Exam 2: Hypersensitivities Flashcards
Hypersensitivity
An exaggerated or inappropriate immune response that causes damage to the tissue.
Stimuli
for
Hypersensitivity
The pathological effects may occur during:
-
The course of eradicating a disease
- Granuloma formation in TB
- Bacterial endocarditis following strep infection due to cross-reactivity / molecular mimicry
-
By-product of the introduction of agent for another purpose
- Drug reaction
- Food allergy
-
Disorder in immune regulation
- Auto-immune diseases
- SLE
Defects
Causing
Hypersensitivity
-
Recognition
- Discriminate self vs non-self or altered self
- Self-tolerance
-
Targeting
- Effector functions should target the threat with little damage to surrounding tissues
- CTL killing via apoptosis ⇒ clean
- Macrophage killing via necrosis ⇒ tissue damage
Hypersensitivity reactions result from the same ___ or ___ that are critical for host defense.
normal humoral or cell-mediated responses
Hypersensitivity
Types
ACID
- Type I: Anaphylactic / Allergy / Asthma
- Type II: Cytotoxic reactions (membrane-bound Ag)
- Type III: Immune-complex reactions
- Type IV: Delayed Type Hypersensitivity (DTH) reactions
Type I Hypersensitivities includes…
- Systemic anaphylaxis
- Allergic rhinitis
- Bronchial allergic asthma
- Food allergies
- contact urticaria
Type I Hypersensitivity
Overview
- Sensitization
- Activation
- Early phase response
- Late phase response
Type I Hypersensitivity
Sensitization Phase
IgE synthesis and binding to mast cells and basophils.
- Allergen exposure
- Stimulation of TH2 cell (via IL-4) and B cell interactions
- IgE synthesis
- IgE binds to high affinity FcεRI receptors on tissue mast cells and circulating basophils
- T½ of IgE is 2-3 days (serum) or months (bound)
- Site of sensitized mast cells
- Congregate near blood and lymphatic vessels
- Skin
- Mucosal membranes
Type I Hypersensitivity
Activation Phase
- Subsequent Ag exposure ⇒ cross-link of bound IgE on mast cells/basophils ⇒ activation
-
Activated mast cells:
- Exocytosis of granule contents mainly histamine (seconds - minutes)
- Production of lipid mediators via arachidonic acid pathway (~20 mins)
- Synthesis of cytokines (minutes to hours)
Type I Hypersensitivity
Early Phase Response
- Within minutes of mast cell degranulation ⇒ ~ 1-2 hours
- Mostly due to mast cell mediators (histamine) and products of arachidonic acid pathway
- Results in:
- Smooth muscle contraction
- Small blood vessel dilation
- ↑ vascular permeability
- Platelet activation
- Stimulation of sensory nerve endings
- See significant edema w/ sparse cellular filtrate, mostly neutrophils
Type I Hypersensitivity
Late Phase Response
- Generally preceded by clinically evident early-phase reaction
- Timing:
- Begins 2-8 hours after mast cell stimulation
- Peaks 6-9 hours after Ag exposure
- Takes 24-48 hours to resolve
-
Mast cell mediators stimulate:
- Intense cellular infiltration
- Stimulation of lymphocytes, eosinophils, neutrophils, basophils, and macrophages
-
Activation of leukocytes can cause:
- Additional vasopermeability
- Smooth muscle contraction
- Role in permanent changes in tissue structure w/ chronic Type I hypersensitivity
- Ex. cutaneous disase & asthma
Mast Cell
Granule Mediators
Preformed and released during degranulation
Effects seen within minutes
- Histamine (10% granule by weight)
- Serotonin
- Heparin
-
Proteases
- Tryptase
- Kinins
Histamine
Overview
-
Key mediator in the pathophysiology of allergic disease
- Esp. urticarial and rhinitis
- Binds 4 known receptors ⇒ H1, H2, H3, H4
- Leads to ↑ vasodilation and ↑ vascular permeability
H1 Binding
Effects
- Contraction of intestinal and bronchial smooth muscles
- ↑ vascular permeability
- ↑ mucus production by globlet cells
H2 Binding
Effects
- ↑ vascular permeability
- Vasodilation
Histamine
Clinical Effects
- Mucosal edema
- Rhinorrhea
- Hypotension
- Bronchoconstriction
- Abdominal cramping
- Gut hypermobility
- Itching
- Sneezing
- Angiogenesis
Mast Cell
Lipid Mediators
Generated from arachidonic acid.
