Chronic Frustrated Immune Response Flashcards
What important cytokine is present in Peyer’s patches as it relates to Treg differentiation?
TGFB
- TGFB promotes Th0 cells -> Treg
What important cytokine do dendritic cells produce in Peyer’s patches at it relates to Treg development?
IL-10
- IL10 released by DC’s promote T-reg development
Big picture Q: Why do we want Treg in the gut anyways?
- T-reg suppresses Th1, Th2, & Th17 (i.e. immune response); it prevents our body from anhialating the microbiome and benign foreign material present in our GI system.
Normal state of GI is high amounts of T-reg & TGFB
How can T-reg stimulate IgA release? (indirectly)
- T-reg can easily differentiate into Tfh
- Tfh can drive B-cells to make IgA allowing for some frontline immune response
Assuming a healthy person, how would an infection affect T-reg stimulation in the gut?
- Pathogens stress/damage tissue
- Damaged tissues induce innate immunity -characteristic cytokine is IL-6
- Combo of IL-6 and TGF-B -> upregulation of Th1, Th2, and Th17 (instead of T-reg)
So big picture here is that you live with your bugs in your gut by having a TGF β-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
What two diseases fall under “IBD” (inflammatory bowel disease)?
Describe each of them generally
-
IBD
- Includes Crohns Disease (CD) 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
Describe the genetic component of IBD
- Early genetic events can lead to increased gut permeability
- Becomes “ leaky” in a special way.
- This allows defensins to penetrate back into the tissues and act as DAMPs
- DAMPs stimulate macrophages to produce IL-6 → Th1, Th2, Th17 to act against commensal (natural microbiome of our GI) organisms.
- This leads to chronic inflammation because you cannot actually kill the microbiome, but the inflammation changes the profile of it in a significant way.
Say you had 100 people with the genetic mutations for inflmmatory bowel diseases.
Would all 100 people be symptomatic?
NO
- There is a strong environmental and luck factor involved, that is not really well understood. Only 10-30% of people with the genetic disposition towards IBD actually develop it.
What are s/s (signs & symptoms) of Celiac Disease (aka Gluten-sensitive enteropathy)?
- Presents as malabsorption, diarrhea, and failure to thrive
- Villi in the gut atrophy
- Diagnostic hallmark is a small intestinal biopsy
What causes Celiac disease?
- Big picture: Essentially the direct ability to respond to gluten
- Issue with TG2
- can form a B-cell autoantigen via the Type II autoimmunity (foreign + self hybrid help mechanism)
**Remember:T cell immunity to gliadin (essentially gluten) peptides that is responsible for the chronic inflammation component
What “treatment” would you reccomend to a patient with Celiac Disease?
Restrict/eliminate gluten intake and they will be asymptomatic!
What are the two genes most associated with Celiac Disease?
HLA-DQ2 & HLA-DQ8
What is Chronic Beryllium Disease and what is it’s mechanism?
- What: Pulmonary inflammatory and fibrotic disease that comes from inhaling beryllium dust (mining
-
Mechanism:
- Inhaled [Be] covalently links to peptides
- Creates novel epitopes for Th1 & Th17 to initiate response
- Cannot be fixed by macrophages leading to CFR (chronic frust response)
- Inhaled [Be] covalently links to peptides
- 1 million exposed with 15% symptomatic
What is the Hygeine hypothesis to maturing your immune system?
Is this hypothesis comprehensive enough?
- Suggested that exposure to dirt and infections helped the immune system mature
- Newborns start with a Th2-dominated system
- Gradually balances to Th1 with exposure to pathogens/”dirt”
- Explains why Th2 diseases are increasing in 1st world countries, but does not explain why Th1 diseases are still prevalent and on the rise in more wealthy/hygeinic (hence the name) populations
- This idea is too simple of a model
What is the Old Friends Hypothesis to maturing your immune system
- Old friends (Mycobacteria, lactobacilli, and helminth worms) are harmless bugs that teach our immune system the rules of engagement
- They teach our immune system to tolerate good bugs, and not overreact to low level pathogens
- Old friends teach balance between activation and regulation (T-reg)
- Too few T-reg and you get a premature/overresponse
- Feed yo kids dirt.
