What is hypersensitivity?
A group of disorders in which the immune system responds in an exaggerated or inappropriate fashion to environmental antigens in a way which causes harm to the body, instead of protecting it
What are the 4 types of hypersensitivity
Type I - IgE mediated
Type II - IgG mediated cytotoxic response
Type III - IgG mediated - immune complex
Type IV - T cell mediated
What happens in the sensitisation stage of the type I hypersensitive response?
1) Allergen enters body
2) Allergen carried to lymph nodes by APC - presented to naive T cells
3) T cell primed and differentiates into a Th2 cell (in response to interleukins)
4) Th2 cells release various interleukins that activate B cells and eosinophils
5) B cell produces IgE antibodies that bind onto Fc receptors on mast cells - sensitises them
What are interleukins?
A type of cytokine
Small protein molecules
- Type I -
What happens when interleukins activate eosinophils?
Interleukins stimulate proliferation of eosinophils
Eosinophils can then degranulate, killing parasites and host cells
- Type I -
What happens in the second exposure to an allergen?
1) Body exposed to allergen
2) Allergen binds to IgE antibodies on surface of sensitised mast cell
3) Activates the mast cell which degranulates, releasing mediators and enzymes - leading to the allergic response
What are mediators?
Communicatory molecules
In the context of hypersensitivity; they are Pro-inflammatory molecules
Describe how an allergic response causes breathing difficulty and oedema
1) Sensitised mast cell binds binds to allergen
2) Sensitised mast cell releases various mediators (degranulates)
3) Histamine (a type of mediator) causes:
- Smooth muscle contraction in bronchi ∴ breathing difficulty
- Vasodilation + increased permeability ∴ oedema
- Type I - early phase
What are the effects of the mediators and enzymes released by mast cells when they degranulate
(BIVVIT)
Bronchial constriction
Intestinal hypermotility
Vasodilation
Vascular leakage
Inflammation
Tissue damage
- Type I - early phase
What 2 ways does degranulation of mast cells lead to tissue damage?
1) Degranulation releases enzymes such as tryptase that damage tissues
2) Degranulation releases mediators that attract eosinophils that degranulate - killing pathogens but also surrounding tissue
- Type I - late phase
Several hours after an allergic reaction, Th2 cells, basophils and yet more eosinophils are recruited to the location of the allergen
What causes this?
Cytokines produced in early phase reactions:
- Interleukins
- Leukotrienes
What is atopy?
Predisposition to allergy
What is the main factor determining atopy?
Genetics
Allergies often run in families
What is type II hypersensitivity caused by?
Auto-antibodies binding to our own cells
- Type II -
Describe the reaction mechanism that causes neutrophils to kill our own cells
1) C1 protein binds to Fc portion of antibody attached to cell
2) Compliment cascade initiated leading to production of C3a, C4a and C5a
3) These are chemotactic - attract neutrophils
4) Neutrophils degranulate - cytotoxic - leads to tissue damage
- Type II -
Describe the reaction mechanism involving the membrane attack complex
1) C1 compliment protein binds to Fc portion on auto-antibody on cell
2) Compliment cascade initiated leading to production of MAC
3) MAC punches hole in cell - causing swelling and bursting (cell lysis)
- Type III -
Describe the reaction mechanism involving opsonisation
1) C3b compliment protein binds to Fc region on IgG antibody on cell
2) This opsonises the cell
3) This causes phagocytes to phagocytose the cell in the spleen
- Type II -
Describe the mechanism behind antibody-dependant cell mediated cytotoxicity (ADCC)
1) Bound antigen-antibody complex on our own cells is recognised by NKCs
2) These release perforins and granzymes
3) Perforins create pores in the cell, granzymes enter the cell and cause apoptosis
- Type II -
Why does ADCC not cause surrounding inflammation to the reaction site?
Granzymes cause apoptosis
Only cells with antibody on the surface are killed - surrounding cells are fine
- Type II -
What is antibody-mediated cellular dysfunction?
