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
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
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 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
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
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
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
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).
