Lecture 16: Gut Immunology Flashcards
Why is the gut microbiota important?
- important to immunity, metabolism, homeostasis
- disruption associated with disease
Why is cross-talk between host gut associated lymphoid tisuse (GALT) and microbiota important?
microbiota regulates GALT/ILT development
GALT/ILT regulates microbiota in turn
What are the main players in GALT?
ILF (isolated/single B lymphoid follicles) and Peyer’s Patches (aggregated lymphoid nodules)
How are pathogens detected in the gut?
Gut microbiota help mature the GALT and mucosa (mutualism)
DCs deliver antigens to GALT + M cells digest microbes and are endocytosed by DCs
After pathogen detection, how is the immune response activated?
- DCs present to local lymphocytes in the gut > TH and Tc activated
- TH cells activate B cells > plasma cells > igA transported to intestinal lumen
- TC cells activate cytotoxic responses
After immune response activation, what structurally happens to the components of gut mucosa?
- MAMPs from microbes activate PRR on intestinal epithelium and DCs > recruit the T and B cells to area > nearby cryptopatches mature into more ILFs
- Epithelial cell proliferates > Paneth cells are formed
What type of cells are found on the intestinal epithelium?
- Goblet cell that produce mucin
- Enterocytes, colonocytes (large intestine) + Paneth cells (small intestine) that produce AMPs, mostly defensins
- Secretory IgA
How does secretory IgA in the intestinal epithelium maintain tolerance against microbiota?
does not activate complement, phagocytes and is resistant to proteolysis
What are the innate responders of the GI tract?
1st line of defense: defensins - have both + charged and hydrophobic ends that form pores, that allow them to penetrate membrane and block pathogen colonization (acts as a barrier)
If the pathogen is able to penetrate the defensin barrier, how does the immune system react?
if pathogen penetrates defensins > attacked by macrophages
If pathogen penetrates the areas with M cells > attacked by macrophages or carried by DCs for presentation to T and B cells in Peyer’s patches or mesenteric lymph nodes
What is the pathway of T cells and B cells that travel via lymph?
thoracic duct > blood stream > venous return to intestinal mucosa
What is the role of TReg’s in GI tract?
if no inflammation, TGF B > naive T cells differentiate into TRegs > inhibit TH1, TH2 and TH17 responses inducing tolerance
What is symbiosis and why is it important?
- balance of microbe composition > affected by diet, environment and genetics
- changes in the above leads to dysbiosis > immune system dysregulation > GI inflammation
How does gut microbiota help the immune system?
How does malnutrition relate to this?
- gut microbes produce short chain fatty acids that influence immune system development
- gut microbiota needs to be nourished to have a nourished immune system (Malnutrition > dysfunctional GI immunity - recurrent infections)
What specific roles does SCFAs produced by gut microbiota play?
-SCFAs are fermented by gut microbiota from undigested carbs
Effects:
- increased IgA and mucus production
- Acetate > increase TRegs and IL-10
- Butyrate > increase TRegs and DCs ability to induce TRegs
- Capsular Polysaccharide A > bind to TLR2 on TRegs to increase IL-10 and TGF-B production
Why doesn’t the GI system react to food?
- oral tolerance to food proteins in the GI tract
- if tolerance is lost we get food allergies and celiac disease
What is the difference between Central and Peripheral tolerance and what mechanisms do immune cells employ to be tolerant?
- happens in the lymphoid organs (deletion, BCR changes, become TRegs by expressing FoxP3)
- main type of tolerance in the GI since gut pathogens not present in thymus to train lymphocytes (anergy, deletion, suppression by TRegs)
How does Oral tolerance develop?
Macrophages take Ags in lumen > lamina propia DC take the Ags > DCs recruited to mesenteric LNs by chemokines > DCs release RA, TGF -B and IDO > T cells induced to be TRegs
What roles do Retinoic acid, TGF B and IDO have in TReg induction to maintain oral tolerance?