Non-cytotoxic mechanism
Antibody gets ‘in the way’ of the cell it is bound to
Example - Myasthenia Gravis. ACh receptors at NMJ are blocked by antibodies
What happens in type III hypersensitivity?
Antigen-antibody complexes are deposited in blood vessel walls
Causing inflammation and tissue damage
What are immune complexes?
Antibodies bound to soluble antigens
Why do immune complexes only form in type III reactions?
In other types, the antigen is attached to a cell ∴ not soluble
Antibody-antigen complexes that form in other types are not immune complexes
If something is very immunogenic, what does this mean?
It is very attractive to phagocytes
A strongly immunogenic pathogen will be quickly engulfed
- Type III -
Describe the mechanism of type III hypersensitivity and what it’s effects are
1) IgG antibodies bind to soluble antigen ∴ immune complex forms
2) Travels in bloodstream until it attaches to basal lamina
3) Immune complexes activate the compliment system
4) C3a, C4a, C5a - anaphylatoxins ∴ increase vascular permeability ∴ oedema
5) C3a, C4a, C5a also attract neutrophils
6) Neutrophils arrive and degranulate ∴ inflammation and tissue damage
What is the difference in compliment protein usage between type II and type III hypersensitivity
Type III uses large amounts whereas type II uses relatively small amounts
- Type III -
When neutrophils arrive to the adhered immune complex, they degranulate.
What is the name of the condition they cause?
Vasculitis
Inflammation of blood vessels
What is the basic difference in the clinical symptoms shown by type II and type III hypersensitivity?
Type II reactions show symptoms where the immune complexes are formed
Type III show symptoms where the immune complexes are deposited
- Type III -
Where are immune complexes often deposited?
Kidneys - where blood is filtered. This causes glomerulonephritis
Joints - plasma filtered to make synovial fluid. Responsible for rheumatoid arthritis
What is type IV hypersensitivity?
Delayed type hypersensitivity that is mediated by T cells
What are the two mechanisms of type IV hypersensitivity?
Cytokine mediated inflammation
T cell-mediated cytotoxicity
- Type IV -
Describe the mechanism of cytokine mediated inflammation
1) Antigen engulfed by APC and presented to T cell
2) T cell activated and turns into Th1 helper cell
3) Th1 cell releases cytokines & proliferates
4) Cytokines activate phagocytes
5) Phagocytes release various molecules that cause inflammation and damage local tissue
- Type IV -
In cytokine mediated inflammation, phagocyte activation by T cells causes inflammation and tissue damage.
Explain how
Phagocytes release:
- Pro-inflammatory cytokines: Oedema, redness and fever
- Enzymes, Compliment proteins and Reactive oxygen species to destroy antigen: Damage local tissue
- Type IV -
In the cytokine mediated inflammation mechanism, CD4+ T cells can also differentiate into Th17 cells instead of Th1 cells.
What causes this, and what do these Th17 cells do?
Dendritic cells release cytokines that cause activated CD4+ to change into Th17 cells instead of Th1
These Th17 cells release specific cytokines that attract neutrophils
- Type IV -
How does the T cell mediated cytotoxicity mechanism work?
1) Cells in our body present an auto-antigen
2) CD8+ killer T cell binds to auto-antigen
3) Stimulated release of perforin and granzymes
4) Perforin creates holes in membrane and granzymes enter and induce apoptosis ∴ cell death
- Type IV -
Under normal circumstances, T cell mediated cytotoxicity is necessary to protect our body. Why is this?
They kill cells that are infected with viruses ∴ present virus antigen
They kill cells that have mutated DNA ∴ present different antigens
What health conditions are associated with Type II hypersensitivity?
AIHA - Anaemia
ATP
Rheumatic fever
What health conditions are asociated with type III hypersensitivity
SLE - (Lupus)
Rheumatoid arthritis
Glomerulonephritis
What health conditions are associated with type IV hypersensitivity
Dermatitis
Rheumatoid arthritis
MS
Inflammatory bowel disease
What is immunological tolerance?
State of non-reactivity of the immune system towards a specific antigen
that would normally cause an immune response
What mainly causes immunological tolerance?
Prior exposure to the antigen