Mechanisms Of Hypersensitivity Flashcards
Which of the hypersensitivities involves complement and Fc receptor-mediated recruitment and activation of leukocytes and results in immune complex deposition in vascular basement membrane?
Type III (immune-complex mediated diseases)
Which of the hypersensitivities involves IgM and IgG antibodies against cell surface or extracellular matrix antigens?
Type II (antibody-mediated diseases)
Which of the hypersensitivities is T cell mediated and involves macrophage activation and direct target cell lysis?
Type IV (T cell mediated diseases)
In Type IV hypersensitivity, which type of T cell is the basis for DTH?
CD4+ T cells
Which of the hypersensitivities is Th2 mediated, as well as IgE antibodies, mast cells, and eosinophils?
Type I (Immediate hypersensitivity)
T/F: Each cell involved in an immediate hypersensitivity response is restricted to carrying a receptor of a single antigen specificity
False! They carry a range of IgE representing that present in the circulation; thus they are not restricted to carrying a receptor of single antigen specificity
What must occur prior to someone having a type I hypersensitivity response to an allergen?
They must be sensitized to it in an initial exposure (priming)
What type of cell involved in type I hypersensitivities is especially prominent in skin and mucosa?
Mast cells
What type of receptor is present on mast cells that make them integral to a type I hypersensitivity response?
High affinity Fc receptors for IgE (FceRI = CD23a)
What do mast cells contain that make them potent type I hypersensitivity cells?
Preformed pro-inflammatory mediators (granules): histamine, serotonin, heparin, serine proteases
Newly formed lipid mediators (eicosanoids): prostaglandin D2, leukotrienes
What role do pre-formed mediators like histamine and heparin from mast cells play in type I responses?
Toxicity to parasites
Increase in vascular permeability
Smooth muscle contraction
Which cytokines play a role in type I hypersensitivities?
IL-4, IL-13: amplify Th2 response
IL-3, IL-5, GM-CSF: promote eosinophil production and activation
TNF-a: pro-inflammatory, activation of endothelium
Which chemokine plays a role in type I hypersensitivities?
CCL3 - Attracts monocytes, macrophages, and neutrophils (not as potent as IL-8)
What is the major contributor to tissue damage in type I hypersensitivities?
Eosinophils –> lead to chronic allergic inflammation
What receptor’s expression is inducible on eosinophils, making them a big player in type I hypersensitivities?
FceRI
What enzymes contained by eosinophils contribute to type I hypersensitivities?
Eosinophil peroxidase - triggers histamine release from mast cells
Eosinophil collagenase - remodels CT matrix
Matrix metalloproteinase-9 - matrix protein degradation
What toxic proteins are contained by eosinophils that cause major tissue damage in type I hypersensitivities?
Major basic protein (MBP) - toxic to parasites and mammalian cells, triggers histamine release from mast cells
Eosinophil cationic protein - toxic to parasites, neurotoxin
Eosinophil-derived neurotoxin
What cytokines are associated with eosinophils in a type I hypersensitivity response?
IL-3
IL-5
GM-CSF
TGF-alpha and beta
chemokine: IL-8
What type of mediators associated with mast cells and eosinophils are considered SRS-A’s (slow reactive substances of anaphylaxis)?
Leukotrienes
What are some examples of leukotrienes?
LTC4
LTD4 (very potent)
LTE4
LTB4 (pro-inflammatory)
Leukotrienes have overlapping activities with ___________.
They are associated with ________ onset, but _______ powerful and _______ duration as compared to histamine in bronchoconstriction.
They cause a __________ in capillary permeability and mucous production.
Histamine
Slower; more; longer
Increase
Which cytokine is considered a Th2 growth factor?
IL-4
What are the 2 primary functions of IL-4 in Th2 responses?
Isotype switching to IgE
Increase in VCAM-1
Which cytokine is associated with airway eosinophilia, mucous gland hyperplasia, and airway fibrosis and remodeling?
IL-13
What cytokine is the regulator of Eo production and survival?
IL-5
Which cytokine is in charge of recruitment and activation of inflammatory cells and causes altered function and growth of airway smooth muscle cells?
