Hypersensitivity + Chronic Inflammation Flashcards
What are hypersensitivity and chronic inflammation?
= both examples of an overactive or inappropriate immune response that causes damage
Hypersensitivities
= occur when immune system responds to foreign antigens but too vigorously
= can be classed into 4 types: I,II,III,IV
= allergy refers to environmental antigens , usually a type I response (sometime III or IV)
Chronic Inflammation
= occurs when immune system responds to foreign antigens but is not properly turned off
= when attacking self-antigens = autoimmunity
= different to the response to foreign antigens
What are the key cells involved in Type I hypersensitivity?
Mast cells + basophils
= main mediators of type I response
but also eosinophils (to a lesser extent)
Type I hypersensitivity reactions
= mediated by IgE
IgE antibodies
= bind to antigen via their variable regions
= and to one of two types of Fc receptors via their constant regions: (FcεRI, FcεRII)
What are the IgE receptors?
= (FcεRI, FcεRII)
FcεRI
= high affinity
= found on mast cells and basophils (mainly responsible for Type I receptors)
= expressed by eosinophils and contribute to allergy
(stimulated by cytokine and chemokines released by mast cells)
= also found on dendritic cells and macrophages (internalised IgE-antigen complexes for antigen presentation and stimulation of Th2 type responses)
FcεRII
= low affinity
= expressed by B cells, macrophages and epithelial cells
= functions in antigen presentation
= BUT not involved in allergy
What are the properties of IgE?
= IgE isotype has lowest abundance in vivo and is tightly regulated
(~5-200 lower)
= serum half life of IgE is the shortest of all Ig isotypes
(~2 days)
= low steady state level of serum IgE and transient nature of IgE responses may help to minimise IgE cross-reactivity that would trigger unwanted allergic reactions
= BUT IgE bound to cell surface receptors can persist for a long time, acting as a waiting trigger
= IgE is beneficial in fighting parasitic infections (worms)
What are allergens?
Those who suffer from allergies
= predisposed to make IgE in response to common environmental antigens
(not just parasitic worms)
Wide range of substances can be allergens
= not clear what gives them this property
= and why they only affect atopic individuals
Most allergens are proteins / glycoproteins and are multivalent antigens, many are proteases
Do not pose threat to human body
= but can elicit powerful response
E.g.
= plant pollens
= drugs
= foods
= insects
What are the symptoms of allergy?
Common types of allergy include:
= hay fever (sneezing, runny nose)
= asthma (constriction of airways)
= dermatitis (skin rashes and itching)
= food allergies
= effects can be local or systemic
(depends on extent / type of exposure to allergen)
Most serious
= anaphylactic shock
(strong systemic effect occurs, can be fatal)
= occurs when allergen enters bloodstream
(e.g. insect stings, absorbed from gut or skin)
= symptoms include: difficulty breathing, low blood pressure, contraction of small muscles and bronchiolar constriction leading to asphyxiation
What is the mechanism of Type I hypersensitity?
Primary exposure
= stimulates Th2 response and production of IgE
Secondary exposure
= cross links FcεRI receptors on mast cells and basophils
= triggers degranulation and release of pharmacologically active mediators
What are the types of mediators of Type I hypersensitivity?
Mediators released by mast cells, basophils and eosinophils
= cause local inflammation
= act systemically on eosinophils, neutrophils, T cells, monocytes and platelets
In response to parasitic worms
= these effects are beneficial
= cause direct damage, mucus production and bring immune cells and antibodies to attack the parasites
In allergy
= mediators cause inflammation and tissue damage with little or no benefit
Primary mediators
= substances released from intracellular granules by degranulation with direct effects
Secondary mediators
= synthesised or released from membranes following stimulation
What are some examples of mediators of Type I hypersensitivity?
Histamine from granules (primary)
= acts rapidly via binding to histamine receptors on various cells and tissues
= causes contraction of intestinal and bronchial smooth muscles
= causes increased vascular permeability and vasodilation
= causes increased mucus secretion
Eosinophil chemotactic factor (ECF-A) and neutrophil chemotactic factor (NCF-A)
= released from granules (primary)
Platelet-activating factor (PAF) / leukotrienes / prostaglandins / bradykinins
= all secondary
= cause further increased in vascular permeability and smooth muscle contraction
Range of cytokines and chemokines
= secondary
= increase inflammation
= increase IgE production by B cells
What is chronic type I hypersensitivity?
= can develop into chronic form
= characterised by extravasation of basophils
= which stimulate other cells like fibroblasts to release chemokines
= attracts other granulocytes and contributes to chronic inflammation
What is the susceptibility, diagnosis and treatment of hypersensitivity?
Individuals predisposed to allergic responses
= Atopic
(both genetic and environmental factors)
Environmental
= exposure to pathogens and diet
Skin tests
= effective way to diagnose allergies
= small quantities introduced into skin + check for swelling / redness from local mast cell degranulation
Allergies can be treated by:
= hyposensitisation, increases IgG responses to allergies, inhibiting IgE
= pharmacological inhibitors
(antihistamines, leukotriene inhibitors, corticosteroids)
What is Hyposensitisation treatment?
= administer small repeated low / increasing doses of allergen
= can be successful long term treatment of allergy
= immune tolerance via immunosuppressive cytokines: TGF-ß and IL-10 = inducing Tregs
= also generation of IgG4 antibodies that compete with IgE or reduce FcεRI signalling by co-clustering with inhibitory FcγRII receptors
What is the hygiene hypothesis?
= allergies and autoimmunity are increases
= happens mainly in the developed industrialised world
= Hygiene Hypothesis argues it is a result of decreased exposure to pathogens and potential allergens during early life
= would normally regulate maturation of the immune system
= results in increased reactivity to non-infectious environmental antigens and increased allergic and autoimmune disease
= type I hypersensitivity such as Asthma is then driven by polarised Th2 type responses
What is the Diet (Microbiome) hypothesis?
= diet contributes to increase in allergies
= maternal diet can influence immune response of the breastfed child to dietary and environmental antigens
(breast milk contains both food allergens and aeroallergens)
= exposure favours induction of oral tolerance to these innocuous antigens
(helps prevent allergies in offspring)
= later dietary compounds from solid food are processed by the commensal flora into range of secondary metabolites
(which regulate immune homeostasis through various receptors)
= imbalances in diet that lead to obesity or micronutrient deficiency have been suggested as factors that influence susceptibility to allergic diseases and asthma
What is Type II hypersensitivity?
= caused by IgG and IgM antibodies
= they bind to an antigen on RBCs and induce cell destruction
(by recruiting complement or via antibody-dependent cell-mediated cytotoxicity by NK cells and granulocytes)
3 main situations:
= blood transfusions
= haemolytic disease of the newborn
= haemolytic anaemia
What is the mechanism of a DTH response?
Sensitisation phase
= contact with bacteria promotes TH1 type response
Effector phase
= re-exposure stimulates TH1 cytokine release and inflammation due to activation
= and recruitment of macrophages
= symptoms occur 2-4 days later (delay)
