LECTURE 1 (Hypersensitivity) Flashcards
What is Hypersensitivity?
An immune response that causes disease and is exaggerated or inappropriate
What do all hypersensitivities have in common?
- First contact with antigen “sensitises” the host (generation of immune response + formation of antibodies and memory cells)
- Second contact -> hypersensitivity (patients develop symptoms from overreaction of immune response)
What are the four types of hypersensitivity reactions?
TYPE I, II, III and IV
Describe the TYPE I hypersensitivity reaction
also known as “allergies”
- Immediate reaction to an antigen (occur within minutes)
- Patients have pre-formed IgE antibodies (from primary exposure)
- Antibodies are bound to MAST CELLS -> antigen binds and cross links IgE antibodies -> Mast cell degranulation (releases contents into tissues -> symptoms)
Describe TYPE I hypersensitivity immunology
- Susceptible individuals make IgE to antigens whereas normal people do not (IgG does NOT trigger hypersensitivity response)
- IgE results from B cell class switching driven by Th2 cells (humour response)
- IL-4 is a KEY CYTOKINE for IgE production
- IgE does not lead to a complement reaction
What are the TYPE I symptoms?
- Skin = Urticaria (hives)
- Respiratory tract = Rhinitis/wheezing (asthma)
- Eyes = Conjunctivitis (itchy, red & watery)
- GI tract = diarrhoea
What is Anaphylaxis?
A systemic type I hypersensitivity reaction
SYMPTOMS:
- Itching, diffuse hives/erythema
- Respiratory distress from bronchoconstriction
- Hoarseness (caused by laryngeal swelling/edema)
- Vomiting, cramps, diarrhoea
- Shock and death
TREATMENT:
- Epinephrine (vasoconstrict -> increase BP & dilate bronchioles)
What is Atopy?
A genetic tendency to localised hypersensitivity developing symptoms such as Urticaria (hives), rhinitis and asthma
Additional information: There is usually a positive family history of a similar reaction
What are some TYPE I examples?
- Asthma
- Penicillin drug allergy
- Seasonal allergies (allergic rhinitis)
- Allergic conjunctivitis
- Peanut/shellfish allergy
What is the difference between TYPE I Early symptoms and Late symptoms?
EARLY SYMPTOMS
- occur within minutes
- caused by degranulation of cells -> release pre-formed mediators (histamine)
- caused by synthesis/release of leukotrienes & prostaglandins
- edema, redness & itching
LATE SYMPTOMS
- 6 hours later
- synthesis/release of cytokines -> leads to influx of inflammatory cells (neutrophils, eosinophils)
- induration of skin (area of hardness in skin)
What are the Type I mediators?
HISTAMINE
- vasodilation (warmth)
- increased permeability of venules (swelling)
- smooth muscle contraction (bronchospasm)
LEUKOTRIENES, PROSTAGLANDINS & THROMBOXANES
- derived from arachidonic acid
- produced in early & late phase of hypersensitivity reactions
How are Eicosanoids formed?
1) Lipids (cell membranes) are acted on by PHOSPHOLIPASE A2 to form ARACHIDONIC ACID
2) Arachidonic acid is acted on by LIPOXYGENASE to form LEUKOTRIENES + acted on by CYCLOOXYGENASE to form THROMBOXANES & PROSTAGLANDINS
What are the effects of PGE2 (prostaglandin)?
- Redness (caused by vasodilation)
- Edema (increasing vascular permeability)
- Fever (increasing set temp in hypothalamus)
- Pain (sensitise nerves)
What are the effects of PGD2 (prostaglandin)?
- Bronchoconstriction
- Draws Eosinophils into sites of TYPE I hypersensitivity reactions
What are the effects of LTC4/LTD4 (leukotrienes)?
- Vasoconstriction
- Bronchoconstriction
What are the effects of LTB4 (leukotrienes)?
Draws in neutrophils and eosinophils to sites of TYPE I hypersensitivity reactions
What is ECF-A (Eosinophil chemotactic factor of anaphylaxis)?
- TYPE I mediator
- preformed in mast cells
- attracts eosinophils in allergic reactions (some are pro-inflammatory)
What are some other TYPE I mediators?
- Serotonin (preformed in mast cells -> causes vasodilation)
- Platelet activating factors (causes bronchoconstriction)
- Natural proteases (e.g chymase, tryptase) released by mast cells that dissolve proteins
- Heparin (released by mast cells -> anticoagulant)
Describe allergy testing for IgE
Allergy testing for IgE to an allergen is done to see if a patient is sensitised to a particular substance
HOW IT WORKS
- pinprick/puncture of skin
- intradermal injection
POSITIVE RESPONSE: wheal formation (red, swollen mark)
Describe densitisation for IgE
Patients are desensitised to allergens if their response is dangerous or life threatening (sometimes done when pt needs drugs they really need for a condition)
HOW IT WORKS
1) gradually administer increasing amounts of allergen
2) Response changes IgE -> IgG
3) IgG antibodies can “block” mediator release by mast cells (“modified Th2 response”)
Describe the TYPE II hypersensitivity reactions
also known as “auto-immune reactions”
- Antibodies (IgG/IgM) are directed against tissue antigens and bind to normal structures
- Three mechanisms of tissue/cell damage (Phagocytosis, Complement-mediated lysis & Antibody-dependent cytotoxicity)
Describe the three mechanisms of tissue/cell damage in TYPE II reactions
- Phagocytosis (antibodies bind to cells -> cells consumed by phagocytosis -> phagocytes recognise Fc receptors on IgG antibodies or C3b receptors from complement pathway)
- Complement cascade (IgG or IgM can trigger CLASSIC COMPLEMENT CASCADE -> form MAC -> cell death)
- ADCC (natural killer cells bind Fc portion of IgG -> release contents -> destroy cells and tissues)
What are some TYPE II samples?
