Define: Hypersensitivity
- Unnecessary, non-beneficial immunopathology driven by an external antigen
- Set of undesirable reactions ranging from irritating (allergy) to life-threatening (anaphylaxis)
Define: Autoimmunity
- System of immune responses of an organism against its own healthy cells and tissues
- Any disease that results from this response = an autoimmune disease
What is Immunopathology?
Branch of medicine focusing on immune responses associated with disease
What causes hypersensitivity and autoimmunity?
When damage is caused by adaptive immune mechanisms and no hazard can be identified
What is the difference between hypersensitivity and autoimmunity in terms of source of antigen?
- Hypersensitivity = external source of antigen
- Autoimmunity = internal source of antigen
What is the difference between hypersensitivity and autoimmunity in terms of effector mechanism?
A
How are hypersensitivities classified?
By the effector mechanism by which damage occurs:
- Different types of antibody
- Binding and blocking
- Histamine
- Phagocytosis
or
- T-cells
- CD8 Killers (direct killing of infected cells)
- CD4 helpers (cytokine release and inflammation or control B cell antibody responses)
What do all hypersensitivity reactions have in common?
Sensitisation to external antigen
Explain the cellular basis of hypersensitivity
- Not born with allergy, at some point develop hypersensitivity reaction to particular antigen
- Expansion of B lymphocytes = lots of them = sensitisation
- Can be identified in blood samples - B cells sticking strongly to the particular antigen
Define: Atopic
A form of allergy in which a hypersensitivity reaction may occur (e.g. eczema, asthma) in a part of the body not in contact with the allergen
What are the 4 classes of hypersensitivities?
- Type I
- Type II
- Type III
- Type IV
What is the effector mechanism of Type I hypersensitivity reaction?
IgE antibody-mediated degranulation of mast cells
What is the effector mechanism of Type II hypersensitivity reactions?
IgM and IgG antibody-mediated cell killing
What is the effector mechanism of Type III hypersensitivity reactions?
IgG antibody immune complexes
What is the effector mechanism of Type II hypersensitivity reactions?
T-cells
Give 3 examples of a Type I hypersensitivity reaction
- Hayfever
- Asthma
- Anaphylaxis
Give 3 examples of a Type II hypersensitivity reaction
- Mismatched blood transfusion
- Penicillin
- Haemolytic anaemia of a newborn
What is haemolytic aneamia?
Abnormal breakdown of red blood cells in the body
Give 2 examples of a Type III hypersensitivity reaction
- Serum sickness
- Long-term use of monoclonal antibodies
Give 1 example of a Type IV hypersensitivity reaction
Contact dermatitis
What is the most common type of hypersensitivity reaction?
Type I
Explain the Type I hypersensitivity reaction
- Allergen binds to IgE antibodies on surface of mast cells
- Triggers degranulation of mast cells and histamine release
- Causes swelling, sneezing, itching, swelling, vasodilation, sudden death
Describe hayfever as a Type I reaction
Allergen/antigen (pollen) in upper respiratory tract and eyes
- Itching
- Sneezing
Describe asthma as a Type I reaction
Allergen/antigen (pollen, dust mites etc.) in lower respiratory tract
- Air vessel constriction
- Shortness of breath
- Wheezing
Descibe anaphylaxis as a Type I reaction
If enough mast cells in the body are triggered at the same time, systemic vasodilation leads to catastrophic blood pressure loss and death
Also:
- Swelling
- Hives (urticaria)
How can an antigen be identified?
- Removal of antigen
- Skin prick test
What is the normal role of IgG and IgM?
(Type II)
Killing pathogens
What is the role of complement?
(Type II)
- Part of the immune system
- Works with antibodies to enhance their ability to kill microbes
- Antigen becomes coated with antibodies (IgG and IgM) which activates complement → punches holes in the microbe’s cell wall = lysis
Explain the Type II hypersensitivity reaction
In the case of allergic reactions to e.g. antibiotics, penicilin:
- Drug molecule may stick to RBCs
- IgG and IgM antibodies bind to drug
- Because of complement, immune system thinks RBCs are pathogens
- RBCs are lysed
= Drug-induced haemolytic anaemia
∴ Direct cell-killing by an antibody-mediated response
What is the normal role of IgG?
(Type III)
- Neutralising toxins and virus
- IgG molecules bind to toxin = immune complex = inactivated toxin
Explain the Type III hypersensitivity reaction
- Caused by high levels of antibody bound to soluble foreign proteins (immune system sees them as antigens)
- = Accumulation of immune complexes of varying sizes
- Larger complexes can be cleared by macrophages but they cannot clear smaller complexes
- These smaller complexes can insert themselves in blood vessels, joints and glomeruli
- Gives rise to inflammatory response and attraction of leukocytes (WBCs)
- = Immune complex disease
What could the foreign proteins which cause a Type III hypersensitivity reacition be?
The foreign proteins could be:
- A protein drug e.g. monoclonal antibodies
- Anti-venom
What is serum sickness?
(Type III)
A reaction to the proteins in anti-serum derived from an animal source
Starts Type III hypersensitivity reaction:
- Body’s immune system sees these foreign proteins as antigens
- IgG antibody produced to bind with proteins
- = Immune complexes
- Starts inflammatory response
How are therapeutic monoclonal antibodies made?
A single re-arranged antibody is selected that binds to a desired antigen - can be made to bind to any antigen
How does anti-venom differ to therapeutic monoclonal antibodies?
- Mixture of all antibodies vs Only 1 antibody
- Horse protein vs Human protein
- Made in animals vs Made in bioreactor
- Made by animal immune response vs Engineered by molecule biologists
What is the normal role of T-helper cells?
(Type IV)
Triggering inflammation in response to microbial peptides (via epitope and MHC)
Explain the Type IV hypersensitivity reaction
- CD4+ T-helper cells recognise the antigen’s epitope/peptide in a complex with MHC on antigen-presenting cells (e.g. dendritic cells)
- Takes a while for allergic reaction to develop (2-3 days)
→ Shows it is T-cell mediated hypersensitivity not histamine (would be instantaneous)
= Type IV also known as Delayed Type Hypersensitivity
e.g. Contact dermatitis - irritant will interfere with MHC complex with T receptor, will take a couple of days for swelling to show
List 2 anti-inflammatory treatments
- Antihistamines
- Sodium cromoglicate
How do antihistamines work?
- Antagonists of H1 receptor - inhibit the release/action of histamine
- e.g. Loratidine, Cetirizine
- Side effects - drowsiness
- Also available as cream - Anthisan (bites etc)
How does Sodium cromoglicate work?
- Prevents release of histamine from mast cells, mechanism not fully undertsood
- Available as nasal spray (Rynacrom), inhaler (Intal) and eye drops (Opticrom)
What effect do Glucocoticoids/Corticosteroids have on the immune system?
- Anti-inflammatory steroid molecules
- Suppress release or action of pro-inflammatory molecules (e.g. histamine)
- Synthetic mimics developed - used in a huge range of conditions = most potent anti-inflammatory
- Major side effects if taken systemically
What is the solution to adverse hypersensitivity effects from glucocorticoids/corticosteroids?
- Topical use
- Delivery to site of inflammation
- Skin response (e.g. insect bite) = hydrocortisone cream
- Inhaled antigen (hayfever) = nasal spray - beclometasone dipropionate