Takes longer to start, effects last longer.
-
Prostaglandins
- Ex. PGD2
-
Leukotrienes
- Ex. LTC4 and LTD4
- Platelet-activating factor (PAF)
- Bradykinin
Prostaglandin
Effects
Smooth muscle contraction
(bronchoconstriction)
Leukotrienes
Effects
- ↑ vascular permeability
- Mucosal edema
- Hypotension
- ↑ mucus production
Platelet-activating Factor (PAF)
Effects
- Recruits basophils and eosinophils
- Platelet degranulation
- Microthrombi
Bradykinin
- ↑ vasodilation and vascular permeability
- Mucosal edema
- Hypotension
- Bronchial smooth muscle contraction
- Bronchoconstriction
Mast Cell
Cytokine Generation
- Varies significantly based on location and microenvironment
- Major role in:
- Regulating mucosal sites
- Recruitment of inflammatory cells
-
Includes:
-
IL-4 ⇒ TH2
- IgE production
- Mast cell proliferation
- Mucus production
-
IL-5 ⇒ eosinophils
- Eosinophil differentiation, recruitment, activation
-
TNF-α
- Shock-like reaction during systemic anaphylaxis
- TGF-β
- IL-3
- IL-6
- IL-8
- IL-13
- GM-CSF
-
IL-4 ⇒ TH2
Type I Hypersensitivity
Severity
The extent and consequence of a Type I reaction depends on:
- Site of antigen exposure
- Mast cell location
- Extent of reaction
Systemic Anaphylaxis
Mechanisms
- Caused by mast cell degranulation throughout the body
- Results in profound shock-like state, often fatal
- Occurs within minutes of a Type I Hypersensitivity reaction
-
Causes:
- Insect stings ⇒ bee, wasp, hornet, ant
- Drugs ⇒ PCN, insulin, antitoxins, IV dyes
- Foods ⇒ seafood and nuts
-
Routes:
- Injected ⇒ effects in minutes
- Ingested⇒ requires longer latent period but can last longer d/t continued absorption
- Symptoms due to systemic vasodilation and smooth muscle contraction
-
Most affected organ systems:
- Respiratory
- GI
- Blood vessels
- Skin
Systemic Anaphylaxis
Manifestations
- SOB and labored breathing
- Throat tightness
- Generalized warmth
- Headache
- Restlessness
- Drop in BP (shock)
- GI cramping / incontience
- Bladder cramping / incontinence
- Catastrophic hypothension or bronchiole constriction may lead to death within 10-20 minutes
Localized Anaphylaxis
- Limited to specific tissue or organ system
- Involves local IgE-mediated mast cell degranulation
- ~20% of the population in developed countries have some form
-
Includes:
- Allergic rhinitis
- Contact urticaria
- Food allergies
- Some forms of asthma
Allergic Rhinitis
“Hay Fever”
- Affects ~10% of US population
- Induced by mast cells in nasal mucosa and conjunctivae of eye
-
Symptoms:
- Watery exudates of nasal mucosa, conjunctivae, and URT
- Itching
- Sneezing
- Coughing
Contact Urticaria
Type I hypersensitivity of the skin characterized by hives
Food Allergies
- Involves mast cell degranulation in the upper and lower GI tract
- Absorption can allow enough Ag into the blood for systemic sx
- Asthma attacks
- Hives
- Systemic anaphylaxis
- Affects ~4% of US population
- Most often appear in infants and young children
- Can develop at any age to food eaten for years
- Most common foods are peanuts, tree nuts, soy, shellfish, fish, eggs
Asthmatic
Hypersensitivity Reaction
Localized Type I Hypersensitivity
Biphasic change in FEV1
Early Phase:
- Inhaled Ag causes mast cell degranulation in lower respiratory tract and arachidonic products
- Results in:
- Bronchoconstriction
- Airway edema
- Mucus secretion
- Inflammation
- Characteristic drop in FEV1 during 1st hour
