Session 1 Flashcards
Define hypersensitivity
“the antigen specific immune responses that are either inappropriate or excessive and result in harm to host”. The mechanisms underlying these aberrant immune responses are those employed by the host to fight infections
What are the types of triggers (antigens) that cause hypersensitivity reactions?
• Hypersensitivity to exogenous antigens:
Non infectious substances (innocuous)
Infectious microbes
Drugs (E.g. Penicillin)
• Hypersensitivity to intrinsic antigens:
Infectious microbes (mimicry)
Self antigens (auto-immunity)
What are the types of hypersensitivity reaction?
- Type I or immediate (Allergy) - IgE
- Environmental non infectious antigens
- Type II or antiBody mediated - IgG or IgM but mainly IgG - Against membrane bound antigens so often organ specific.
- Type III or immune Complexes mediated - IgG or IgM but mainly IgG - soluble antigen complex circulates in blood and where it deposits, is where disease will present.
- Type IV or cell mediated (Delayed)
- Environmental infectious agents and self antigens
Types I, II, and III are antibody mediated
What are the common features of hypersensitivity reaction?
All hypersensitivity types have these phases
• Sensitization phase
First encounter with the antigen. Activation of Antigen Presenting Cells and memory effector cells. A previously exposed individual to the antigen is said to be “sensitized”
• Effector phase
Pathologic reaction upon re-exposure to the same antigen and activation of the memory cells of the adaptive immunity
Describe type II hypersensitivity reactions
- Usually develops within 5-12 hr ftere xposure
- Involves IgG (mostly) or IgM antibodies
- Targets cell bound antigens:
- Exogenous: Blood group antigens, Rhesus D antigens
- Endogenous: self antigens
- Induces different outcomes:
- Tissue/cell damage
- Physiological change - change in function
Describe the mechanisms of type 2 hypersensitivity reactions
Antibodies recognise antigen on cell leading to complement activation which will drive the membrane attack complex which will punch holes in the cell membrane leading to cell lysis
The other way through which these cells will be killed via complement activation is through neutrophil recruitment/ activation (C3a/C5a) and then opsonisation (C3b) which will cause the neutrophils to kill the target cells
Examples of this are haemolytic disease of the newborn (HDN) - Antigen = Rhesus D and Transfusion reactions - Antigen= ABO system
The other way cells will be killed is through antibody-dependent cell cytotoxicity (NK cells)
- Autoimmune haemolytic anaemia (warm and cold) - antibody to red blood cells.
- Immune thrombocytopenia - antibody to platelets - Purpura
- Goodpasture’s syndrome - antibody against basement membrane of glomerula leading to glomerular nephritis
Physiological change:
Receptor stimulation
• Graves’ disease − Increased thyroid activity − Antigen = TSH receptor
Receptor blockade
• Myasthenia gravis − Impaired neuromuscular signalling − Antigen = Acetylcholine receptor
Give an example of disease caused by type II hypersensitivity (IgM) and describe its immune mechanism
Haemolytic transfusion reaction
- Life-threatening condition
- Shock, kidney failure, circulatory collapse, and death Immune mechanism
Mechanism:
- Incompatibility in the ABO or rhesus D antigens
- Donor RBC destroyed by recipient’s immune system
- RBC lysis induced by type II hypersensitivity involving by the naturally occurring antibodies (IgM)
What are the therapeutic approaches to type II hypersensitivity reactions
To deal with Tissue/Cell damage
- Anti-inflammatory drugs - associated with bad side effects.
- Prevents complement activation
- Plasmapheresis
- Remove circulating antibodies and inflammatory mediators
- Splenectomy
- Reduces Opsonisation/Phagocytosis when patient has autoimmune haemolytic anaemia or immune thrombocytopenia (patient )
- Intravenous immunoglobulin (IVIG)
- Causes IgG degradation
To do with physiological change
- Correct metabolism
- Antithyroid drugs in Graves’s disease or thyroidectomy
- Replacement therapy
- Pyridostigmine in Myasthenia gravis
What is Plasmapheresis therapy?
Plasma is removed and filtered to remove antibodies.
Used to treat Myasthenia gravis, Goodpasture’s syndrome and Graves’ disease
Short term relief and allows healing of damaged tissue
Describe Type III hypersensitivity
- Usually develops within 3-8 hr
- Involves immune complexes between IgG or IgM and antigens
- Targets soluble antigens
- Foreign (Infection)
- Endogenous (self antigens)
• Tissue damage caused by the deposition of immune complexes in host tissues
What are the key factors affecting intracellular pathogenesis in type III hypersensitivity reactions?
