4.8 Hypersensitivity Flashcards
What is meant by hypersensitivity?
Immune reaction that damages the body rather than protecting it from infection
What is the name of type I hypersensitivity?
Immediate/anaphylactic hypersensitivity
What are type I hypersensitivity reactions mediated by?
IgE antibodies
What is type I hypersensitivity triggered by?
Multivalent environmental antigens (allergens)
What 2 phases does type I hypersensitivity occur in?
Sensitisation
Re-exposure leading to anaphylaxis
Which 3 factors influence the initial sensitisation of the immune response to allergens?
Genetics, age, environment
Outline the sensitisation phase of type I hypersensitivity
APC present antigen and co-stimulatory molecule to T cell
Naive T cell becomes primed and differentiates into TH2 cell
TH2 cells release IL4 and 12 to promote class switching from IgM to IgE, and IL5 which activates eosinophils
IgE then bind FcE receptors on mast cells
Outline what happens in second exposure in type I hypersensitivity
Allergen binds to IgE on mast cells, crosslinking two IgE molecules
This causes rapid degranulation, releasing pro inflammatory mediators (histamines, cytokines, leukotrienes, prostaglandins)
What effects does histamine have?
Binds to H1 receptors
Causes bronchoconstriction, vasoconstriction, increased vascular permeability
What effects do leukotrienes have?
Smooth muscle contraction
Recruit neutro/eosinophils/mast cells after allergen is cleared
What happens if an allergen encounters cell bound IgE?
Rapid cross linking of IgE and degranulation of the mast cell
What happens in the early phase of type I hypersensitivity?
Effects of molecules released in mast cell degranulation
When does the early phase of type I hypersensitivity occur?
Few minutes after second exposure
What happens in the later phase of type I hypersensitivity?
Recruitment of neutrophils
When does the later phase of type I hypersensitivity occur?
Within a few hours
What happens in the late phase of type I hypersensitivity and when?
Eosinophils are recruited and TH2 cells are present
3-4 days after exposure
Which of an anaphylactic shock reaction or immune complex reaction requires more antigen to trigger?
Immune complex requires more antigen
List 3 treatments for type I hypersensitivity
Antihistamines – reduce bronchoconstriction and vascular permeability
Corticosteroids – decrease inflammatory response
Adrenaline – cause vasoconstriction
What causes anaphylactic shock?
Decrease in blood supply to vital organs (e.g. the brain) due to increased vascular permeability and increased airway constriction
What is the name of type II hypersensitivity?
Antibody mediated cytotoxic hypersensitivity
What does type II hypersensitivity involve?
The destruction of cells/tissue by IgG or IgM antibodies that bind to antigens present on the surface of normally healthy cells
What are examples of type II hypersensitivity reactions?
- Graves disease – antibodies bind to thyrotrophin receptor resulting in the over production of thyroid hormones
- Haemolytic disease of newborn – maternal antibodies can cross the placenta and destroy fetal red blood cells
- Immune thrombocytopenia – antibodies develop against platelets
What are the three mechanisms by which type II hypersensitivity reactions can occur?
- Anti-receptor activity
- Antibody dependant cell mediated cytotoxicity
- Classical activation of the complement cascade
Outline the first mechanism of complement activation in type II hypersensitivity
IgM/IgG binds an antigen that is bound to the surface of a healthy cell and activates complement
C1 binds Fc region of antibody and recruits other complement proteins
The proteins that are cleaved are chemotactic – attract neutrophils
Neutrophils degranulate and release enzymes that produce ROS, causing cell death
What enzymes do neutrophils release when they degranulate?
Myeloperoxidase, peroxidase, proteinase 3
Outline the second mechanism of complement activation in type II hypersensitivity
Complement proteins form membrane attack complexes
MACs create holes in the cell membrane, causing cell death by water influx
Outline the third mechanism of complement activation in type II hypersensitivity
C3b binds IgG antibodies coating a cell
Cell becomes opsonised and targeted for phagocytosis
Antibody-antigen complex and cell encounters phagocytes in the spleen
Phagocyte binds Fc tail or C3b, engulfing the cell
Outline antibody dependent cell-mediated cytotoxicity as a cytotoxic mechanism of type II hypersensitivity
NK cells recognise the antigen-antibody complex, specifically the Fc tail
Thus they release granules that contain perforin
Perforin forms pores in the cell membrane which allow granzymes and granulysin to enter and trigger apoptosis
Inflammatory mediators, chemokines and cytokines are also released
Outline antibody-mediated cellular dysfunction
Antibody stops antigen from binding receptor
How does antibody-mediated cellular dysfunction work in myasthenia gravis?
Antibody blocks Ach receptors, thus muscles weaken over time
How does antibody-mediated cellular dysfunction work in graves disease?
Antibody targets and binds TSH receptors on thyroid follicular cells, causing overproduction of thyroid hormone
How does type 2 hypersensitivity cause tissue damage?
Local or systemic inflammation
Cell depletion thus loss of function
Imbalance in organ function
How do you test for autoimmune haemolytic anemia?
