Increased cleanliness (usually in 'Westernised' countries) leading to higher rates of allergies and autoimmune diseases.
There is very little allergy in 'developing' countries
What is atopy?
A genetic predisposition to develop allergic diseases.
Atopic individuals have higher levels of IgE & eosinophils in their blood.
Strong genetic component to risk - polymorphisms of multiple genes on chromosomes 5, 6 & 11
What is the role of eosinophils in type I hypersensitivity?
Have FcεRs for IgE on their surface
Contain pre-formed toxic mediators in granules -> released on receptor crosslinking
Also can secrete cytokines
Th2 cells regulate the eosinophil arm of the immune response
secrete cytokines (e.g. IL-5) -> promote development & survival of eosinophils
promote recruitment of eosinophils to sites of inflammation by stimulating release of chemokines by activated endothelial & epithelial cells
Where are eosinophils found?
Present in small numbers in blood
Resident in connective tissue under mucosal surfaces
Where are basophils found?
A minor population in peripheral blood & not usually found in large numbers in peripheral tissues
Recruited to sites of inflammation
What is the role of basophils in type I hypersensitivity?
Have FcεR for IgE
When activated, receptors crosslink -> release histamine & other mediators
Cytokine production (IL-4 & IL-13) -> important in initiation of Th2 responses
What are the different ways that an allergen can enter the body?
Intravenous
Subcutaneous
Inhalation
Ingestion
What happens when an allergen is introduced by IV?
Antigen is distributed widely across the body
Release of histamine -> systemic increase in blood vessels permeability
= Anaphylactic shock
What happens when an allergen is introduced subcutaneously?
Local release of histamine -> oedema & reddening of the area
= wheal & flare reaction
What happens when an allergen is introduced via inhalation?
In upper airways
-> nasal irritation & increased mucous production
In lower airways
-> contraction of smooth muscle & increased mucous production
= runny nose & bronchoconstriction
When happens when an allergen is ingested?
Contraction of smooth muscle
Increased fluid loss
= diarrhoea, urticaria, atopic eczema
There is a risk of anaphylaxis, due to absorption of allergen into blood
What happens in a type I hypersensitivity?
First exposure (sensitisation)
allergen is picked up by APC (usually at the mucosal surface) -> antigen presented to Th cells (Th2 response) -> Th cells then activate B cells -> B cells become plasma cells -> IgE production -> IgE 'sticks' to all of the local mast cells (FcεR), but allergen is gone
Second exposure
allergen enters -> becomes bound to IgE pre-bound on mast cells -> cross-linking of IgE -> mast cells degranulate & release its granule contents -> vasodilation & increased permeability
Atopic individuals have haver levels of IgE & eosinophils in their blood.
What cytokines are involved in type I hypersensitivity?
IL-4
IL-5
IL-13
Histamine
What happens in a type II hypersensitivity?
IgG antibodies bind to cell surfaces -> their destruction
2 ways this can be initiated;
intrinsic -> antibodies to a self antigen
extrinsic -> antibodies to a neo- or foreign antigen (e.g. an infection or drug that attaches to a cell)
Give an example of a type II hypersensitivity.
Response to an ABO- incompatible blood transfusion
What are preformed in mast cell granules?
Enzymes (e.g. tryptase)
Histamine
Heparin
Cytokines (TNF-a)
What happens in type III hypersensitivity?
IgG binds to soluble antigen (not attached to cells) -> forms 'clumps' (immune complexes) -> small immune complexes circulate in the body & deposit in highly vascularised areas (as positively charged complexes are attracted to the negatively charged basement membrane) -> immune complexes activate & deposit complement -> vascular response & phagocytes are recruited -> inflammation is triggered, phagocytes take up immune complexes & ROS are produced -> can result in vasculitis
What is serum sickness?
Systemic reaction to an injected foreign antigen
Antigen is removed & is self-limiting
In type III hypersensitivity, a reaction to a self-antigen could cause autoimmunity (e.g. SLE).
What are the differences between the different types of hypersensitivities?
Type I -> IgE, soluble antigen
Type II -> IgG, cell-associated
Type III -> IgG, soluble antigen
Type IV -> cell mediated
Fill in the blanks
A) IgE
B) IgG
C) IgG
D) Cell mediated
E) soluble
F) cell-associated
G) soluble
H) soluble
I) cell
J) mast
K) complement
L) phagocytes
M) complement
N) phagocytes
O) macrophage
P) eosinohpil
Q) cytotoxicity
Give 2 examples of type I hypersensitivity.
Allergic asthma
Eczema
Give an example of a type II hypersensitivity.
Chronic urticaria
Given an example of a type III hypersensitivity.
Serum sickness
Give 3 examples of type IV hypersensitivity.
Allergic contact dermatitis
Chronic asthma
Graft rejection
What is the pathophysiology of allergic (acute) asthma (immediate phase)?
Immediate phase
antigen enters -> taken up by APC -> mast cells activate & degranulate -> releases