Hypersensitivities Flashcards
Stimulus
for
Hypersensitivity
- Course of eradicating a disease
- granuloma formation in TB
- bacterial endocarditis following strep infection due to cross-reactivity / molecular mimicry
- By-product of introduction of agent for another purpose
- drug reaction
- food allergy
- Disorder in immune regulation
- auto-immune diseases
- SLE
Defects
Causing
Hypersensitivity
- Recognition
- Self-tolerance
- Targeting
- CTL killing via apoptosis = clean
- Macrophage killing via necrosis = tissue damage
Type I Hypersensitivities
Sensitization Phase
Anaphylactic / Allergic / Asthma
Systemic anaphylaxis, allergic rhinitis, bronchial allergic asthma, food allergies, contact urticaria.
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Sensitization Phase
- Ag exposure stimulates TH2 cell via IL-4
- T & B cell interaction results in IgE synthesis
- IgE binds to FCεRI receptors on tissue mast cells and circulating basophils ⇒ called priming/sensitizing mast cells & basophils
- Mast cells congregate near blood and lymphatic vessels, skin, and mucosal membranes
Type I Hypersensitivities
Activation & Effector Phases
Anaphylactic / Allergic / Asthma
Systemic anaphylaxis, allergic rhinitis, bronchial allergic asthma, food allergies, contact urticaria.
-
Activation Phase and Effector Phases
-
Early Phase Response
- Occurs within minutes and can last for ~ 1-2 hours
- Subsequent Ag exposure cross-links bound IgE on mast cells/basophils
- Exocytosis of granule contents mainly histamine (seconds - minutes)
- Smooth muscle contraction
- Small blood vessel dilation and vascular permeability
- Significant edema
- Sparse cellular filtrate mostly neutrophils
- Platelet activation
- Stimulation of sensory nerve endings
- Production of lipid mediators via arachidonic acid pathway (~20 mins)
- Synthesis of cytokines (minutes to hours)
-
Late Phase Response
- Generally preceded by clinically evident early-phase reaction
- Begins 2-8 hours after mast cell stimulation
- Peaks 6-9 hours after Ag exposure
- Takes 24-48 hours to resolve
-
Mast cell mediators prompt:
- Intense cellular infiltration
- Stimulation of lymphocytes, eosinophils, neutrophils, basophils, and macrophages
- Additional vasopermeability
- Smooth muscle contration
- Can cause permanent changes in tissue structure
-
Early Phase Response
Mast Cell Mediators
Factors Affecting
Extent of Type I Hypersensitivity
- Site of antigen exposure
- Mast cell location
- Extent of reaction
Systemic Anaphylaxis
- Caused by systemic mast cell degranulation
- Results in profound shock-like state
- Causes:
- insect stings
- drugs
- foods
- Routes:
- injected - effects in minutes
- ingested - requires longer latent period but can last longer
- Symptoms due to systemic vasodilation and smooth muscle contraction (airway and GI)
Localized Anaphylaxis
- Limited to specific tissue or organ system
- Involves IgE-mediated mast cell degranulation
- Ususally occurs in GI tract
- Absorption can allow enough Ag into blood allowing systemic sx
- Includes:
- Allergic rhinitis
- Contact urticaria
- Food allergies
- Some forms of asthma
Asthmatic
Hypersensitivity Reaction
Localized Type I Hypersensitivity
Biphasic change in FEV1
Early Phase:
- Inhaled Ag causes mast cell degranulation in lower respiratory tract
- Mediator release
- Smooth muscle contraction
- Edema
- Characteristic drop in FEV1 during 1st hour
Late Phase
-
Lymphocytes (especially TH2) infiltrate
-
IL-4
- Increased IgE production
- Mast cell development
- Mucus production
- Drives TH2 response
-
IL-5
- Induces eosinophil differentiation and activation
-
IL-13
- same effect as IL-4
-
Eotaxin
- eosinophil recruitment
-
IL-4
-
Eosinophils infiltrate
- Either a primary or secondary effector cell in causing respiratory epithelium damage
- Through deposition of granule proteins (MBP)
- Increases mucus production
- Alters matrix formation
- Cytokine production
- Lipid mediator release
- Either a primary or secondary effector cell in causing respiratory epithelium damage
- Second drop in FEV1 follows 4+ hours later and continues for 12+ hours while cellular infiltrates accumulate
- Induces lung hypersensitivity
RAST
(Radioallergosorbent test)
Measures antigen specific IgE in the serum.
