Lecture 18: Gut Immunity, Nutrition, and Adverse Food Reactions

Question 1

Homeostasis in the gut mucosa is normally preserved by what 2 mechanisms?

Answer 1

Balance between:

1) Secretory IgA-dependent immune exclusion of Ags
2) Suppression of proinflamatory responses by induced oral tolerance

Question 2

Food allergy is considered to be the consequence of abolished oral tolerance due to innapporpriate interactions between?

Answer 2

Genes and the enviornment

Question 3

What immune cell is the key element in induction of oral tolerance and how is this accomplished?

Answer 3

• Treg cells found within the lamina propria
• Produce IL-10, blocking induction of immune responses
• Produce TGF-beta, which is anti-inflammatory
• Switching of Ab’s toward Ig’s

Question 4

What occurs when Ag’s are captured in the lamina propria and Peyer’s patches by DC’s; what important things do the DC’s do?

Answer 4

• Carried to mesenteric LN by DCs
• DC’s stimulate expansion of iTreg cells by a mechanism dependent on TGF-beta, retinoic acid, and indoleamine-2,3-dioxgenase (IDO)
• DC’s induce IgA-secreting plasma cells also through RA-dependent mechanisms

Question 5

Gut-homing iTregs are expanded in the lamina propria by what cytokine? Why are these Tregs important?

Answer 5

• IL-10 expressing macrophages
• iTregs suppress systemic immune response, including allergic sensitization, in an Ag-specific manner

Question 6

What dietary components suppress and promote inflammation?

Answer 6

• Vit D, A, and folate suppress inflammation
• High-fat diet (HFD) promotes inflammation

Question 7

What can the gut microbiota suppress?

Answer 7

• Microbiota suppress allergic immune responses through the induction of Treg cells.
• Treg cells suppress Th2 cells that are central to generating IgE and allergic effector cells
• Micorbiota suppress basophils and mast cells

Question 8

What dietary factors promote and which suppress allergy?

Answer 8

• High fat diet and MCT’s promote allergy
• Vitamin A, D, and LCFA’s suppress allergy

Question 9

Balanced microbial composition results in ______ that maintains the ________?

Answer 9

Symbiosis; homeostasis

Question 10

What can lead to dysbiosis?

Answer 10

Various enviornmental factors (i.e., antibiotics/medications, stress, hygiene, age, and infections)

Question 11

How do the microbiota and immune system evolve; what affect does malnutrition have?

Answer 11

• Co-evolve
• Malnutrition affects both the immune system and microbiota

Question 12

Undernutrition is associated w/ defects in what kind of immunity?

Answer 12

Innate and adaptive

Question 13

How are adverse food reactions classified?

Answer 13

• Immune-mediated (food allergy and celiac disease)
• Nonimmune mediated (food intolerances)

Question 14

Food allergies are caused by what type of response?

Answer 14

Ag-specific immune responses (adaptive)

Question 15

What are the two main types of adverse food reactions?

Answer 15

Toxic and non-toxic

Question 16

Non-immune mediated mechanisms of food intolerance may include?

Answer 16

• Pharmacological
• Enzymatic
• Irritants
• Psychomatic reponses

Question 17

Immune mediated mechanisms of food allergy include what type of responses?

Answer 17

• IgE-mediated (type I hypersensitivity)
• Non-IgE-mediated such as type III (IgG or IgM immune complex rxns) or type IV hypersensitivity (delayed-type or cell-mediated rxns)

Question 18

Non-IgE mediated reactions are believed to be mediated by what immune cells; and how quick do these reactions occur?

Answer 18

T cells; delayed in onset and occur 4-28 after ingestion

Question 19

What immunoglobulin is associated w/ hypersensitivity type I and type IV mechanisms?

Answer 19

Type I: IgE-mediated

Type IV: non-IgE-mediated

Question 20

What is the most common food allergy?

Answer 20

Milk

Question 21

Even though they may be allergic early on, children often lose their sensitivity to what foods within the first 3 to 5 years?

Answer 21

Milk, eggs, what, and soy

Question 22

Allergies to what foods typically continue into adulthood?

