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*GIGU I > Lecture 18: Gut Immunity, Nutrition, and Adverse Food Reactions > Flashcards

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

1
Q

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

A

Balance between:

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

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2
Q

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

A

Genes and the enviornment

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3
Q

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

A
  • 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
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4
Q

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?

A
  • 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
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5
Q

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

A
  • IL-10 expressing macrophages
  • iTregs suppress systemic immune response, including allergic sensitization, in an Ag-specific manner
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6
Q

What dietary components suppress and promote inflammation?

A
  • Vit D, A, and folate suppress inflammation
  • High-fat diet (HFD) promotes inflammation
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7
Q

What can the gut microbiota suppress?

A
  • 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
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8
Q

What dietary factors promote and which suppress allergy?

A
  • High fat diet and MCT’s promote allergy
  • Vitamin A, D, and LCFA’s suppress allergy
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9
Q

Balanced microbial composition results in ______ that maintains the ________?

A

Symbiosis; homeostasis

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10
Q

What can lead to dysbiosis?

A

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

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11
Q

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

A
  • Co-evolve
  • Malnutrition affects both the immune system and microbiota
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12
Q

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

A

Innate and adaptive

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13
Q

How are adverse food reactions classified?

A
  • Immune-mediated (food allergy and celiac disease)
  • Nonimmune mediated (food intolerances)
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14
Q

Food allergies are caused by what type of response?

A

Ag-specific immune responses (adaptive)

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15
Q

What are the two main types of adverse food reactions?

A

Toxic and non-toxic

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16
Q

Non-immune mediated mechanisms of food intolerance may include?

A
  • Pharmacological
  • Enzymatic
  • Irritants
  • Psychomatic reponses
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17
Q

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

A
  • 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)
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18
Q

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

A

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

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19
Q

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

A

Type I: IgE-mediated

Type IV: non-IgE-mediated

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20
Q

What is the most common food allergy?

A

Milk

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21
Q

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

A

Milk, eggs, what, and soy

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22
Q

Allergies to what foods typically continue into adulthood?

A

Peanuts, tree nuts, fish, and shellfish allergies

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23
Q

Describe the initiation steps of developing an allergy

A

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

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24
Q

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

A

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

25
Q

How do Treg cells provide tolerance to allergens?

A
  • 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
26
Q

Upon activation what do Mast Cells release from their granules?

A
  • Proteases (tryptase) -> Tight junction rearrangement
  • Histamine
  • De novo synthesis of Cytokines (IL-1β and TNF-α)

*Will increase epithelial permeability*

27
Q

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

A
  • Prick or puncture test
  • Prooduce quick results in 15 min.
  • If results are negative, they may be followed by intradermal tests
28
Q

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

A
  • NO IgE specific for CM proteins in the blood
  • These reactions are classified as a delayed hypersensitivty type IV
29
Q

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

A

Mast cells

30
Q

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

A
  • Th2 cytokines: IL-4, IL-13, and IL-9
  • PAF and serotonin mediate the local acute GI response (diarrhea)
31
Q

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

A

Histamine and PAF

32
Q

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

A
  • Anaphylaxis
  • Sudden release of multiple chemical mediators, as a result of events mediated by IgE antibodies
33
Q

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

A

Airborne exposure to food allergens

34
Q

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

A
  • 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
35
Q

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

A
  • Severe itching, hives
  • Swelling of the throat
  • Bronchoconstriction
  • Lowered BP
  • Unconciousness and even death
36
Q

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

A
  • Mast cells activated by IgE cross-linking FcERI
  • Histamine and PAF released by mast cells
37
Q

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

A
  • IgG-induced activation of macrophages and neutrophils which also produce PAF
38
Q

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

A

Vascular permeability and smooth muscle contractlity

39
Q

Explain how C3a and C5a are involved in anaphylaxis?

A
  • 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
40
Q

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

A
  • Occupational asthma
  • Food allergy
  • Wheat-dependent exercise-induced anaphylaxis
  • Contact urticaria
41
Q

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

A
  • WDEIA
  • Sx’s result from the combination of causative food intake and physical exercise (as well as NSAID or alcohol)
42
Q

What problems can irritable bowel syndrome cause?

A
  • Muscle contractions in the intestine
  • Nervous system
  • Severe infection
  • Inflammation
  • Changes in bacteria in the gut (microflora)
43
Q

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

A

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

44
Q

Are people w/ celiac disease at risk of anaphylaxis?

A

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

45
Q

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

A

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
46
Q

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

A

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

47
Q

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

A

Anti-tTG2 antibodies against tissue transglutaminase 2 (TG2)

48
Q

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

A
  • 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
49
Q

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

A
  • Deamidated by tissue enzyme TG2
  • Results in formation of negatively charged glutamic acid residues
50
Q

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

A
  • 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
51
Q

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

A
  • 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
52
Q

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

A

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

53
Q

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

A
  • 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
54
Q

How do Th2 cytokines play a role in celiacs disease?

A

Drive the production of auto-Abs to gluten and TG2

55
Q

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

A

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

56
Q

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

A

IL-15

57
Q

How to test for CD?

A
  • 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
58
Q

Which genetic test can be done for CD?

A
  • 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
59
Q

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?

A

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

*GIGU I (67 decks)

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