Allergy Flashcards
What is the definition of an allergen?
An environmental Ag that elicits allergic responses in susceptible individuals.
these Ags have little or no intrinsic toxicity
True or False:
Allergens have intrinsic toxicity.
False - allergens have little or no intrinsic toxicity.
What is an allergy?
Clinically adverse reactions to environmental Ags mediated by acquired immune responses which are marked by:
> presence of allergen-specific IgE.
> Mast-cells and eosinophils recruitment and/or activation.
> Th2-type of responses and IL-4, IL-5, and IL-13 are key elements.
What is atopy?
The propensity for developing immediate hypersensitivity reactions to common environmental allergens.
An allergy is a clinically adverse reaction to environmental Ags mediated by acquired immune responses which are marked by what?
> The presence of allergen-specific IgE.
> Mast-cells and eosinophils recruitment and/or activation.
> Th2-type of responses and IL-4, IL-5, and IL-13 are key elements.
What are the common mechanistic aspects of an allergic disease?
> All result from harmful immune responses.
> Immune responses are driven by non-infectious Ags.
> Immune responses are all associated with the generation of IgE.
What are all immune responses in allergic diseases associated with?
Immune responses are all associated with the generation of IgE.
What type of immune response did the study of allergic diseases focus on in the past?
adaptive immune response
What type of immune response dose the study of allergic diseases today focus on?
innate immune mechanisms
Allergens are a diverse group of what type of molecules?
- proteins
- glycoproteins
How do allergens (proteins and glycoproteins) activate the innate immune response?
- An intrinsic enzymatic activity.
- Activation of pattern-recognition receptors (PRRs).
may bias the immune response toward a Th2 phenotype
can elicit IgE-specific responses in genetically susceptible individuals
What can allergens elicit in genetically susceptible individuals?
IgE-specific responses
True or False:
Allergens represent a very small group of the antigenic universe to which humans are routinely exposed to.
True
What specific type of T helper cell phenotype does allergens bias the immune response toward?
Th2 Phenotype
What are aeroallergens?
Airborne proteins or glycoproteins derived from a variety of different sources:
-pollinating trees and grasses
- mold spores
- animal dander (cat, dog, and rodent)
- particulates secreted by dust mites and cockroaches
What disease are indoor allergens usually associated with?
asthma
What disease are outdoor allergens more important in?
allergic rhinitis
Aeroallergens are airborne proteins or glycoproteins that are derived from a variety of different sources. What are these sources?
- Pollinating trees and grasses.
- Mold spores.
- Animal dander (cat, dog, and rodent).
- Particulates secreted by dust mites and cockroaches.
What type of enzymatic activity do several allergens have?
Protease Activity
True or False:
Several allergens have protease activity, which is an important property that may play a role for crossing skin or mucosal barriers.
True
Why is it important that several allergens have protease activity?
This is an important property which may play an important role for crossing skin or mucosal barriers.
What kind of particles do allergens tend to be contained within?
Allergens tend to be contained within carrier particles.
Why is it an important property that allergens tend to be contained within carrier particles?
Small particles are aerodynamic which may be important properties in gaining aerial access to nasal and bronchial mucosa.
What is the most prevalent pollen in the air in the UK?
timothy grass pollen (hay fever)
What is the most prevalent pollen in the air in Scandinavia?
Birch pollen
What are the genetic factors that influence the development of atopy?
- Presence of specific HLA alleles.
- Polymorphisms of Fc-epsilon RI-beta.
- Polymorphisms of the IL-4 family of cytokine genes.
- Polymorphisms of CD14.
- Polymorphisms at other loci.
What are the environmental factors that influence the development of atopy?
- Allergen sensitization
- Having few siblings
- Excessive hygiene
- Receipt of antibiotics in first 2 years of life
- Vaccination and prevention of disease
What are the defects in target organs that influence the development of atopy?
- Bronchial epithelium
- Skin
- Gut
What are the triggers that influence the development of atopy?
- Viral infections
- Exposure to allergens
- Tobacco smoke
- Indoor and outdoor pollutants
What do the multitude of factors (genetic factors, defects in target organs, environmental factors, and triggers) that influence the development of atopy mediate?
Th2-mediated allergic inflammation.
Th1 cells of the cellular mediated immune system provide protective immunity to an individual. List factors that favor the Th1 phenotype.
- Presence of older siblings.
- Early exposure to day care.
- Tuberculosis, measles, or hepatitis A infection.
- Rural environment.
Th2 cells of the cellular mediated immune system provide immune responses to allergic diseases, including asthma. List the factors that favor the Th2 phenotype.
- Widespread use of antibiotics.
- Western lifestyle.
- Urban environment.
- Diet.
- Sensitization to house-dust mites and cockroaches.
True or False:
The tendency to allergic reactions has a strong heritability.
True
The TENDENCY has been termed atopy.
How is atopy most easily defined?
As the presence of a type I hypersensitivity reaction to an allergen.
What type of test is atopy usually demonstrated in the clinic?