• Complex size
- Small and large size immune complexes cleared
- Intermediate size immune complexes harder to remove
• Host response
- Low affinity antibody favour intermediate size immune complexes
- Complement deficiency causes type 3 hypersensitivity. Opsonisation allows large immune complexes to bind to red blood cells so that they can be taken to the liver but withoutcomplement this is not possible.
Persistence of IC deposition causes multisystem disease
- Joint
- Kidney
- Small vessels
- Skin
How does the body remove immune complexes?
Large complexes are opsonised and then attach to red blood cells where they are then taken to the liver to be disposed of.
Intermediate sized immune complexes are deposited in tissues activate complement which starts opsonising the tissue which attracts neurtorphils which go on to damage the tissue.
Small immune complexes macrophages/monocytes
Give 3 examples of diseases caused by type III hypersensitivity reactions
Rheumatoid arthritis (self-antigen) - symmetrical peripheral inflammatory arthritis
- Antigen = Fc portion of IgG (75%)
- Articular and extra-articular features
- Episodes of inflammation/remission
- Poor prognosis factors
- <30 year-old
- High-titre of Rheumatoid factor which is the antibody against Fc portion of IgG
- Female
- DR4 allele
- Joint erosions
Glomerulonephritis (infectious)
Caused by:
- Bacterial endocarditis
- Hepatitis B infection
(they cause long term systemic production of the microbe which tends to cause intermediate immune complex production which end up in the kidney)
Systemic lupus erythematosus
- Antigen = Double stranded-DNA
- Most prevalent immune complexes disease
- Ratio female:male (9:1)
- 40-60% patients with cardiac, respiratory, renal, joint and neurological features
- Repeated miscarriage
- Every patient is unique
Describe type IV hypersensitivity reactions
- Usually develops within 24-72hr
- Involves lymphocytes and macrophages
- Different subtypes (clinical outcomes)
- Contact hypersensitivity
- Tuberculin hypersensitivity
- Granulomatous hypersensitivity
What are the mechanisms of tissue destruction in type IV hypersensitivity reactions?
Antigen presenting cells and macrophages in the sensitisation phase trigger a T cell response (TH1 response) so activate CD8 and cytotoxic T lymphocytes.
In the effector phase the TH1 will remmeber the microbe and so macrophages will be activated which will recruit more TH1 at the site and go onto form a granuloma.
Compare Hashimoto’s disease versus Graves’ disease
Hashimoto’s disease involves immune destruction of the thyroid gland by tissue infiltration of CD4+/CD8+ T cells and is a type IV hypersensitivity reaction which leads to hypothyroidism. Treatment is giving atient lifelong thyroxine.
Grave’s disease is a physiological increase in thyroid function caused by a type II hypersensitivity reaction as antibodies bind to TSH receptors and stimulate thyroid cells causing hyperthyroidism. Treatment is anti thyroid medication, plasmapheresis or thyroidectomy in order of commonality.
Why do people have allergies?
Origin of mast cells and tissue distribution
Mast cells produced by bone marrow. Progenitor enters blood and matures in the tissue and you can tell it has matured by the presence of the FcϵR1 receptor and this is where the IgE will bind. Mature due to stem cell factor/
Strategic location:
- Most mucosal and epithelial tissues = gastrointestinal tract, skin, respiratory epithelium
- In connective tissue surrounding blood cells
Effeicient against parastitc infections which these areas are commonly attacked by.
Describe the immune mechanism of allergic reaction
First exposure will drive a TH2 response and produce IgE against the allergen which will bind against the FcϵRI receptor of the mast cell. The Ige will bind systemically to all mast cells arming them ready for next exposure. In the subsequnt exposure, after sensitization, the allergen will crosslink to the IgE bound to the mast cell in a process called IgE cross linking. which will then activate the mast cell causing it to degranulate. This will happen wherever the mast cells are activated, so if you only have a local exposure then you will have a local response but if you have a systemic exposure you will have systemic response.
Mast cells are mostly present in the muscos membranes and blood vessels so in the vessels you will have increased vascular permeability, vasodialtion and lose some blood volume. If activated in the lungs you will have brocnhoconstriction.There can aslo be mast cell activation in the heart.
How does an allergic reaction manisfest in the skin?
Urticaria
Characerised by wheals (white, raised and itchy area) and flares (erythetamous area caused by vasodilation)
Caused by mast cell activation within the epidermis
Mediators = Histamine and leukotrienes/cytokines
If prolonged and chronic exposure you will end up with atopic dermatitis and eczema
How does an allergic reaction manifest in the face?
Angioedema
Non-itchy swelling
Caused by mast cell activation in the deep dermis.
Mediators = Histamine and bradykinin
Lip, eyes, tongue and upper respiratory airways can all be affected
If aiways affected, it can be life threatening.
What are the signs and symptoms of anaphylaxis?
Other allergic mediated diseases?
