B3.021 - Hypersensitivity Flashcards
What is a hypersensitivity reaction
Injurious or pathologic immune reactions
What are two mechanisms of hypersensitivity
- ) An immune response to a microbe or environmental allergy causes tissue injury due to repeated or poorly controlled reactions
- ) Failure of self tolerance when an immune response is generated
What is type 1 HS
Immediate hypersensitivity mediates by IgE binding to mast cells
What is type 2 HS
Antibody IgE mediated cell or tissue destruction
What is type 3 HS
Antibody/antigen complex deposition causing inflammation and tissue injury
What is type 4 HS
T cell mediated
Which type of HS is true allergy or “atopy”
Type 1
Type 1 HS affects what percentage of people
10-20%
What diseases are considered Type 1 HS
- ) Allergic rhinitis/conjunctivitis
- ) Atopic asthma
- ) Atopic asthma
- ) Atopic dermatitis
- ) Anaphylaxis
- ) Venom allergy
What is the sensitization phase
First exposure to an allergen protein or chemical that binds proteins (haptens)
In a true IgE mediated immediate hypersensitivity what shouldn’t happen
a reaction to the first exposure to anything, only on a subsequent exposure
Aberrantly, Tfh and Th2 cells cause what using which ILs
B cells to stimulate class switching IgE against the allergen via IL-4, IL-13
IgE to the allergen is produced long term by what
Plasma cells, binds to the FCeR1 high affinity IgE receptors on mast cells, coating mast cells with IgE to that particular allergen
What is the elicitation phase
the hypersensitivity reaction upon repeat exposure, only in a person who’s sensitized
How does type I HS work with regards to mast cells and IgE
Allergen cross-links the IgE on the mast cell FceR1 high affinity IgE receptors which activates the mast cell and prompts release of its contents
What contents of the mast cell are released upon activation during T1 HS
Vasoactive amines, lipid mediators, cytokines
What mast cell contents cause symptoms immediately
vasoactive amines, lipid mediators
What content of mast cells causes symptoms in a delayed fashion
Cytokines
What is the immediate response to T1 HS
Increased vascular permeability
smooth muscle contraction
What happens in the late phase of T1 HS
Tissue injury with repeated bouts
Mediated by cytokines, recruit neutrophils and eosinophils
Where are mast cells located
In all connective tissues, adjacent to blood vessels
How are mast cells activated
Locally depending on allergen point of entry
What is FceR1
a high affinity receptor present on mast cells and basophils
What do 3 polypeptide chains do in T1 HS
1 binds to Fc portion of the e chain, 2 are signaling proteins
What is mast cells role in T1 HS
Allergen cross links two IgE molecules causing degranulation, synthesis, and secretion
ITAM phosphorylation occurs activating what
signaling pathways:
Release of preformed mediators
Arachidonic acid metabolism secreting lipid mediators
Activation of cytokine transcription
What are mast cell mediators
Histamine
Proteases
Prostaglandins
Leukotrienes
What are cytokine mediators
TNF
IL-4
IL-5
What are some immediate hypersensitivity treatments
Antihistamines Epinephrine Corticosteroids LT receptor antagonists Phosphodiester inhibitors Desensitization Cromolyn
What do antihistamines do
reduce potential for histamine to bind and cause symptoms
What are some first gen H1 antagonists
Cause sedation, short acting
Cyproheptadine, diphenhydramine, hydroxyzine, doxepin
What are some 2nd gen H1 antagonists
Cetrizine, levocetirizine, loratadine, desloratiadine, fexofenadien
What are some H2 antagonists
Receptors mostly in the gut
Ranitidine, famotidine
Mostly used for indigestion/heartburn but could be added to an H1 antagonist for allergy treatment
What does epinephrine do
1st line anaphylais,
Vascular smooth m. contraction, increased cardiac output, inhibits bronchial smooth muscle contraction, stabilizes mast cells
What do corticosteroids do
reduce inflammatory mediator production, stabilize mast cells, reduce eosinophils
* inhaled topically and oral
What do LT receptor antagonists do
reduce inflammation and relax bronchial smooth muscle
What doe phosphodiester inhibitors do
relax bronchial smooth muscle (inhaled)
What is desensitization
repeated increasing dose of allergens to help the system overcome allergy
How does desensitization work
Inhibits IgE prod
Allergy shots
Oral desensitization for food allergies
What does cromolyn do
inhibits mast cell degranulation
What are some monoclonal antibodies used for treatment of immediate hypersensitivity
Anti IgE therapy
Anti IL-5 therapy
Anti IL-4,13
How does anti IgE therapy work
binds/inhibits IgE so ti cannot bind to the receptors down regulation of the FceR1 on mast cells
What is an anti IgE therapy rug
Omalizumab injectable
What does anti IL-5 therapy do
binds/inhibits IL-5 to reduce eosinophil production and survival
What are some IL-5 drugs
Mepolizumab, reslizumab, benralizumab
What does anti IL-4,13 do
binds and inhibits shared receptor, reducing inflammation and decreasing the effects of both products
What is an anti IL-4,13 drug
Dupilumab, atopic dermatitis, asthma studies pending
Can you be allergic to more than one thing?