Late Phase
-
Lymphocytes (especially TH2) infiltrate
-
IL-4
- ↑ 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
- FEosinophil recruitment
-
IL-4
-
Eosinophils infiltrate
- Either a primary or secondary effector cell in type I hypersensitivity-associated tissue damage
- ↑ mucus production
- ∆ matrix formation
- Through deposition of granule proteins (MBP)
- Cytokine production
- Lipid mediator release
-
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 ⇒ 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
Type II Hypersensitivity
Cytotoxic Mechanism
-
Immune reactions damage the cell or membrane where Ab is attached to:
- Integral part of cell membrane
- Components covalently bound to the cell membrane
- Penicillin and Quinidine
- Immunogenic response
- Penicillin and Quinidine
- 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
- Damages host tissues ⇒ inflammation
-
ADCC
- NK cells, neutrophils, and macrophages kill host cells
-
Phagocytosis
Transfusion Reactions
Type II Hypersensitivity
Ex. 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
**Complement is usually not involved because Ag sparsely distributed on RBC and cannot crosslink.
Hyperacute Allograft Rejection
Type II Hypersensitivity
Preformed Ab binding to graft endothelium
Autoimmune Hemolytic Anemia
Type II Hypersensitivity
Auto-Ab bind to RBCs leading to destruction
Autoimmune Thrombocytopenia
Type II Hypersensitivity
Auto-Abs bind to platelets leading to destruction
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
Drug-induced Hemolytic Anemia
Type II Hypersensitivity
- Penicillin & Quinidine break down to form haptens
- Haptens bind non-specifically to proteins on RBCs
- Hapten-carrier complexes can induce Ab production
- Ab binds to the drug bound to the RBC causing destruction
Myastenia Gravis
Type II Hypersensitivity
Anti-acetylcholine receptor auto-Ab binds to the NMJ causing removal from the membrane, destruction and neurological deficits
Pernicious Anemia
Type II Hypersensitivity
- Auto-Ab bind to intrinsic factor on intestinal mucosa causing destruction
- Intrinsic factor required for absorption of Vit B12
- Vit B12 necessary for RBC development
Type II Hypersensitivity
Non-cytotoxic Mechanism
Antibodies alters or interferes with normal cell function
Graves’ Disease
Non-cytotoxic Type II Hypersensitivity
Auto-Abs bind to the receptor on acinar cells for TSH → mimics TSH binding → unregulated activation of the thyroid → over-production of thyroid hormones
Auto-Ab called long-acting thyroid stimulating (LATS) auto-antibodies
Type III Hypersensitivity
“Immune-complex deposition”
Large doses of both Ag and Ab required
- Ab bind small Ag ⇒ immune complexes
- Deposit near or within blood vessels
- Results in damage at the sites of deposition
Distribution of the complexes determines the outcome of the reaction:
-
Localized reaction
- Immune complexes formed in tissues near site of Ag entry w/ preformed Ab
- Commonly called the Arthrus reaction
-
Systemic reaction
- Immune complexes formed in the blood and deposit at different sites causing damage
- Glomerular membrane of the kidney
- Blood vessel walls
- Synovial membrane of joints
- Skin
- Commonly called serum sickness
- Immune complexes formed in the blood and deposit at different sites causing damage
Arthrus Reaction
Mechanism
Localized reaction with preformed Ab
Injection of Ag into tissues
