17 - Hypersensitivity Flashcards
Type 1 / immediate hypersensitivity
- Allergies
- Caused by the release of mediators from mast cells
- Depends on the production of IgE against environmental antigens and binding of IgE to mast cells in various tissues
Type 2 hypersensitivity
Caused by antibodies directed against cell or tissue antigens
Type 3 hypersensitivity
- Caused by antibodies against soluble antigens in blood forming immune complexes
- Immune complexes deposit in blood vessels in various tissues causing inflammation and tissue injury
Type 4 hypersensitivity
T cell-mediated hypersensitivity reactions mainly due to autoimmunity and exaggerated or persistent responses to microbial or ther environmental antigens
Atopic
People prone to type 1 hypersensitivities (high levels of IgE)
Steps of type 1 hypersensitivity
- Activation of Th2 and IL-4 secreting Tfh cells, which stimulate production of IgE
- Binding of IgE to IgE specific Fc receptors of mast calls (FcεRI)
- On subsequent exposure to antigen, cross linking of the bound IgE activates the mast cells to release various mediators
Mast cell mediators in type 1 sensitivity
- Immediate reaction: Rapid increase in vascular permeability and smooth muscle contraction
- Late phase reaction: Recruit neutrophils and eosinophils to site of reaction
When does immediate reaction occur
Minutes after exposure to antigen
When does late phase reaction occur
6-24 hours after exposure to antigen
Common types of allergies
hay fever, food allergies, asthma, and anaphylaxis.
Activation of mast cells
- Cross-linking of IgE on a mast cell by an allergen
stimulates phosphorylation of immunoreceptor tyrosine based activation motifs (ITAMs) in the signalling chains of the IgE Fc receptor (FcεRI) - Initates multiple signalling pathways
What do signalling pathways activated by IgE cross linking stimulate
- Release of mast cell granule contents (amines, proteases)
- Synthesis of arachidonic acid metabolites (leukotrienes)
- Synthesis of various cytokines
Effects of release of mast cell granule contents (amines, proteases)
- Vascular dilation, smooth muscle contraction
- Tissue damage
Effects of synthesis of arachidonic acid metabolites (leukotrienes)
- Vascular dilation
- Smooth muscle contraction
Effects of synthesis of various cytokines
Inflammation (leukocyte recruitment)
Anaphylaxis
Shock caused by vascular dilation and airway obstruction due to laryngeal edema
Steps of type 2 hypersensitivity
- Typically IgG antibodies causing disease by binding to their target antigens in different tissue
- Most often autoantibodies against self antigens
- Cause disease by IOI
What does IOI stand for in antibodies causing disease
I: Inducing inflammation at site of deposition
O: Opsonising cells for phagocytosis
I: Interfering with normal cellular functions (e.g. hormone receptor signalling)
Diseases caused by type 2 hypersensitivity
- Haemolytic transfusion reaction (HTR)
- Haemolytic disease of the newborn
- Myasthenia gravis
- Graves disease
Haemolytic transfusion reaction
- Blood from a type A donor is administered to a patient with type B blood
- Anti-A antibodies in the recipient bind to and agglutinate the incoming donor type A red blood cells
- Bound anti-A antibodies activate the classical complement cascade, resulting in destruction of the donor red blood cells
Haemolytic disease of the newborn
- If an Rh− woman carries an Rh+ baby to term, the mother’s immune system can be exposed to Rh+ fetal red blood cells.
- Problems occur in subsequent pregnancies if foetus is Rh+
- Treated with anti-Rh antibodies which inactivate foetal Rh antigens before they stimulate immune response in mother
Myasthenia gravis
Autoantibodies against the acetylcholine receptor inhibit neuromuscular transmission, causing paralysis
Graves disease
- Autoantibodies to TSH receptor stimulate receptor without hormone
- Thyroid produces excessive amounts of thyroid hormones, which regulate metabolism
Steps of type 3 hypersensitivity
- Antigen-antibody complexes (produced during normal immune responses), cause disease when they are formed in excessive amounts and not efficiently removed by phagocytes, and become deposited in tissues
- Causes vasculitis
Vasculitis
- Immune complexes deposit in blood vessels, activating complement and binding Fc receptors on neutrophils, causing them to release damaging proteases and ROS
- Leads to renal disease if occurs in kidney glomerulus
Diseases caused by type 3 hypersensitivity
- Systemic Lupus Erythematosus (SLE)
- Serum sickness
- Arthus reaction
SLE
- Immune complexes of anti-DNA antibodies and DNA can deposit in the blood vessels of almost any organ, causing vasculitis and impaired blood flow, leading to a multitude of different organ pathologies and symptoms
- Causes by susceptibility genes and external factors (e.g. UV radiation)
Serum sickness
Can occur as a complication of any therapy involving injection of foreign proteins, such as antibodies against microbial toxins, snake venoms and T cells, that are usually made in goats or rabbits
Arthus reaction
- Formation of immune complexes at the site of antigen injection and a local vasculitis.
- Vaccine recipients who have previously been vaccinated or already have antibodies against the vaccine antigen, a painful swelling that develops at the injection site
Two main mechanisms of type 4 hypersensitivity
- Inflammation may be triggered by cytokines produced by CD4 T cells, causing tissue injury by activated inflammatory cells
- Direct killing of target cells mediated by CD8 CTLs
Delayed type hypersensitivity reaction in the skin
- Occurs 24 to 48 hours after an individual previously exposed to a protein antigen is challenged with the antigen
- Delay due to time taken for circulating effector T lymphocytes to home to the site of antigen challenge and respond to the antigen at this site.
What are DTH reactions manifested by
- Infiltrates of T cells and blood monocytes in the tissues
- Increased vascular permeability in response to cytokines
- Tissue damage induced by leukocyte products, from macrophages and neutrophils (that are activated by the T cells)
Examples of diseases caused by type 4 hypersensitivity (DTH)
- Chronic inflammation and tubercular granuloma
- Type 1 diabetes
Chronic inflammation and tubercular granuloma
- In TB, a T cell–mediated immune response develops against protein antigens of Mycobacterium tuberculosis
- Response becomes chronic because the infection is difficult to eradicate.
- The resultant granulomatous inflammation causes injury to normal tissues at the site of infection.
Tuberculin reaction
- Sensitised for DTH by infection or injection of protein antigens
- Subsequent exposure to same antigen elicits the reaction (testing for IFN-gamma)
Example of tuberclulin reaction
Purified protein derivative (PPD), a protein antigen of Mycobacterium tuberculosis, elicits the tuberculin reaction
when it is injected into individuals who have been exposed to M. tuberculosi
Type 1 diabetes
- Activated B cells interact with CD4+ and CD8+ T cells, as well as dendritic cells (DCs)
- Antigen presentation by B cells and DCs drives the activation of β-cell-specific CD8+ T cells.
- In addition, the exposure of B cells to β-cell autoantigens leads to the production of islet-targeting autoantibodies,
