Gut Immunology

Question 1

Development of cryptopatches into mature isolated lymphoid follicles (ILFs)

Answer 1

Microbe associated molecular patterns MAMPs, recognized by PRRs on intestinal epithelial cells and DCs adjacent to cryptopatches stimulate the recruitment of B and T cells, causing maturing of cryptopatches into ILFs

Question 2

What are ILFs

Answer 2

Single B-cell follicles that act as inductive site for IgA production

Question 3

What are some cells in small/large intestine that sense microbiota and induce production of AMPs (antimicrobial peptides)

Answer 3

Enterocytes and Paneth cells in small intestine
Colonocytes in large intestine
Defensins are a major constituent of AMPs

Question 4

What makes secretory IgA maintain a peaceful bacteria-host interaction

Answer 4

IgA does not activate complement
It does not activate phagocytes in Fc-receptor dependent manner
It is resistant to proteolysis by peptidases produced in the stomach, small intestine and pancreas

Question 5

Differentiation of naïve T cells to Treg cells

Answer 5

Lack of proinflammatory expression by APCs and excess of TGF-b result in differentiation
Treg cells suppress Th1, Th2 and Th17 responses
Treg cells make up ~10% of GALT lymphoid cells

Question 6

Dysbiosis

Answer 6

Leads to dysregulation of the immune system and to inflammation in susceptible host
May occur due to changes in diet and other environmental factors

Question 7

Short chain fatty acids and gut microflora

Answer 7

Butyric acid, propionic acid and acetic acid
Produced by microbial fermentation of undigested dietary fibers and have broad effects on host immune system development
Help support effective IgA mediated response to gut pathogens
Stimulate production of mucus

Question 8

Acetate effects

Answer 8

Stimulates the accumulation of IL-10 producing colonic Tregs

Question 9

Butyrate effects

Answer 9

Similar to acetate by either directly acting on Tregs or through modulating DC function to enhance their Treg inducing ability

Question 10

Capsular polysaccharide

Answer 10

Can directly act on Tregs through TLR2 to promote Treg function by enhancing expression of effector molecules such as TGF-b and IL-10

Question 11

Oral tolerance

Answer 11

Suppression of immune responses to Ags that have been administered previously by the oral route
Transfer of CD4+ and CD25+ Treg cells to naïve organism can induce oral tolerance

Question 12

Food allergy

Answer 12

Failure to induce tolerance to food protein results in food allergy and celiac disease

Question 13

Natural Treg cells in intestine and lack of central tolerance production

Answer 13

T cells with high affinity for self Ags will express Foxp3 and become natural Tregs
Requires the interaction of the TCR with its cognate Ag in the thymus
Since intestine Ags are not available in the thymus, the central tolerance does not prevent responses against such Ags in the lamina propria
Thus, additional layers of peripheral tolerance are needed to ensure tolerance to Ags such as food and commensal organisms

Question 14

Mechanisms of oral tolerance

Answer 14

Macrophages, DCs and Treg cells play crucial role
Macrophages take up Ags and give to DCs in lamina propria
Goblet cells can also acquire Ags
DCs move from LP to the mLNs in chemokine process
DCs stimulate CD4 naïve cells to differentiate to CD25+ Foxp3 Treg cells via release of RA, TGF-b and IDO

Question 15

Foxp3, TGF-b and IDO function in Treg differentiation and oral tolerance

Answer 15

RA- directly induces Treg differentiation
TGF-b mediates Foxp3 upregulation
IDO exerts immunosuppressive functions causing anergy of effector T cells and inducing proliferation of Treg cells

Question 16

Non immune mediated food adverse reactions

Answer 16

Absence of enzyme needed to fully digest a food
Irritable bowel syndrome
Food poisoning
Recurring stress or psych factors

Question 17

Immune mediated food adverse reactions

Answer 17

Food allergy/celiac disease arise from a specific immune response that occurs reproducibly on exposure to a given food

Question 18

Celiac disease

Answer 18

Chronic digestive condition triggered by eating gluten
Pts not at risk of anaphylaxis
Genetic predisposition HLA-DQ2/DQ8 molecules are the main factors
They play a key role in orchestrating adaptive immune response against gluten
Serum Abs against TG2 are specifically associated w/CD

Question 19

Most common immune mediated adverse reaction to food is what type of hypersensitivity

Answer 19

Type I mediated- IgE

Question 20

Type II/III reactions to food

Answer 20

Involves activation of macrophages by allergen Ab complexes in FcyR dependent manner and activation of allergen specific T cells, respectively
Non-IgE mediated

Question 21

Primary/secondary allergen responses

Answer 21

Th2 response- adaptive response by B cells which mature into plasma cells to make IgE to allergen
IgE enters circulation and is rapidly bound by FcRe on mast cells
FcRe is only Fc receptor that can bind Ig before it binds antigen. Binding changes FcRe receptor so it can recognize the allergen
Second exposure to allergen creates much larger response

Question 22

Early allergic reaction mediators

Answer 22

Histamine
TNFa
Tryptase, peroxidase
Bradykinin
Prostaglandin

Question 23

Later allergic reaction

Answer 23

IL-1-6
GM-CSF
TNF-a

Question 24

Mediators of local acute GI response (diarrhea) to allergen exposure

Answer 24

PAF and serotonin

Question 25

Treg cells effect on B cells and mast cells in allergic reaction

Answer 25

TGF-b and IL-10 suppress mast cell degranulation

Inhibit IgE production and may increase IgA/IgM production

Question 26

What is the primary tool for assessing immediate hypersensitivity reactions

Answer 26

Patient history NB

Question 27

Non-IgE mediated allergic reaction to peanuts - cause of shock

Answer 27

Production of C3a is large contributor to shock
C3a stimulates macrophages, basophils and mast cells to release PAF (platelet activating factor) and histamine which increase vascular permeability and smooth muscle contractility

Question 28

Induction of anaphylaxis-2 pathways

Answer 28

IgE mediated cross-linking of FcRe

IgG induced activation of macrophages and release of PAF

Question 29

Food dependent exercise induced anaphylaxis FDEIA

Answer 29

Ingested foods are digested into intestine, no immuno-reactive allergens are entered into circulation
Exercise and/or aspirin enhance absorption of undigested immuno-reactive allergens into the circulation

Question 30

Non-IgE mediated allergic reactions timing

Answer 30

Delayed reaction, can take up to 48 hours to show signs

Question 31

Majority of CD patients express what

Answer 31

HLA-DQ2.5 heterodimer - required to load gluten peptide AND induce response

Question 32

Celiac disease immune response, damage

Answer 32

Self reactive T cells are generated
Tissue damage occurs via type IV hypersensitivity
Gluten peptides are cross linked and deamidated by TG2 and create potent immunostimulatory epitopes that are presented via HLA-DQ2.5 or HLA-DQ8 on APCs
Activated CD4 cells secret mainly Th1 cytokines such as IFN-y which induces release of MMPs by myofibroblasts causing mucosal remodeling and villus atrophy

Question 33

Testing for CD

Answer 33

Recommended initial testing for CD starts with measurement of IgA antibody to tTG
AGA test is no longer recommended because of inferior accuracy

Question 34

What cytokines help polarize and maintain Th1 response to gluten Ags

Answer 34

IL-18, IFN-y and IL-21

Question 35

What cytokine links adaptive immune system to innate immune responses

Answer 35

IL-15 serves as a growth factor for T cells causing there proliferation