Usually takes 4-8 hours
- Subcutaneous or intradermal injection of Ag → formation of immune complexes in tissue
-
Activation of complement cascade
-
Deposition of MAC and C3b
- MAC generally cannot kill nucleated cells but causes damage and inflammation
- C5a / C3a released
-
Deposition of MAC and C3b
- C5a and C3a → mast cell degranulation → ↑ vascular permeability → ↑ accumulation of immune complexes at basement membrane
- Clumping of platelets → release of clotting factors → microthrombi
-
Neutrophils recruitment by C5a → attempts phagocytosis of immune complexes
- C3b and Fc-associated opsonization
-
Phagocytosis unsuccessful → frustrated phagocytes → releases superoxide radicals & proteolytic enzymes into tissue → local destruction of the internal elastic membrane → tissue damage and capillary damage
- Non-blanching erythema and ulceration
Arthrus Reactions
Examples
- Insect bites
-
Farmer’s lung
- Inhalation of thermophilic actinomycetes from moldy hay
-
Pigeon fancier lung
- Inhalation of serum protein in dust containing dried pigeon feces
-
Allergy desensitization injections
- Stimulates production of IgG that competes with IgE for Ag binding
Immune Complex Clearance
Normal clearance of immune complexes in the blood:
- Complement activation
- C3b binds Ab-Ag complex
- Binding to CR1 receptors on RBCs
- Immune complexes carried to the spleen and liver (Reticuloendothelial system)
- “Vacuumed” from RBC by tissue-dwelling macrophages
Serum Sickness
Mechanism
Occurs with antigen excess ⇒ small immune complexes ⇒ inefficient complement activation ⇒ poor clearance
- Ab binds Ag ⇒ immune complexes form
- Complexes in blood are not harmful
- Pathological effects manifest when deposited in tissues
Serum Sickness
Timing
If preformed antibodies present ⇒ takes minutes to a few hours to develop
Without preformed antibody ⇒ time needed for Ab synthesis ⇒ effects in 8-12 days after Ag exposure
Immune Complex
Deposition Sites
Deposit where there is turbulent flow:
- Kidney ⇒ glomerulonephritis
- Joints ⇒ arthritis
- Skin ⇒ rash
- Arteries ⇒ vasculitis
Immune Complex
Diseases
-
Autoimmune diseases
-
Systemic lupus erythematous (SLE)
- See glomerulonephritis, arthritis
-
Rheumatoid Arthritis
- Rheumatoid factor binds IgG ⇒ complement activation
-
Systemic lupus erythematous (SLE)
-
Drug reactions
- Penicillin and sulfonamides
-
Infectious diseases
-
Post-streptococcal glomerulonephritis
- Circulating complexes of Ab-StrepAg deposit in kidney
-
Hepatitis B
- Virus releases free Hep B surface Ag into blood to absorb neutralizing Ab
- Ab binds free Ag and deposit in the skin causing rash
-
Post-streptococcal glomerulonephritis
Type IV Hypersensitivity
“Delayed type hypersensitivity or DTH”
Sensitization Phase
(1-2 weeks)
-
Initial exposure to Ag leads to T-cell proliferation and activation
- TDTH cells are mostly TH1 but sometimes TC involved
- Ag usually extracellular or from phagosome
- Most likely on MHC class II
- Requires both signals (TCR:MHC II & B7:CD28)
- IL-2 dependent
- No initial reaction b/c it takes 1-2 weeks to generate enough T cells
Effector Stage
(48-72 hours)
- Pre-existing memory CD4+ TDTH cell activated by subsequent Ag exposure
- Activated TDTH cells produce 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
DTH
Role in Immunity
TH1 cells and macrophages in DTH response critical for control of intracellular pathogens.