RIST
(Radioimmunosorbent test)
Measures total IgE in the serum
Skin Prick Test
Skin test for allergy that usually correlates with a positive RAST test for that allergen.
Small amount of Ag introduced by either intradermal injection or superficial scratching.
Induces degranulation of local mast cells and mediator release leading to a wheal-and-flare reaction.
Eosinophil Levels
Normal = 1-3% eosinophils in peripheral blood.
Asthmatics often have 5-15% eosinophils.
Anaphylactic Reaction
Physiological Role
Mast cells / IgE / eosinophils involved in defense against helminthic parasites (worms) and ectoparasites (ticks).
- Parasites in the gut stimulate IgE & IgG production by GALT.
- Local mast cells become sensitized and activated.
- Degranulation causes edema and attracts inflammatory cells.
- Eosinophils can kill the parasite or make survival difficult.
Atopy
The genetic predisposition to develop allergies e.g. make IgE.
- Multifactorial inheritance
- Candidate genes
- IL-4 / IL-5
- Enviromental factors which may affect allergy development:
- pollution
- increased/altered Ag exposure
- maternal effects
- hygeine hypothesis
Cytotoxic/membrane bound
Type II Hypersensitivity
Mechanism
Immune reactions damage the cell or membrane where Ab is attached.
or
Components covalently bound to the cell membrane (penicillin and quinidine) induce an immunogenic response.
Can lead to cell mediated damage:
- Phagocytosis:
- opsonized targets in tissues removed by local phagocytes
- opsonized targets in the blood removed by fixed macrophages in the spleen and liver
- Complement
- induces osmotic lysis of RBCs
- PCN breaks down to form haptens which bind to RBCs causing Ab binding resulting in hemolysis/anemia
- damages host tissues resulting in inflammation
- induces osmotic lysis of RBCs
- ADCC
- NK cells, neutrophils, macrophages, and other cells of innate immune system damages or kills host tissues
Transfusion Reactions
Type II Hypersensitivity
Type B blood into Type A individual → C’ activation → hemolysis.
Rh incompatibility
Type II Hypersensitivity
Clearance of fetal Rh+ RBCs coated with maternal IgG by the reticuloendothelial system.
Goodpasture’s Syndrome
Type II Hypersensitivity
Auto-Ab react against the basement membrane of the glomerulus leading to glomerulonephritis and tissue destruction.
Immunofluoresence with a confulent “lacy” pattern.
Arthrus Reactions
Localized reaction with preformed antibodies.
Injection of antigen into tissues.
Usually takes 4-8 hours.
- Subcutaneous or intradermal injection of Ag → immune complexes form in tissue
- Activation of complement cascade → deposition of MAC and C3b / C5a / C3a release.
- MAC generally cannot kill nucleated cells but causes damage and inflammation.
- C5a and C3a induce mast cell degranulation and increased vascular permeability → promotes increased accumulation of immune complexes at basement membrane
- Clumping of platelets → release of clotting factors → microthrombi
- Neutrophils are recurited primarily by C5a → attempts phagocytosis of immune complexes through C3b and Fc-associated opsonization
- Phagocytosis is unsuccessful → frustrated phagocytes release superoxide radicals & proteolytic enzymes into tissue → local destruction of the internal elastic membrane → tissue damage and capillary damage causing non-blanching erythema and ulceration
Serum Sickness
Tends to develop with antigen excess as the small immune complexes that form do not efficiently activate complement and are not readily cleared.
- If preformed antibodies present, reaction can take minutes to a few hours to develop.
- In the absence of preformed antibody, time needed for Ab synthesis and effects usually seen 8-12 days after Ag exposure.
Type IV Hypersensitivity
(Delayed type hypersensitivity, DTH)
Sensitization Phase
(1-2 weeks)
- Initial exposure to Ag leads to T-cell proliferation and activation.
- Ag usually extracellular or from phagosome most likely on MHC class II
- Requires both signals (TCR:MHC II & B7:CD28)
- IL-2 dependent
- Overt hypersensitivity reaction does not occur because it takes 1-2 weeks to generate enough T cells.