Answer 22

Peanuts, tree nuts, fish, and shellfish allergies

Question 23

Describe the initiation steps of developing an allergy

Answer 23

1) DCs present peptide allergens to naive CD4+ T cells, which are induced to Th2 cells in presence of IL-4
2) Th2 cells produce cytokines IL-3, IL-4, IL-5, IL-9, and IL-13
3) B cells switch to produce IgE and bind to specific Fc£ receptors on mast cells and basophils = sensitization
4) Next time allergen is encountered, mast cells and basophils degranulate, leading to immediate hypersensitivity

Question 24

What are important survival signals for mast cell, basophils, and eosinophils?

Answer 24

Th2-type cytokines (IL-3, IL-4, IL-5)

Question 25

How do Treg cells provide tolerance to allergens?

Answer 25

- Release IL-10 and TGF-β, which... - Suppresses Th2 homing to tissues and mucus production - Early induction of IgG4 and late decrease in IgE - Early desensitization of Mast cells and Basophils

Question 26

Upon activation what do Mast Cells release from their granules?

Answer 26

- Proteases (tryptase) -\> Tight junction rearrangement - Histamine - De novo synthesis of Cytokines (IL-1β and TNF-α) \*Will increase epithelial permeability\*

Question 27

What is the go to for testing allergies and what is another method if this test is negative?

Answer 27

- Prick or puncture test - Prooduce quick results in 15 min. - If results are negative, they may be followed by intradermal tests

Question 28

A high percentage of children with CMA show NO, what? These reactions are classified as?

Answer 28

- NO IgE specific for CM proteins in the blood - These reactions are classified as a **delayed hypersensitivty type IV**

Question 29

What plays a central role in both local and systemic manifestations of food allergies?

Answer 29

Mast cells

Question 30

Local, GI, manifestations of food allergy are dependent on which cytokines and what other hormones (the local response)?

Answer 30

- **Th2** cytokines: **IL-4, IL-13, and IL-9** - **PAF** and **serotonin** mediate the local acute GI response (diarrhea)

Question 31

Systemic manifestations of food allergy involve mechanisms dependent on which hormones?

Answer 31

Histamine and PAF

Question 32

What is the most severe form of systemic reaction to food allergens; what occurs?

Answer 32

- Anaphylaxis - Sudden release of multiple chemical mediators, as a result of events mediated by IgE antibodies

Question 33

Anaphylactic reactions can be produced in some individuals highly sensitive to food via which route?

Answer 33

Airborne exposure to food allergens

Question 34

How is food anaphylaxis commonly diagnosed i.e., presenting sx's?

Answer 34

- Intense pruritus and generalized erythematous plaques that tend to converge - Accompanied by lip, eye, or even tongue and uvula angioedema, followed by further involvement of the respiratory, cardiovascular, GI, or neurological systems

Question 35

What does mast cell activation and granule release lead to in anaphylactic shock?

Answer 35

- Severe itching, hives - Swelling of the throat - Bronchoconstriction - Lowered BP - Unconciousness and even death

Question 36

What plays the central role in food-induced anaphylaxis and what are the mediators?

Answer 36

- Mast cells activated by IgE cross-linking FcERI - Histamine and PAF released by mast cells

Question 37

Other than IgE what is another way that anaphylaxis is induced?

Answer 37

- **IgG-induced** activation of **macrophages** and **neutrophils** which also produce **PAF**

Question 38

What does the release of PAF and histamine cause during anaphylaxis?

Answer 38

Vascular permeability and smooth muscle contractlity

Question 39

Explain how C3a and C5a are involved in anaphylaxis?

Answer 39

- Release of histamine increases vascular permeability and the resulting exudation likekly contains C3 and C5 - **Tryptase** released from activated mast cells acts on C3 and C5 to locally **generate C3a and C5a** which activate mast cells to further **exacerbate symptoms**

Question 40

Depending on the route of allergen exposure, how is wheat allergy classified?

Answer 40

- Occupational asthma - Food allergy - Wheat-dependent exercise-induced anaphylaxis - Contact urticaria

Question 41

What is the most common variant of what allergy in adults?

Answer 41

- WDEIA - Sx's result from the combination of causative food intake and physical exercise (as well as NSAID or alcohol)

Question 42

What problems can irritable bowel syndrome cause?

Answer 42

- Muscle contractions in the intestine - Nervous system - Severe infection - Inflammation - Changes in bacteria in the gut (microflora)

Question 43

What is a food additive that can trigger asthma attacks in sensitive people?