Direct coomb’s test
Antibodies are separated from plasma and mixed with coomb’s reagent which is anti-human globulin (antibodies against human antibodies)
If agglutination occurs, this indicates presence of antibody
What happens in type III hypersensitivity?
When immune complexes cannot be cleared and are thus deposited in blood vessel walls and tissue, causing inflammation and tissue damage
What is an immune complex?
Soluble antigens bound to antibody
(i.e. non-cell bound antigen-antibody complexes)
Why do immune complexes deposit in blood vessel basement membranes?
The small complexes are less immunogenic, thus less attracted to macrophages and less easily removed
What is the difference between complement activation in type 2 and type 3 hypersensitivty?
Type III uses complement proteins in large amounts compared to type II
What issues can type III hypersensitivity lead to?
Fever, rash, protein in blood, joint pain
Glomerulonephritis – kidney
Arthritis – joints
Vasculitis – blood vessel walls
What effect do C3 and C4 have in type III hypersensitivity?
They act as chemokines by attracting neutrophils to the side
What do neutrophils do when they arrive at the immune complexes in type III hypersensitivity?
They degranulate and result in tissue necrosis and vasculitis
What happens in systemic lupus erythmatosus?
IgG is produced against DNA self-antigens released from damaged cells
Thus IgG-DNA autoantigen complexes form and remain in blood vessels, depositing on the basement membrane
When deposited, they activate the complement system
What happens when complement is activated in systemic lupus erythmatosus?
Complement proteins act as:
Anaphylatoxins – increase vascular permeability, leading to oedema
Chemokines – recruit neutrophils which degranulate, releasing enzymes that produce ROS, causing vasculitis
What types of antigens cause type 3 hypersensitivity?
Autoantigens
Foreign antigens (e.g. from persistent infection)
Describe serum sickness
Patient given serum with anti-venom antibodies
Exposure to foreign antibody in serum triggers B cells to differentiate into plasma cells and produce IgG against the foreign antibody
If the serum is given a second time, IgG forms immune complexes with the anti-venom antibodies, causing vasculitis and tissue necrosis
What is a membrane attack complex?
Fragments of the complement system form a complex which attaches to the cell surface membrane
This creates a channel that disturbs the osmotic integrity of the cell, causing lysis
Why do immune complexes not initiate complement cascade?
Classical complement pathway involves formation of MAC which occurs in cell walls, whilst immune complexes are free floating
What are the primary cells involved in type IV hypersensitivity reactions?
T cells
What causes type IV hypersensitivity?
CD8 T cells releasing cytotoxic granules
CD4 T cells releasing cytokines
APCs presenting antigens
Outline the sensitisation phase in type IV hypersensitivity
Dendritic cells carry antigen to draining lymph node
CD4+ T cells recognise antigen and bind MHCII with TCR and CD4 receptor
Dendritic cell releases interleukins, causing differentiation into Th1 cells
Th1 cells release IL-2 for the proliferation of other T cells and IFN-gamma for macrophage activation
What do activated macrophages do in type IV hypersensitivity?
Release pro-inflammatory cytokines, causing leaky endothelial barriers and immune cell recruitment
Release lysosomal enzymes, complement proteins and ROS, causing tissue damage
What’s the most common example of type IV hypersensitivity and what happens?
Contact dermatitis due to poison ivy
Small molecules urushiol acts as hapten and binds proteins in skin
Upon re-exposure, memory T cells release cytokines that promote pro-inflammatory activation of macrophages, causing oedema, swelling and lesions
What do active macrophages release?
Pro-inflammatory cytokines like TNF, IL-1 and IL-6
Which Interleukin has an autocrine effect?
IL-2
The test for what infection is conducted via the means of a type 4 hypersensitivity reaction?
Tuberculin skin test, where a protein from mycobacterium tuberculosis is injected into the skin
In a positive test – TB-specific TH1 cells migrate to site of injection, cause induration (skin becomes thick and hard)
Why are type IV hypersensitivity reactions called the delayed type?
It takes 48-72 hours to recruit TH1 cells to the site
In which auto-immune disease do patients develop IgGs against DNA or proteins present in the nucleus, forming persistent immune complex deposits and a variety of pathologies?
Systemic lupus erythematosus
What symptoms can immune complexes not being efficiently cleared lead to?
Symptoms such as fever, rashes, joint pain or protein in the urine
What needs to occur before T cells can initiate type IV?
Sensitisation phase where antigen is presented to naive T cells by antigen presenting dendritic cells
Results in the generation of antigen specific memory T cells
What systemic diseases are type IV hypersensitivity involved in?
Multiple sclerosis – Th1 cells damage myelin around nerve fibres
Inflammatory bowel disease – Th1 cells cause inflammation in intestinal lining
Give an example where TH2 cells cause type IV hypersensitivity
Asthma, where allergens cause Th2 overreaction
This produces soluble mediators, leading to bronchoconstriction
What other antigens can cause type IV hypersensitivity?
Nickel salts, hair dyes, intracellular pathogens
Give 3 examples where CD8+ T cells cause type IV hypersensitivity
Type 1 diabetes mellitus – attacks pancreatic islet cells
Hashimoto’s thyroiditis – attacks thyroid epithelial cells
Graft rejection – destruction of transplanted cells
