GI Immunology Flashcards
Immunological homeostasis depends on the balance between what?
induced oral tolerance and productive immunity (secretory IgA-mediated and systemic)
Where are Ags captured in the GI tract to be carried to the mesenteric lymph node by DC’s?
Lamina propria and Peyer’s patch
How do the LN DCs stimulate expansion of induced Treg cells? (iTregs)?
By mechanism dependent on TFG-beta, retinoic acid, and indoleamine-2,3-dioxygenase
How do DCs induce IgA-secreting plasma cells?
RA-dependent mechanisms
Gut-homing iTregs are expanded by what?
in the lamina propria by IL-10 expressing Mo
What is the role of iTregs?
suppress systemic immune responses, including allergic sensitization in Ag-specific manner
The gut microbiota and its constituents can suppress allergic immune response through what process? What type of diet is needed?
microbiota can induce Treg cells which suppress Th2 cells
They can also suppress basophils and mast cells and decrease IgE
With a vitamin D, A, and folate diet (Long chain FA and AHR ligands),
What type of diet can promote inflammation and allergy?
High fat diet and medium chain TG
How can a high fat diet promote inflammation?
Cause the epithelium to release chemokines IL-1 and IL-21
Increases the amount of Th2
Th2 releases IL-4, 5, 9, and 13
these activate IgE producing B cells, mast cells, and basophils
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What type of diet may promote tolerance or suppress allergy?
Vitamin A and D and long chain fatty acids
What can exposure to food allergens through non-oral routes such as skin do?
predispose to sensitization
particularly in the context of genetic barrier defects or inflamed skin
When can bacteria in the gut help with homeostasis?
Balanced microbial composition that results in symbiosis
What can dysbiosis lead to?
Due to various environmental factors, it could lead to dysregulation of the immune system and to inflammation in susceptible host (genetics)
What barrier function may be disrupted by malnutrition?
microbiota barrier against enteropathogen infection
Malnutrition also is associated with defect in the innate and adaptive immunity
How are all adverse food reactions classified?
Immune-mediated (food allergy and celiac disease)
Non-immune mediated (formerly known as food intolerances)
What is food allergy caused by?
Ag-specific immune response that occurs reproducibly on exposure to a given food
The term used when an immunological mechanism has been defined
There are two main types of adverse food reactions, toxic and non-toxic. Which one induces pathogenic mechanisms that are both immune and non-immune mediated?
Non-toxic
What does non-immune mediated mechanisms include?
pharmacological, enzymatic and unclear causes, such as certain irritants and psychosomatic responses
What does immune-mediated mechanisms include? (Food allergy)
IgE-mediated: type I hypersensitivity
non-IgE-mediated: Type III (IgG or IgM) or type IV (delayed-type T cell mediated)
What are IgE-mediated reactions divided into
Immediate onset reactions
Late-phase (prolonged or on-going symptoms)
Non-IgE mediated reactions are typically delayed in onset and can occur how long after ingestion of the offending food?
4 to 28 hours
_____ disposition and _______might abrogate oral tolerance leading to food allergy.
Genetic
Environmental factors
Food allergies affect what percentage of children and adults in westernized countreis?
5% of children
3-4% of adults
What are the most common food allergies in the U.S?
milk (2%), egg(1.3%), peanu(.5%)t, soy, wheat, tree nuts, fish and shellfish
With milk allergy most common
What allergens after 5 years of life, do most children lose their sensitivity to?
milk, eggs, wheat and soy
What allergies continue into adulthood?
peanuts, tree nuts, fish and shellfish
Where are mast cells most commonly found in the body?
skin, GI tract, and respiratory tract
What do mast cells release upon activation?
Proteases: tryptase->tight junction rearrangement (via granules)
Histamine (via granules)
Cytokines de novo: IL-1b, TNFa
Mast cells in skin, lung or systemic circulation release ____ and _____ that cause systemic symptoms
Histamine
PAF
Mast cell degranulation of what products causes local acute GI response- diarrhea upon exposure to allergen? What is necessary for the local symptoms?
Serotonin
PAF
Mastocytosis
What is GI manifestations of food allergy dependent on?
Th2 cytokines
IL4, 13, and 9
The spread of Ags can trigger _____ and ______
utricaria and bronchospasm
What is anaphylaxis?
systemic reaction against allergens Sudden release of multiple chemical mediators mediated by IgE antibodies Sever itching, hives swelling of throat bronchoconstruction lowered BP unconsciousness death
What foods are most frequently associated with anaphylaxis?
peanuts, tree nuts, seeds, seafood, spices, celery, eggs, milk and some fruit
During anaphylactic reaction, the release of granules from mast cells induce what effects on the GI tract, airways and blood vessels?