Skin Prick Test
Does the potentially allergic state (atopy) always result in disease?
No - the potentially allergic state (atopy) NOT always result in disease.
In the westernized world, what percentage of the population is atopic?
20-30% of population
What is the percentage of risk that parents will pass on an atopic trait to their children?
- 75% (two parent atopic)
- 50% (one parent atopic)
- 15% (no atopic parent)
In the inheritance of allergic disease, what polymorphism in genes is known to be involved?
- Beta chain of the high affinity receptor for IgE (Fc-gamma-RIIB).
- IL-4 gene.
- HLA-DR alleles.
- CD14
Why does CD14 have a role in the development of allergy?
CD14 constitutes part of the receptor for bacterial cell wall LPS, and infection may have a role in the development of allergy.
CD14 polymorphisms affecting sensitivity to pathogens could promote hypersensitivity.
What did the studies on HLA associations in a North American population reveal about allergic disease?
Studies on HLA associations show that in a North American population IgE and IgG hypersensitivity to the RAGWEED Ags is associated with HLA-DR2 in patients with ragweed pollen allergy.
What is the concordance (both twins having the disease) for asthma in monozygotic identical twins?
only 20%
The two-fold increase in allergy in Sweden over a 12-year period arose without any fundamental change in the genetic stock of the inhabitants. Why?
Environmental factors have a huge role in allergic reactions.
Give an example of environmental factors playing a huge role in allergic reactions.
IgE hypersensitivity was much less common in East Germany before reunification with West Germany, but not is rising alarmingly.
one possibility is that ATOPIC TENDENCIES arise during fetal or infant life
True or False:
It has been demonstrated that high levels of IgE in the cord blood of infants predicts future development of atopy.
True
**Support - peak allergy incidence caused by birch pollen (common in Scandinavia) is found amongst children born during the months of birch pollen release (February to April).
What is the cause of increasing prevalence of allergies?
- Hygiene Hypothesis
- Environmental changes in indoor air quality.
- Changes in lifestyle.
What is the hygiene hypothesis for explaining the cause of increasing prevalence of allergies?
The increased incidence of allergy is associated with the decrease in exposure to common infections during early life.
- Shift from Th1 to Th2 type of immunity.
- Decreased number/activity of Treg cells.
Which phenotype of T helper cells shows a bias in neonates?
Neonatal immune system shows a Th2-type bias.
How can the development of atopic (Th2-type) phenotype in a child can be prevented by?
Th1-type responses.
thus, infections in the childhood causing Th1-type responses (viruses and intracellular bacteria) can restore the Th1/Th2 balance
the increased number of T regulatory cells after infections (all infections including helminthes) can limit the development of unrelated allergies (allergen-mediated disease)
Where is the major site of maturation for mast cells?
connective tissue
Where is the major site of maturation for basophils?
bone marrow
Where is the major site of maturation for eosinophils?
bone marrow
Between mast cells, basophils, and eosinophils, which have the proliferative ability of mature cells?
ONLY Mast Cells
NOT basophils or eosinophils
Between mast cells, basophils, and eosinophils, which mature cells resides in connective tissue?
Mast cells and Eosinophils
NOT basophils
Between mast cells, basophils, and eosinophils, which mature cells can be recruited into tissues from the circulation?
Basophils and Eosinophils
NOT mast cells
Between mast cells, basophils, and eosinophils, which of these cells are found in circulation?
Basophils and Eosinophils
NOT mast cells
What is the life span of mast cells?
Weeks to Months
What is the life span of basophils?
Days
What is the life span of eosinophils?
Days to Weeks
What is the major development factor (cytokine) of mast cells?
- Stem cell factor
- IL-3
What is the major development factor (cytokine) of basophils?
IL-3
What is the major development factor (cytokine) of eosinophils?
IL-5
Between mast cells, basophils, and eosinophils, which expresses high levels of Fc-epsilon-RI?
Mast cells and Basophils
eosinophils express low levels
What is the major granule contents of mast cells?
- histamine
- heparin and/or chondroitin sulfate
- proteases
What is the major granule contents of basophils?
- histamine
- chondroitin sulfate
- protease
What is the major granule contents of eosinophils?
- major basic protein
- eosinophil cationic protein
- peroxidases
- hydrolases
- lysophospholipase
True or False:
Mast cells and basophils mediators include biogenic amines and enzymes stored preformed in granules as well as cytokines and lipid mediators, which are largely newly synthesized on cell activation.
True
the biogenic amines and lipid mediators induce immediate response which include vascular leadage, bronchoconstriction, and intestinal hypermotility
The biogenic amines and lipid mediators from mast cells and basophils induce immeidate response. What are these immediate responses?
- Vascular Leakage
- Bronchoconstriction
- Intestinal Hypermotility
CYTOKINES and LIPID MEDIATORS contribute to inflammation, which is part of the late-phase reaction. ENZYMES probably contribute to tissue damage.
What is the mechanism in the sensitization of allergens?