-
Intracellular bacteria
- Mycobacterium tuberculosis
- Listeria monocytogenes
-
Intracellular viruses
- Herpes simplex
- Rubella
- Variola (smallpox)
-
Intracellular parasites
- Leishmania sp.
-
Intracellular fungi
- Pneumocytis carinii
- Candida albicans
DTH
Damage
-
Immune response is poorly focused
- Tissue damage common
-
Pathogen usually cleared rapidly
- Tissue damage minor, localized, and temporary
-
If pathogen is not cleared ⇒ prolonged DTH reaction
- Chronic inflammation & granulomas
Tuberculin-type
Hypersensitivity
Painful area of induration and swelling at the site of injection of Ag
Ag → APC → TH1 → IFN-γ → MØ recruitment and activation → release of lytic enzymes and ROIs
Takes 48-72 hours for a reaction
Clinical uses:
-
Test for previous exposure to an organism
- Effector cells need a much lower [Ag] for activation
- Test for immune competence ⇒ anergy test
Allergic Contact
Hypersensitivity
“Allergic contact dermatitis”
Eczematous reaction at site of contact with sensitizing agent.
Takes 48-72 hours.
Mechanism:
- Ag exposure
- Langerhan cells present Ag to T-cells at local lymph nodes
- Mononuclear cell infiltration of dermis and epidermis
- Macrophage activation & effector functions
- Edema of the epidermis and microvesicle formation
Contact Hypersensitivity
Agents
Common agents that induce contact hypersensitivity:
Salts
- Most likely alter the conformation of self-peptides in the groove (Ag appears foreign)
- Ex:
- Nickel salts
- Chromate
- Dinitrochlorobenzene
- Rubber accelerators
Haptens
- Able to penetrate the epidermis
- Conjugates to proteins found within the skin
- Hapten-protein conjugate presented on MHC class II to T-cell
- Ex:
- Poison ivy - urushiol in plant leaves
- Poison oak
- Some drugs (often topical abx)
Contact Dermatitis
Causes
- 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 in the same individual
Granulomatous Hypersensitivity
Overview
- Severe pathological effects involving T cell-mediated immunity
- Associated with extensive tissue necrosis and fibrosis → tissue destruction
- Usually results from persistence of intracellular pathogens within macrophages or long-lasting stimulating Ag
Granuloma
Function
Prevent infectious microbes from persisting in the circulation
- Ex: form calcified walls around TB finections in the lungs ⇒ Ghon complexes
- Can live for decades with TB isolated in granulomas
- ↓ TH function can lead to reactivation
- Aging
- Infection
- Cancer
- AIDS
Granuloma Formation
Mechamism
- Ag ⇒ APC ⇒ TH1 ⇒ IFN-γ & chemoattractants
- Mononuclear cells accumulate around blood vessels ⇒ perivascular cuffing
- Failure to clear stimulus
- Release of toxic mediators
- Mφ accumulate @ site of Ag
- Mφ ⇒ epitheliod cells
- Mφ and fibroblasts proliferate & produce collagen
- Walls off Ag through granuloma formation
Granuloma
Structure
Inside → Outside
- Central zone of necrosis
-
Mφ and epithelioid cells in surrounding core
- Often contain giant cells
- End-stage Mφ after long-term IFN-γ and GM-CSF stimulation
- Often contain giant cells
-
Lymphocytes surround the structure
- Produces IFN-γ and GM-CSF
Type I Hypersensitivity
Summary
Mediated by:
IgE
Onset:
Early phase 2-30 minutes, late phase 2-8 hours (continues for 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)
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.
Resulting SOLUBLE antigen-antibody complexes overwhelm existing mechanisms of Ag-Ab clearance.
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 cytokines (IFN-γ, TNF-α, MCF, and MIF) that recruit and activate macrophages to the site of the reaction.
Macrophages have increased phagocytic activity and release cytotoxic factors including lytic enzymes and by-products from the respiratory burst (ROIs).