yes, once you are atopic you are more prone to other atopic sensitizations
What plays a role in allergy development?
Genetics, environment
What do type 1 and 2 sensitivity have in common
Antibody mediated
How does T2 HS work
Antibodies can be directed against cells or ECM components
How does T3 HS work
Antibody/antigen complex can bind and direct deposits in BVs
In T2 HS antibody that is directed against cell surface markers causes what
Complement and Fc receptor induced activation of leukocytes
Bring in neutrophils and macrophages eliciting tissue damage
What happens in complement and FcR mediated T2 HS
Antibodies bind to activate neutrophil
Complement activation releases C3a and C5a to activate neutrophils
Neutrophils generate ROS and lysosomal enzymes that cause inflammation/injury
Can occur after strep
How does Opsonization and phagocytosis work in T2 HS
Complement activation occurs releasing C3b that opsonizes cell
Fc receptor on phagocytes recognizes C3b on an opsonized cell and phagocytosis the infected cell
T2 HS may occur on what type of cells to induce disease
Erythrocytes and platelets causing anemia and thrombocytopenia
What happens in Graves disease
thyroid stimulation even in the absence of thyroid stimulation hormone leading to hyperthyroidism
What happens in myasthenia gravis
MSK paralysis disease where antibodies are made against the acetylcholine receptor and inhibit transmission of signals to the muscle to move
What is disease caused by in T3 HS
Deposition of circulating antibody/antigen complexes in blood vessels
- activation of complement
- activation of inflammatory cascade
What is arthrus rxn
localized antigen/antibody deposition
What are symptoms of an arthus rxn
Formation of complexes at site of antigen injection
Local vasculitis
What are examples of an arthus reaction
tetanus vaccine
- pt gets vaccine
- development of normal Ab to tetanus toxoid
- repeat vaccination occurs within a short time
- pre formed Ab complex w additional vaccine antigen and deposit in the subcutaneous tissue
- Localized inflammation, pain, swelling
What is the goal of treatment for T2,3 HS
Limit inflammation and injury
What medications are there for T2,3 HS
systemic corticosteroids to reduce inflammation and cell activation
What is plasmapheresis
Process by which antibodies can be removed from circulation to reduce antibody driven damage
What is IVIg
Intravenous immunoglobulin
What doe IVIg do
Induce expression of and bind to the inhibitory Fc receptor on myeloid cells and B cells
Compete with the pathogenic antibodies for binding
What does Anti CD20 Ab do
Reduce the B cell population that is producing the aberrant Ab
What is T4 HS
T lymphocyte mediated delayed HS
What do T cells do in T4 HS
Local immune rxn with T cells directed against cellular antigens within that local tissue
What are some environmental triggers than induce a persistent T cell response
Poison ivy, mediations, chemicals, metals
What disease causes a T cell response to microbes in T4 HS
TB
What is the mechanism of T4 HS
CD4 cells targeting cell or tissue antigens presented by APCs
CD 8 cells targeting host cells
CD4/8 cells may work together
What is DTH
delayed type hypersensitiviy
What are characteristics of DTH
Rxn occurs 24-48 hours after repeat exposure
In T4 HS how do T lymphocytes home to the site fucntion
respond to antigen
T cells and monocyte infiltration
CD4 cytokine production causes increased vascular permeability, leading to edema and fibrin depo
Leukocyte products lead to tissue damage
What is the clinical utility of DTH
Determine prior exposure
Purified protein derivative - TB skin test
Describe T4 HS
chronic and progressive typically
Antigen never cleared
Self perpetuating processes
What are treatments for T4 HS
Anti inflammatories * Corticosteroids Decrease T cell response or effects * TNF inhibitors IL-1,6,17 antagonists * Anti CD20 B cell
