17
• 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)
- Indigestable fragments of gluten induces enterocytes to release zonulin protein, which loosens tight junctions
- Gluten fragments cross the intestinal lining in abundance and accumulate under epithelial cells
- Gluten induces enterocytes to secrete IL-15, which arouses lymphocytes against enterocytes
- Tissue transglutaminase (TTG), are released by damaged cells –> modifies the gluten
- APC of immune system joins the modified gluten to HLA molecules and display to helper T cells
- helper T cells cause Killer T cells to attack enterocytes
- 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
chronic beryllium disease: what is it? Discuss the mechanism? how many exposures does it take? What HLA is it linked to?
- 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
Dendritic cells in peyer’s patches make what? Which does what?
IL-10 which helps Treg development
What cytokines are found in Peyer’s patches? What does it do?
Cytokine TGF -beta
This favors differentiation of Th0 cells → Treg.
What is celiac disease? How does it present?
• Gluten-sensitive enteropathy that affects 1% of the world’s population.
• Presents as malabsorption, diarrhea, and failure to thrive ○ Villi in the gut atrophy ○ Diagnostic hallmark is a small intestinal biopsy