- TDTH cells are mostly TH1 but sometimes TC cells involved
Effector Stage
(48-72 hours)
- Pre-existing memory TDTH cell activated by subsequent Ag exposure.
- Activated TDTH cells produce many cytokines
- IL-2
- IL-3
- GM-CSF
- IFN-γ
- Macrophage “specific” chemokines (MCAF, MIF)
- Recruited/activated macrophages generate ROIs and lytic enzymes
- Some leak out and damage surround tissues
Agents Inducing
Contact Hypersensitivity
Common agents that induce contact hypersensitivity:
-
Salts
- Most likely alter the conformation of self-peptides in the groove (Ag appears foreign)
- poison ivy - urushiol in plant leaves
- poison oak
- nickel salts
- chromate
- dinitrochlorobenzene
- rubber accelerators
- some drugs (often topical abx)
-
Haptens
- Able to penetrate the epidermis
- Conjugates to proteins found within the skin
- Hapten-protein conjugate processed and presented on class II MHC by Langerhan cells to T-cell
Types of Contact Dermatitis
- Can be caused by different types of reactions or a mixture of different hypersensitivity reactions.
- Multiple hypersensitivities can cause similar manifestations.
- A single event can have multiple underlying mechanisms.
Structure of Granuloma
Inside → Out
- Zone of necrosis
- Surrounding core of macrophages and epithelioid cells
- Lymphocytes surround structure producing IFN-γ and GM-CSF
- Often contain giant cells
- End-stage macrophages after long-term IFN-γ and GM-CSF stimulation
Type I Hypersensitivity
Summary
Mediated by: IgE (humans)
Onset: Early phase 2-30 minutes, late phase 2-8 hours (continues 24-72 hours)
Action site:
Systemic: reflects normal mast cell distribution
Local: effected tissues (e.g., upper and/or lower respiratory tract, GI tract, and skin)
Typical reactions: systemic anaphylaxis, allergic rhinitis (hay fever), bronchial asthma, some food allergies
Mechanism: An IgE-mediated-hypersensitivity reaction can often be viewed as consisting of two phases:
Early phase - mast cell degranulation and the release of mediators of anaphylaxis
Late phase - cellular infiltration including lymphocytes, eosinophils, macrophages, basophils, & neutrophils.
Type II Hypersensitivity
Summary
Mediated by: Circulating antibody (generally IgM or IgG rarely IgA) which can bind a membrane-bound antigen
Onset: Immediate (minutes to 5-8 hours with preformed antibodies)
Action site: Cell membranes on blood cells or tissues
Typical reactions: Transfusion reactions, hemolytic disease of the newborn, hyperacute allograft organ rejection, certain drug reactions, some autoimmune diseases.
Mechanism: Circulating-antibody binds to a cell-bound antigen. This leads to complement fixation, ADCC (e.g., neutrophils, macrophages and NK cells) and/or changes in cell function.
Type III Hypersensitivity
Summary
Mediated by: large doses of antigen combine with IgG or IgM
Onset: Preexisting antibodies (minutes to 5-8 hours) or requiring antibody induction (6-12 days)
Action site: Local or perivascular tissues, vascular endothelium and glomerular basement membrane
Typical reactions: Acute inflammatory reactions, vasculitis, serum sickness, Arthurus reaction, certain drug reactions
Mechanism: Large doses of antigen react with high titers of antibodies. The resulting SOLUBLE antigen-antibody complexes overwhelm existing mechanisms of Ag-Ab clearance. This leads to Ag-Ab disposition in a variety of tissues.
Type IV Hypersensitivity
Summary
Mediated by: CD4+ Th1 cells (predominantly) (occasionally CD8+ cells)
Onset: delayed 24-72 hours (following earlier sensitization)
Action site: skin and multiple organs
Typical reactions: Contact hypersensitivity, tuberculin reaction, granulomatous reactions, chronic allograft reaction (?)
Mechanism:
Sensitization phase: TH1 cells are stimulated by APCs and proliferate.
Effector phase: TH1 cell are re-stimulated and secrete a series of cytokines (IFN-γ, TNF-α, MCF, and MIF) that recruit and activate macrophages to the site of the reaction. These macrophages have increased phagocytic activity and release cytotoxic factors including lytic enzymes and by-products from the respiratory burst (ROIs).