GI: increased fluid secretion, increased peristalsis (diarrhea, vomiting)
Airways: decreased diameter, increase mucus secretion (phlegm, coughing)
Blood vessels: Increased blood flow and permeability (edema, inflammation)
What receptor does IgE bind to on mast cells?
FceRI
Describe how C3 and C5 becomes involved in anaphylaxis
Mast-derived mediators like histamine causes vascular permeability and C3 and C5 can enter area
Tryptase released from activated mas cells act on C3 and C5 to locally generate C3a and C5a which activate mast cells further to exacerbate the symptoms
Peanut-induced anaphylaxis is also mediated by IgG-induced activation of Mo. What is the receptor on the Mo?
FcyRII and FCyRIII
Release of PAF
What are reactions that wheat allergy can induce?
IgE plays a central role (systemic) -wheat-dependent, exercise-induced anaphylaxis (WDEIA) -occupational asthma (baker's asthma) Rhinitis Contact Urticaria
*progressively increases with age
What are the types of food intolerance?
Absence of an enzyme (lactose)
Irritable bowel syndrome - chronic
Food poisoning - bacteria
Sensitivity to food additives - sulfites used to preserve can trigger asthma
Recurring stress or psychological factors
Celiac disease
What is celiac disease?
chronic digestive condition is triggered by eating gluten, a protein found in wheat and other grains Some features of true food allergy Symptoms mostly GI NOT at risk of anaphylaxis 15-20% also have autoimmune diseases
What are highly variable non-GI findings that Celiac disease can be associated with?
failure to thrive delayed puberty autoimmune disorders inflammation neruological disorders metabolic disorders
What is the main genetic predisposing factor of Celiac disease?
HLA-DQ2 and DQ8 molecules
They play a key role in orchestrating an adaptive immune response against gluten peptides
Serum autoantibodies against what molecule is is specifically associated with celiac disease?
Ubiquitous enzyme tissue transglutaminase 2
TG2
How do APCs process Ag?
Via phagocytosis(Mo) or endocytosis (DCs and B cells) Protein Ags undergo enzymatic degradation into peptides Peptide Ags loaded into Class II MHC and presented for recognition by CD4 T helper cells
NB! no Ag-free MHC molecules are displayed on APCs
What is gluten? is it digested?
proline-rich protein that is poorly digested in the small intestinal tract due to lack of prolylendopeptidases
Rich in glutamine residues
Gluten peptides 10-15 aa in length are formed and left incompletely digested
How does gluten become an antigen?
Some glutamines in the peptides can be deamidated by TG2->negatively charged glutamic acid residues in lamina propria
Peptides with a specific spacing of proline and glutamic acid bind to HLA class II on APCs
The majority of CD patients express the HLADQ2.5 heterodimer
How does gluten cause a immune response in celiac disease?
The peptides become crosslinked with TG2
HLADQ2.5 heterodimer displays peptide
self-reactive T cells (CD4 and CD8) are generated
cell-mediated autoimmunity is warrant
tissue damage occurs in Type IV hypersensitivity manner
TH2 cytokines produced driving production of Antibodies to gluten and TG2 are made
Chronic inflammatory response, damage to mucosa and malabsorption continues if patients continues to eat gluten
How does a reaction to gluten cause mucosal remodeling and villus atrophy? What maintains the response?
Activated CD4 T cells secrete mainly Th1 cytokines like IFN-y which induced the release of MMPs by myofibroblasts which results int he remodeling
IL-18, IFN-y or IL-21 seem to play a role in polarizing and maintaining the Th1 response
Which cytokine links the adaptive immune system to innate immune responses?
IL-15
Who should be tested for CD?
children with a failure to thrive and persistent diarrhea
GI symptoms including recurrent abdominal pain, constipation and vomiting
Non-Gi symptoms including dermatitis herpetiformis, dental enamel hypoplasia, osteoporosis, short stature, delayed puberty
iron-deficient anemia resistant to iron
How do you test for CD?
initial test of measuring IgA antibody to TTG
Measurement of total serum IgA when tTG IgA is low (IgA deficency?)
Intestinal biopsy - for seronegative CD and to confirm all CD cases
Genetic test: for HLA alleles DQ2 or DQ8
