Lecture 18: Gut Immunity, Nutrition, and Adverse Food Reactions Flashcards
Homeostasis in the gut mucosa is normally preserved by what 2 mechanisms?
Balance between:
1) Secretory IgA-dependent immune exclusion of Ags
2) Suppression of proinflamatory responses by induced oral tolerance
Food allergy is considered to be the consequence of abolished oral tolerance due to innapporpriate interactions between?
Genes and the enviornment
What immune cell is the key element in induction of oral tolerance and how is this accomplished?
- 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
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?
- 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
Gut-homing iTregs are expanded in the lamina propria by what cytokine? Why are these Tregs important?
- IL-10 expressing macrophages
- iTregs suppress systemic immune response, including allergic sensitization, in an Ag-specific manner
What dietary components suppress and promote inflammation?
- Vit D, A, and folate suppress inflammation
- High-fat diet (HFD) promotes inflammation
What can the gut microbiota suppress?
- 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
What dietary factors promote and which suppress allergy?
- High fat diet and MCT’s promote allergy
- Vitamin A, D, and LCFA’s suppress allergy
Balanced microbial composition results in ______ that maintains the ________?
Symbiosis; homeostasis
What can lead to dysbiosis?
Various enviornmental factors (i.e., antibiotics/medications, stress, hygiene, age, and infections)
How do the microbiota and immune system evolve; what affect does malnutrition have?
- Co-evolve
- Malnutrition affects both the immune system and microbiota
Undernutrition is associated w/ defects in what kind of immunity?
Innate and adaptive
How are adverse food reactions classified?
- Immune-mediated (food allergy and celiac disease)
- Nonimmune mediated (food intolerances)
Food allergies are caused by what type of response?
Ag-specific immune responses (adaptive)
What are the two main types of adverse food reactions?
Toxic and non-toxic
Non-immune mediated mechanisms of food intolerance may include?
- Pharmacological
- Enzymatic
- Irritants
- Psychomatic reponses
Immune mediated mechanisms of food allergy include what type of responses?
- 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)
Non-IgE mediated reactions are believed to be mediated by what immune cells; and how quick do these reactions occur?
T cells; delayed in onset and occur 4-28 after ingestion
What immunoglobulin is associated w/ hypersensitivity type I and type IV mechanisms?
Type I: IgE-mediated
Type IV: non-IgE-mediated
What is the most common food allergy?
Milk
Even though they may be allergic early on, children often lose their sensitivity to what foods within the first 3 to 5 years?
Milk, eggs, what, and soy
Allergies to what foods typically continue into adulthood?
Peanuts, tree nuts, fish, and shellfish allergies
Describe the initiation steps of developing an allergy
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
What are important survival signals for mast cell, basophils, and eosinophils?
Th2-type cytokines (IL-3, IL-4, IL-5)
How do Treg cells provide tolerance to allergens?
- 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
Upon activation what do Mast Cells release from their granules?
- Proteases (tryptase) -> Tight junction rearrangement
- Histamine
- De novo synthesis of Cytokines (IL-1β and TNF-α)
*Will increase epithelial permeability*
What is the go to for testing allergies and what is another method if this test is negative?
- Prick or puncture test
- Prooduce quick results in 15 min.
- If results are negative, they may be followed by intradermal tests
A high percentage of children with CMA show NO, what? These reactions are classified as?
- NO IgE specific for CM proteins in the blood
- These reactions are classified as a delayed hypersensitivty type IV
What plays a central role in both local and systemic manifestations of food allergies?
Mast cells
Local, GI, manifestations of food allergy are dependent on which cytokines and what other hormones (the local response)?
- Th2 cytokines: IL-4, IL-13, and IL-9
- PAF and serotonin mediate the local acute GI response (diarrhea)
Systemic manifestations of food allergy involve mechanisms dependent on which hormones?
Histamine and PAF
What is the most severe form of systemic reaction to food allergens; what occurs?
- Anaphylaxis
- Sudden release of multiple chemical mediators, as a result of events mediated by IgE antibodies
Anaphylactic reactions can be produced in some individuals highly sensitive to food via which route?
Airborne exposure to food allergens
How is food anaphylaxis commonly diagnosed i.e., presenting sx’s?
- 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
What does mast cell activation and granule release lead to in anaphylactic shock?
- Severe itching, hives
- Swelling of the throat
- Bronchoconstriction
- Lowered BP
- Unconciousness and even death
What plays the central role in food-induced anaphylaxis and what are the mediators?
- Mast cells activated by IgE cross-linking FcERI
- Histamine and PAF released by mast cells
Other than IgE what is another way that anaphylaxis is induced?
- IgG-induced activation of macrophages and neutrophils which also produce PAF
What does the release of PAF and histamine cause during anaphylaxis?
Vascular permeability and smooth muscle contractlity
Explain how C3a and C5a are involved in anaphylaxis?
- 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
Depending on the route of allergen exposure, how is wheat allergy classified?
- Occupational asthma
- Food allergy
- Wheat-dependent exercise-induced anaphylaxis
- Contact urticaria
What is the most common variant of what allergy in adults?
- WDEIA
- Sx’s result from the combination of causative food intake and physical exercise (as well as NSAID or alcohol)
What problems can irritable bowel syndrome cause?
- Muscle contractions in the intestine
- Nervous system
- Severe infection
- Inflammation
- Changes in bacteria in the gut (microflora)
What is a food additive that can trigger asthma attacks in sensitive people?
Sulfites used to preserve dried fruit, canned goods, and wine
Are people w/ celiac disease at risk of anaphylaxis?
Although it has some features of a true food allergy, symptoms are mostly GI related and these patients are NOT at risk of anaphylaxis
What is celiacs disease; commonly associated with what type of findings?
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
What are the main genetic predisposing factors for celiacs disease; what do they do?
HLA-DQ2 and HLA-DQ8 play a key role in orchestrating adaptive immune response against gluten peptides
Autoantibodies against which ubiquitous enzyme are specifically associated w/ celiacs disease?
Anti-tTG2 antibodies against tissue transglutaminase 2 (TG2)
What is gluten composed of and why is it poorly digested?
- 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
What happens to some of the glutamines in the gluten peptide?
- Deamidated by tissue enzyme TG2
- Results in formation of negatively charged glutamic acid residues
How can gluten act as an antigen; what do the majority of CD patients express?
- 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
Explain the immuno-pathogenic response via self-reactive T cells in celiacs and what type of hypersensitivity tissue damage occurs?
- 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
What type of inflammatory response is caused by gluten and what part of the bowel is damaged?
T-cell mediated inflammaotry response in the proximal small bowel that damages the mucosa and leads to malabsorption
Gluten peptides that are highly resistant to intestinal proteases reach the lamina propria and then what occurs via TG2 and activated CD4 T cells?
- 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
How do Th2 cytokines play a role in celiacs disease?
Drive the production of auto-Abs to gluten and TG2
What cytokines seem to play a role in polarizing and maintaining the Th1 response in Celiacs diseas?
IL-18, IFN-y, or IL-21
Which cytokine links the adaptie immune system to innate immune system in Celiacs?
IL-15
How to test for CD?
- 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
Which genetic test can be done for CD?
- 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
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?
Late‐phase reaction typically develops after 2‐6 h and peaks 6–9 h after allergen exposure.