- DCs pick up the allergen and migrate to a regional LN.
- Allergens are processed by DCs and presented within class II MHC for naive T cells.
- Allergens stimulate DCs to produce IL-4.
- Naive T cell specific for allergen peptide recognizes it in the context of class II MHC.
- Thereby a Th cell response is activated.
- IL-4 bias the development of the Th2 cells.
- Activated T cell differentiates into Th2-type helper lymphocyte.
- Clonal expansion occurs.
- Th2 type cells produce IL-4 and IL-13.
- Naive B cell (Ag-presenting) picks up allergen and processes it for presentation to Th cell.
- Activated Th2 cell recognizes the allergen/MHC II and releases IL-4 and IL-13.
- The B cell is fully activated, switches to IgE production and becomes a plasma cell.
- Some activated B cells become memory cells.
What is the mechanism of the effector (immediate) reaction?
- Mast cells resign in the tissue.
- Basophils are found in the circulation.
- Due to expression of Fc-epsilon-RI, anti-allergen IgE are selectively bound to mast cells and basophils.
- Fc-epsilon-RI has very high affinity for Fc or IgE.
- Crosslinking of Fc-epsilon-RI leads to activation of the cells and release of inflammatory mediators.
What are the mediators of mast cells?
- Histamine
- TNF-alpha and IL-1
- Tryptase
- Prostaglandin E2 (PGE2)
- PGD2 and Leukotrienes, LT (C4, D4, E4)
- Bradykinin
- IL-5
What is the targets/effects/results of histamine, which is a mediator released by mast cells?
- smooth muscle contraction
- vascular permeability
What is the targets/effects/results of TNF-alpha and IL-1, which is a mediator released by mast cells?
- endothelial cells
- inflammation
What is the targets/effects/results of tryptase, which is a mediator released by mast cells?
- trypsin-like activity
- anaphylaxis
- urticaria
What is the targets/effects/results of prostaglandin E2 (PGE2), which is a mediator released by mast cells?
- pain
- vascular permeability
What is the targets/effects/results of PGD2 and leukotrienes, LT (C4, D4, E4), which is a mediator released by mast cells?
- smooth muscle contraction
- vascular permeability
What is the targets/effects/results of bradykinin, which is a mediator released by mast cells?
- vasodilator
- smooth muscle contraction
What is the targets/effects/results of IL-5, which is a mediator released by mast cells?
Sputum Eosinophils
What are the steps in chronic disease development?
- ACTIVATION of Th2 lymphocytes and macrophages.
- RECRUITMENT and DEGRANULATION of eosinophils.
- Obstruction and increased in AIRWAY RESPONSIVENESS.
- Progression inflammation towards AIRWAY REMODELING.
What is the mechanism for tissue remodeling?
- INFLAMMATORY MEDIATORS and reactions cause chronic structural changes to the airway.
- Activation of TISSUE FIBROBLASTS; increased production of collagen and its deposition.
- Increased production of mucus by GOBLET CELLS.
- SMOOTH MUSCLE hyperplasia and hypertrophy.
- Increase RISK of acute obstruction of airflow in the lung in response to irritants allergens and other irritants.
What is the role of Th2-type cytokines, IL-4 and IL-13, involved in?
- Production of IgE
- Development of mast cells.
- Overproduction of mucus.
What is the role of Th2-type cytokines, IL-4, IL-5, and IL-13, involved in?
Development and accumulation of eosinophils and basophils.
What is the role of Th2-type cytokines, IL-13, involved in?
Airway hyper-responsiveness.
True or False:
Desensitization by allergen immunotherapy has an important place in the management of allergic disease.
True
What kind of disorder is desensitization an indicator for?
Indicated for disorders in which IgE hypersensitivity is clearly confirmed.
Skin tests and allergen-specific IgE detection must be performed to confirm this.
Typical indications include life-threatening allergy to:
> insect stings
> drug allergy
> allergic rhinitis.
It comprises an induction course of subcutaneous injections of increasing doses of the allergen extract, given once every 1-2 weeks.
Once the maximum dose is achieved (usually after 6-10 weeks), maintenance injections may be required monthly for 2-3 years but may provide benefit for a further number of years.
What are the 3 mechanisms of desensitization?
- IgG blocking antibodies
- regulation
- immune deviation
What is the mechanism of IgG blocking antibodies in desensitization?
During repeated exposure to desensitizing allergen, IgG class Abs develop (especially IgG4); these compete with the pathogenic IgE for allergen binding, and/or prevent IgE-allergen complexes binding to mast cell high affinity IgE receptors.
What is the mechanism of regulation in desensitization?
Exposure to repeated desensitizing allergen induces Treg cells, which recognize allergen but invoke regulatory immune responses, dampening down migration, infiltration, and inflammation.
What is the mechanism of immune deviation in desensitization?
A shift away from Th2 to Th1 producing CD4 cells results in the generation of cytokines (e.g., IFN-gamma), which are inhibitory to IgE production.