Retinoic acid: TReg differentiation
TGF-B: foxp3 expression and Treg differentiation
IDO: inhibits effector T cells and increase TReg proliferation
What is the difference between non immune mediated Food ARs and immune mediated Food ARs?
NIM: lack of digesting enzyme (IBS, food poisoning, stress/psych)
IM: immune response upon exposure to specific food
Celiac disease is what type of food AR? Why?
- immune mediated
- immune response triggered by gluten > GI issues
Immune mediated Food ARs:
Type 1 HS Food AR
Type 3 HS Food AR
Type 4 HS Food AR
IgE mediated:
-IgE vs. food allergens (tested by skin reaction/IgE serum)
Non IgE mediated:
- macrophage activation by food allergen-Ab complex
- allergen specific T cell activation
How does IgE mediated (Type 1) Food AR occur?
1st exposure: primary sensitization
food allergen enters > B cells make IgE against allergin > IgE gets bound to mast cell (sensitization)
2nd exposure: secondary immune response
Allergen binds to IgE on mast cell > cross linking > degranulation of vasoactive stuff (systemic symptoms)
*Anaphylaxis can occur if allergen penetrates GI tract and carried to other systems
What affects the strength of secondary immune response to food allergen in IgE mediated Food AR?
-how much can the allergen penetrate the GI tract > the stronger the allergic reaction
What are early mediators of allergic reaction?
What are late mediators of allergic reaction?
Histamine, TNF-a (preformed), tryptase, chymase, peroxidase (granule associated)
ILs, leukotrienes, bradykinin, PAFs (formed during or after degranualation)
How does food allergy cause GI symptoms?
TH2 > IL-4, 13 and 9 > mastocytosis > PAF, serotonin release > local sx (diarrhea)
How do TRegs prevent food allergy?
TReg > IL10, TGF-B > inhibit mast cell, IgE, TH2, may increase IgG and IgA
What are some allergy suppressors?
vit. A, D, folate
gut microbiota
iTRegs that suppress TH2 effects
What are some allergy stimulators?
high fat diet, IgE, basophils and mast cells
How can you test for IgE mediated allergy?
Skin prick test:
inject substances on dermis, assess redness and swelling after 20-30 minutes exposure
How can you dx IgE mediated allergy?
- detailed allergy hx
- skin/blood test for specific allergen
- oral food challenge is gold standard
How do peanuts cause allergy (complement pathway)?
allergen > increase C3a production > M1, basophils, mast > release PAF and histamine > SM contraction and permeability
How do peanuts cause allergy (IgG pathway)?
IgE/FceRI interaction on mast + IgG/FcY on Mf > histamine and PAF release > anaphylaxis
What kind of allergy is wheat allergy?
What triggers it?
Symptoms?
IgE mediated
a-amylase inh., aggulutinin & peroxidase
asthma, rhinitis, urticaria
What is food dependent exercise induced anaphylaxis (FDEIA)?
Cause
Mechanism
Clinical
- caused by eating some food (seafood, celery, wheat, cheese) before exercise
- allergen digested, but hasn’t entered circulation > patient starts exercising which enhances absorption of allergen
- urticaria/angioedema/upper airway obstruction
What is the main predisposing factor in Celiac disease?
HLA-DQ2 and DQ8 more susceptible
presence of Abs against tissue transglutaminase (TG2)
patient with these traits mount adaptive immune response when exposed to gluten
How does Celiac disease work?
- Gluten molecule: has gliadin that binds with tTG IgA.
- Gliadin/IgA compound is recognized by transferrin receptor and moved from apical side to basolateral side.
- tTG deaminates glutamine > charged glutamate is picked by up by HLA DQ2/8 and presented to CD4 cell
- TH cell recognizes this on the HLA and activates cytokines to attack the GI epithelium (charged glutamate isn’t supposed to be absorbed!)
How can you clinically test for CD?
- tTG-IgA test (to test IgA levels)
- Biopsy to confirm CD or dx seronegative CD
- genetic test for HLA DQ2 or DQ8