- Rheumatic fever (strep antibodies cross-react with cardiac myocytes -> myocardial damage/damage to heart valves)
- Exposure to wrong blood type (RBC lysis by circulating IgG -> can cause ERYTHROBLASTOSIS FETALIS)
- Autoimmune haemolytic anemia (methyldopa and penicillin = drugs bind to surface of RBCs, mycoplasma pneumonia = induces RBC antibodies)
- Pemphigus vulgaris = antibodies against desmosomes in epidermis
- Goodpasture syndrome (nephritic syndrome + pulmonary haemorrhage caused by antibodies against TYPE IV collagen)
- Myasthenia gravis (antibodies against ACh receptors
Describe TYPE III hypersensitivity reactions
Occur when Antigen-antibody (usually with IgG) complexes form -> activates complement cascade -> tissue/cell damage
TWO WAYS IN WHICH REACTIONS OCCUR
- Serum sickness (generalised)
- Arthus reaction (localised)
What is the difference between TYPE II and TYPE III hypersensitivity reactions?
TYPE II = antibodies directly attack tissues or cells
TYPE III = antibodies bind to small antigens and then deposit in the tissues as an antibody-antigen complex
What is Serum sickness?
A form of type III hypersensitivity reaction
- Immune complexes in plasma cause SYSTEMIC DISEASE (usually IgG/IgM since complement activators)
- Immune complexes deposit in various tissues (skin, kidneys and joints)
- Once deposited, trigger an immune response by complement activation -> trigger activation of macrophages and neutrophils (via Fc receptors)
What are the symptoms of Serum sickness?
- Urticaria or palpable purpura (from complex deposition on skin)
- Low serum complement levels (immune complexes consume complement proteins)
- Elevated sedimentation rate (from inflammation)
- Diffuse lymphadenopathy
- Acute glomerulonephritis (from complex deposition in kidneys)
- Lupus
What are some examples of “classic serum sickness”?
- Rabies/tetanus anti-toxin
- Rarely penicillin (drug acts as a “hapten” -> a small molecule that elicits an immune response -> antibodies can be formed and bind to penicillin and deposit in tissues)
- Monoclonal antibodies (rituximab, infliximab)
What is Arthus reaction?
A form of type III hypersensitivity reaction
- form antigen-antibody complexes in local tissue (usually on skin)
- Injection of antigen -> preformed antibodies in plasma/tissue will bind the antigen and form immune complexes LOCALLY
- Local immune complexes form 4-10 hours after injection -> once bound, complement activation, oedema and necrosis occur
- Can identify using IMMUNOFLUORESCENT STAINING (antibodies + complement in vessel wall -> deposited in the tissue and are causing the reaction)
What is the difference between TYPE I hypersensitivity reaction and Arthus reaction?
TYPE I reactions = occur within minutes and are caused by Mast cells and IgE antibodies
Arthur reactions = takes a few hours for immune complexes to bind -> once bound, complement activation, oedema and necrosis occur
Why is Arthus reaction faster than Serum sickness?
Since in Arthus reaction, antibodies are already present (antibodies made during the previous injections of the antigen)
What are some examples of Arthus reaction?
- Reported with skin injections (e.g Tetanus, Hep B vaccines) -> exposure of antigen to already existing antibodies might cause binding at site of skin injection -> swelling, redness at site hours after injection
- Hypersensitivity pneuminitis (patients with “farmer’s lung” have circulating antibodies -> inhale environmental antigens -> bind to tissue of lung -> cause Arthus reaction)
Describe TYPE IV hypersensitivity reactions
- Cell-mediated reaction
- Does not involve any antibodies at all
- Memory T-cell immune response
Describe an example of TYPE IV reaction
PPD test (for tuberculosis)
Administer a small amount of Tuberculin protein under the skin -> patients previously exposed to Tuberculosis will have memory T-cells that can recognise the Tuberculin antigen -> antigen presented by Antigen presenting cells (MHC II) where memory CD4 T-cells can recognise and respond -> Th1 response (cell-mediated response) -> IFN-gamma secreted (activate macrophages) + IL-12 secreted from macrophages which stimulates Th1 cells -> redness + induration 24 to 72 hours later
TYPE IV hypersensitivity reactions are similar to what?
Immune responses to many pathogens (e.g mycobacteria, fungi)
Which diseases are examples of TYPE IV hypersensitivity reactions?
- Contact dermatitis (e.g poison ivy) = chemicals attach to skin cells -> CD8 T-cells recognise those cells and attack skin cells -> erythema and itching -> occurs 12 to 48 hours after exposure
- Multiple Sclerosis (type IV reactions to myelin basic protein lead to demyelination)
