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(OMS1) GIGU Exam > Lecture 16: Gut Immunology > Flashcards

Lecture 16: Gut Immunology Flashcards

1
Q

Why is the gut microbiota important?

A
  • important to immunity, metabolism, homeostasis

- disruption associated with disease

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2
Q

Why is cross-talk between host gut associated lymphoid tisuse (GALT) and microbiota important?

A

microbiota regulates GALT/ILT development

GALT/ILT regulates microbiota in turn

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3
Q

What are the main players in GALT?

A

ILF (isolated/single B lymphoid follicles) and Peyer’s Patches (aggregated lymphoid nodules)

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4
Q

How are pathogens detected in the gut?

A

Gut microbiota help mature the GALT and mucosa (mutualism)

DCs deliver antigens to GALT + M cells digest microbes and are endocytosed by DCs

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5
Q

After pathogen detection, how is the immune response activated?

A
  1. DCs present to local lymphocytes in the gut > TH and Tc activated
  2. TH cells activate B cells > plasma cells > igA transported to intestinal lumen
  3. TC cells activate cytotoxic responses
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6
Q

After immune response activation, what structurally happens to the components of gut mucosa?

A
  1. MAMPs from microbes activate PRR on intestinal epithelium and DCs > recruit the T and B cells to area > nearby cryptopatches mature into more ILFs
  2. Epithelial cell proliferates > Paneth cells are formed
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7
Q

What type of cells are found on the intestinal epithelium?

A
  1. Goblet cell that produce mucin
  2. Enterocytes, colonocytes (large intestine) + Paneth cells (small intestine) that produce AMPs, mostly defensins
  3. Secretory IgA
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8
Q

How does secretory IgA in the intestinal epithelium maintain tolerance against microbiota?

A

does not activate complement, phagocytes and is resistant to proteolysis

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9
Q

What are the innate responders of the GI tract?

A

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)

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10
Q

If the pathogen is able to penetrate the defensin barrier, how does the immune system react?

A

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

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11
Q

What is the pathway of T cells and B cells that travel via lymph?

A

thoracic duct > blood stream > venous return to intestinal mucosa

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12
Q

What is the role of TReg’s in GI tract?

A

if no inflammation, TGF B > naive T cells differentiate into TRegs > inhibit TH1, TH2 and TH17 responses inducing tolerance

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13
Q

What is symbiosis and why is it important?

A
  • balance of microbe composition > affected by diet, environment and genetics
  • changes in the above leads to dysbiosis > immune system dysregulation > GI inflammation
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14
Q

How does gut microbiota help the immune system?

How does malnutrition relate to this?

A
  • 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)
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15
Q

What specific roles does SCFAs produced by gut microbiota play?

A

-SCFAs are fermented by gut microbiota from undigested carbs

Effects:

  1. 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
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16
Q

Why doesn’t the GI system react to food?

A
  • oral tolerance to food proteins in the GI tract

- if tolerance is lost we get food allergies and celiac disease

17
Q

What is the difference between Central and Peripheral tolerance and what mechanisms do immune cells employ to be tolerant?

A
  • 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)
18
Q

How does Oral tolerance develop?

A

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

19
Q

What roles do Retinoic acid, TGF B and IDO have in TReg induction to maintain oral tolerance?

A

Retinoic acid: TReg differentiation
TGF-B: foxp3 expression and Treg differentiation
IDO: inhibits effector T cells and increase TReg proliferation

20
Q

What is the difference between non immune mediated Food ARs and immune mediated Food ARs?

A

NIM: lack of digesting enzyme (IBS, food poisoning, stress/psych)

IM: immune response upon exposure to specific food

21
Q

Celiac disease is what type of food AR? Why?

A
  • immune mediated

- immune response triggered by gluten > GI issues

22
Q

Immune mediated Food ARs:
Type 1 HS Food AR
Type 3 HS Food AR
Type 4 HS Food AR

A

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
23
Q

How does IgE mediated (Type 1) Food AR occur?

A

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

24
Q

What affects the strength of secondary immune response to food allergen in IgE mediated Food AR?

A

-how much can the allergen penetrate the GI tract > the stronger the allergic reaction

25
Q

What are early mediators of allergic reaction?

What are late mediators of allergic reaction?

A

Histamine, TNF-a (preformed), tryptase, chymase, peroxidase (granule associated)

ILs, leukotrienes, bradykinin, PAFs (formed during or after degranualation)

26
Q

How does food allergy cause GI symptoms?

A

TH2 > IL-4, 13 and 9 > mastocytosis > PAF, serotonin release > local sx (diarrhea)

27
Q

How do TRegs prevent food allergy?

A

TReg > IL10, TGF-B > inhibit mast cell, IgE, TH2, may increase IgG and IgA

28
Q

What are some allergy suppressors?

A

vit. A, D, folate
gut microbiota
iTRegs that suppress TH2 effects

29
Q

What are some allergy stimulators?

A

high fat diet, IgE, basophils and mast cells

30
Q

How can you test for IgE mediated allergy?

A

Skin prick test:

inject substances on dermis, assess redness and swelling after 20-30 minutes exposure

31
Q

How can you dx IgE mediated allergy?

A
  • detailed allergy hx
  • skin/blood test for specific allergen
  • oral food challenge is gold standard
32
Q

How do peanuts cause allergy (complement pathway)?

A

allergen > increase C3a production > M1, basophils, mast > release PAF and histamine > SM contraction and permeability

33
Q

How do peanuts cause allergy (IgG pathway)?

A

IgE/FceRI interaction on mast + IgG/FcY on Mf > histamine and PAF release > anaphylaxis

34
Q

What kind of allergy is wheat allergy?
What triggers it?
Symptoms?

A

IgE mediated
a-amylase inh., aggulutinin & peroxidase
asthma, rhinitis, urticaria

35
Q

What is food dependent exercise induced anaphylaxis (FDEIA)?
Cause
Mechanism
Clinical

A
  • 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
36
Q

What is the main predisposing factor in Celiac disease?

A

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

37
Q

How does Celiac disease work?

A
  1. Gluten molecule: has gliadin that binds with tTG IgA.
  2. Gliadin/IgA compound is recognized by transferrin receptor and moved from apical side to basolateral side.
  3. tTG deaminates glutamine > charged glutamate is picked by up by HLA DQ2/8 and presented to CD4 cell
  4. TH cell recognizes this on the HLA and activates cytokines to attack the GI epithelium (charged glutamate isn’t supposed to be absorbed!)
38
Q

How can you clinically test for CD?

A
  • tTG-IgA test (to test IgA levels)
  • Biopsy to confirm CD or dx seronegative CD
  • genetic test for HLA DQ2 or DQ8

(OMS1) GIGU Exam (40 decks)

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