Hypersensitivities Flashcards
1
Q
Stimulus
for
Hypersensitivity
A
- 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
2
Q
Defects
Causing
Hypersensitivity
A
- Recognition
- Self-tolerance
- Targeting
- CTL killing via apoptosis = clean
- Macrophage killing via necrosis = tissue damage
3
Q
Type I Hypersensitivities
Sensitization Phase
A
Anaphylactic / Allergic / Asthma
Systemic anaphylaxis, allergic rhinitis, bronchial allergic asthma, food allergies, contact urticaria.
-
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
4
Q
Type I Hypersensitivities
Activation & Effector Phases
A
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
5
Q
Mast Cell Mediators
A
6
Q
Factors Affecting
Extent of Type I Hypersensitivity
A
- Site of antigen exposure
- Mast cell location
- Extent of reaction
7
Q
Systemic Anaphylaxis
A
- 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)
8
Q
Localized Anaphylaxis
A
- 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
9
Q
Asthmatic
Hypersensitivity Reaction
A
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
10
Q
RAST
(Radioallergosorbent test)
A
Measures antigen specific IgE in the serum.
11
Q
RIST
(Radioimmunosorbent test)
A
Measures total IgE in the serum
12
Q
Skin Prick Test
A
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.
13
Q
Eosinophil Levels
A
Normal = 1-3% eosinophils in peripheral blood.
Asthmatics often have 5-15% eosinophils.
14
Q
Anaphylactic Reaction
Physiological Role
A
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.
15
Q
Atopy
A
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
16
Q
Cytotoxic/membrane bound
Type II Hypersensitivity
Mechanism
A
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
17
Q
Transfusion Reactions
A
Type II Hypersensitivity
Type B blood into Type A individual → C’ activation → hemolysis.
18
Q
Rh incompatibility
A
Type II Hypersensitivity
Clearance of fetal Rh+ RBCs coated with maternal IgG by the reticuloendothelial system.
19
Q
Hyperacute allograft rejection
A
Type II Hypersensitivity
Preformed Ab binding to graft endothelium.
20
Q
Autoimmune Hemolytic Anemia
A
Type II Hypersensitivity
Auto-Ab bind to RBCs leading to destruction.
21
Q
Autoimmune Thrombocytopenia
A
Type II Hypersensitivity
Auto-Abs bind to platelets leading to destruction.
22
Q
Goodpasture’s Syndrome
A
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.
23
Q
Drug-induced Hemolytic Anemia
A
Type II Hypersensitivity
- Certain drugs (e.g. penicillin, quinidine) bind non-specifically to proteins on RBCs
- Hapten-carrier complexes can induce Ab production
- Ab bind to the drug bound to the RBC causing destruction
24
Q
Myastenia Gravis
A
Type II Hypersensitivity
Anti-acetylcholine receptor auto-Ab binds to the NMJ causing destruction and neurological deficits.
25
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.
26
Non-cytotoxic
Type II Hypersensitivity
Antibodies alters or interferes with normal cell function.
27
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.
Aut0-Ab called long-acting thyroid stimulating (LATS) autoantibodies.
28
Type III Hypersensitivity
(**_I_**mmune-complex Deposition)
Mechanism
\*\*Large doses of both Ag and Ab are required for a type III reaction.
* Ab bind small Ag forming immune complexes
* Complexes deposit near or within blood vessels
* Results in damage at the sites where they deposit
Distribution of the complexes determines the outcome of the reaction:
* _Localized reaction:_
* Immune complexes are formed in the tissues near the site of Ag entry in the presence of preformed antibodies.
* Commonly called the **_Arthrus reaction_**
* _Systemic reaction_
* Immune complexes in the blood deposit at different sites and cause damage
* blood vessel walls
* synovial membrane of joints
* glomerular membrane of the kidney
* Commonly called **_serum sickness_**
29
Arthrus Reactions
Localized reaction with **preformed** antibodies.
Injection of antigen into tissues.
Usually takes **4-8 hours.**
1. Subcutaneous or intradermal injection of Ag → **immune complexes** form in tissue
2. Activation of **complement** cascade → deposition of MAC and C3b / C5a / C3a release.
* MAC generally cannot kill nucleated cells but causes damage and inflammation.
3. C5a and C3a induce **mast cell** degranulation and increased vascular permeability → promotes increased accumulation of immune complexes at basement membrane
4. Clumping of **platelets** → release of clotting factors → microthrombi
5. **Neutrophils** are recurited primarily by C5a → attempts phagocytosis of immune complexes through C3b and Fc-associated opsonization
6. 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
30
Examples
of
Arthrus Reactions
* **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**
31
Immune Complex Clearance
Normal clearance of immuen complexes in the blood:
* C' activation
* C3b binding to the antigen-antibody complex
* Binding to the CR1 receptors on RBCs
* Immune complexes carried to the spleen and liver (reticuloendothelial system)
* "Vacuumed" from RBC by tissue-dwelling macrophages
32
Common Sites for Immune Complex Deposition
* kidney = glomerulonephritis
* joints = arthritis
* skin = rash
* arteries - vasculitis
33
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.
34
Pathology Involving
Immune Complexes
* _Autoimmune disease_
* **Systemic lupus erythematous (SLE)**
* See glomerulonephritis, arthritis
* **Rheumatoid Arthritis**
* Rheumatoid factor binding to IgG
* _Drug reactions_
* Penicillin and sulfonamides
* _Infectious disease_
* **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 skin causing rash
35
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
36
DTH
Role in Immunity
Activation of 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
37
Tuberculin-type Hypersensitivity
Ag → APC → TH1 → IFN-γ → MØ recruitment and activation → release of lytic enzymes and ROS by-products → painful area of induration and swelling at the site of injection of Ag
Takes 48-72 hours for 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_**
38
Allergic Contact Hypersensitivity
Allergic contact dermatitis.
Takes 48-72 hours.
Eczematous reaction at site of contact with sensitizing agent.
* Mechanism:
* Ag exposure
* Langerhan cells take Ag and present to T-cells at local lymph nodes
* Mononuclear cell infiltration of both the dermis and epidermis
* Macrophage activation & effector functions
* Edema of the epidermis and microvesicle formation
39
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
40
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.
41
Granulomatous Hypersensitivity
* associated with extensive tissue necrosis and fibrosis → tissue destruction
* usually results from persistence of intracellular pathogens within macrophages or long-lasting stimulating Ag
* functions to prevent infectious microbes from persisting in the circulation
APC → TH1 → IFN-γ & chemoattractants → mononuclear cell accumulation around blood vessels (_perivascular cuffing_) → failure to clear stimulus → release of toxic mediators → macrophage accumulate at site of Ag changing into epitheloid cells → macrophages and fibroblast proliferate and produce collagen → granuloma effectively walls off the antigen.
42
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
43
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.
44
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.
45
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.
46
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).