Answer 43

Sulfites used to preserve dried fruit, canned goods, and wine

Question 44

Are people w/ celiac disease at risk of anaphylaxis?

Answer 44

Although it has some features of a true food allergy, symptoms are mostly GI related and these patients are NOT at risk of anaphylaxis

Question 45

What is celiacs disease; commonly associated with what type of findings?

Answer 45

Systemic immune disorder caused by permanent sensitivity to gluten that can be associated w/: - Gastrointestinal findings - Failure to thrive - Delayed puberty - Autoimmune disorder - Inflammation - Neuro and metabolic disorders

Question 46

What are the main genetic predisposing factors for celiacs disease; what do they do?

Answer 46

HLA-DQ2 and HLA-DQ8 play a key role in orchestrating **adaptive** immune response against gluten peptides

Question 47

Autoantibodies against which ubiquitous enzyme are specifically associated w/ celiacs disease?

Answer 47

Anti-tTG2 antibodies against **t****issue transglutaminase 2 (TG2)**

Question 48

What is gluten composed of and why is it poorly digested?

Answer 48

- Proline-rich protein that is poorly digested due to **lack of prolyl endopeptidases** - Also rich in **glutamine** residues - Gluten peptides of 10-50 AA's are formed and left incompletely digested

Question 49

What happens to some of the glutamines in the gluten peptide?

Answer 49

- Deamidated by tissue enzyme TG2 - Results in formation of negatively charged glutamic acid residues

Question 50

How can gluten act as an antigen; what do the majority of CD patients express?

Answer 50

- Peptides w/ a specific spacing or proline and glutamic acid **bind** to **HLA class II** on **APC's** - Majority of CD patients express the **HLADQ2.5 heterodimer**

Question 51

Explain the immuno-pathogenic response via self-reactive T cells in celiacs and what type of hypersensitivity tissue damage occurs?

Answer 51

- Self reactive CD4+ and CD8+ T cells are generated and **cell-mediated autoimmunity** occurs - Tissue damage occurs in a **type IV hypersensitivity** manner - Chronic inflammatory response continues as long as patients continue to ingest gluten

Question 52

What type of inflammatory response is caused by gluten and what part of the bowel is damaged?

Answer 52

T-cell mediated inflammaotry response in the proximal small bowel that damages the mucosa and leads to **malabsorption**

Question 53

Gluten peptides that are highly resistant to intestinal proteases reach the lamina propria and then what occurs via TG2 and activated CD4 T cells?

Answer 53

- Cross-linking and deamidation of gluten peptides by TG2 creates **potent immunostimulatory epitopes** that are presented via HLA-DQ2 or HLA-DQ8 on APC's - **Activated CD4 T cells** secrete mainly **Th1 cytokines** such as **IFN-y,** which induces the release of **MMPs** by **myofibroblasts** resulting in mucosal **remodeling** and villus **atrophy**

Question 54

How do Th2 cytokines play a role in celiacs disease?

Answer 54

Drive the production of auto-Abs to gluten and TG2

Question 55

What cytokines seem to play a role in polarizing and maintaining the Th1 response in Celiacs diseas?

Answer 55

IL-18, IFN-y, or IL-21

Question 56

Which cytokine links the adaptie immune system to innate immune system in Celiacs?

Answer 56

IL-15

Question 57

How to test for CD?

Answer 57

- Measurement of IgA antibody to human tissue transglutaminase (TTG) - Total serum IgA can facilitate interpretation when the tTG IgA is low - Intestinal biopsy can be helpful to identify the unusual cause of **seronegative CD** - Intestinal biopsy is recommended to **confirm the diagnosis of CD in ALL cases**

Question 58

Which genetic test can be done for CD?

Answer 58

- Looking for associated HLA alleles DQ2 or DQ8 since ALL patients w/ CD will have them - HLA-DQ2 and -DQ8 testing can be done to **exclude the diagnosis of CD**

Question 59

Which reaction occurs 6–8 hours after an initial type I hypersensitivity response manifested by de nova production leukotrienes, chemokines, and cytokines by mast cells?

Answer 59

Late‐phase reaction typically develops after 2‐6 h and peaks 6–9 h after allergen exposure.