TNF
What is the half life of IgE binding to receptors? Is this considered long or short as compared to other isotypes?
Half life = 2 days in serum, up to 10 days when sequestered on FceRI on mast cells and basophils
This is short as compared to other isotypes (like IgG which has 21-23 day half life)
IgE is produced in ______ amounts to a very select group of antigens called _________
Small; allergens
_______ cells and ________ have high affinity Fc receptors for IgE called FceRI or CD23a
Mast cells; basophils
FceR receptors are only found in human cells that contain _______
Histamine
Allergens are small, ______ soluble antigens that are carried on _____ particles.
They can elicit responses in the absence of acute __________
Highly; dry
Inflammation
Mucosal challenge to allergens at ____ dose leads to _______ cell processing and presentation, and eventual ______ response
Low; dendritic; Th2
Allergens are often _____, meaning they are enzymatically active
Proteases
What do allergens contain that are required for T-cell priming?
Peptides that bind MHC class II
What occurs on first exposure to an allergen?
Priming - which results in IgE binding to mast cells, leading to sensitization to the allergen
DOES NOT result in allergic symptoms
Do allergens easily diffuse across mucosal epithelium?
Yes
Allergens easily diffuse across mucosal epithelium, then they are processed and presented, inducing an _________ immune response that generates ______, which then binds FceRI on mast cells
Adaptive; IgE
What would the response to allergen be in a previously primed individual?
Binding and crosslinking of IgE on FceRI on mast cells –> activation of mast cells and release of mediators
Which mediators are released within 5 minutes in a type I hypersensitivity reaction?
Histamine
Heparin
Tryptase
What are the 3 primary newly generated mediators in a type I hypersensitivity reaction and how long do they take to be generated?
5-30 minutes
Arachidonic acid
Leukotriene D4
Prostaglandin D2
How long do the cytokines take to be released in a type I hypersensitivity reaction and what are the 2 primary cytokines released?
Hours; IL-4 and TNFalpha
What is the biological response to biogenic amines like histamine and lipid mediators like PAF, PGD2, and LTC4 in a type I hypersensitivity response?
Vascular leak
Bronchoconstriction
What is the biologic response to cytokines like TNF, lipid mediators like PAF, PGD2, and LTC4, and enzymes like tryptase in a type I hypersensitivity response?
Intestinal hypermotility
Inflammation
Tissue damage
What are the common IgE mediated allergic reaction “syndromes” associated with type I hypersenstivities?
Systemic anaphylaxis
Acute urticaria
Hay fever
Asthma
Food allergy
What are common allergens, route of entry, and responses in systemic anaphylaxis (type I hypersensitivity)
Allergens: drugs, serum, venoms, food (peanuts)
Route: IV, or oral absorption to blood
Response: edema (laryngeal), circulatory collapse, death
What are common allergens, route of entry, and responses in acute urticaria (type I hypersensitivity)
Allergens: animal hair, insect bites, allergy testing
Route: through skin, systemic
Response: local increase in blood flow, vascular permeability
What are common allergens, route of entry, and responses in seasonal rhinoconjunctivities aka Hay Fever (type I hypersensitivity)
Allergens: pollen, ragweed, trees, grass, dust-mite feces
Route: inhalation
Response: edema of nasal mucosa, sneezing
What are common allergens, route of entry, and responses in asthma (type I hypersensitivity)
Allergens: danders, pollen, dust-mite feces
Route: inhalation
Response: bronchial constriction, increased mucous, airway inflammation
What are common allergens, route of entry, and responses in food allergies (type I hypersensitivity)
Allergens: nuts, fish, milk, eggs, soy, wheat
Route: oral
Response: vomiting, diarrhea, pruritis, urticaria, anaphylaxis
An acute atopic response in an immediate hypersensitivity involves crosslinking of IgE, degranulation of mast cells, and what typical symptoms within minutes?
Sneezing
Pruritis
Rhinorrhea
Congestion
What occurs in late phase chronic atopic responses?
Influx/activation of eosinophils, neutrophils, basophils, and Th2 lymphocytes
What is CHES?
Chronic Hyperplastic Eosinophilic Sinusitis, associated with late phase chronic atopic response
What are the systemic symptoms associated with late phase chronic atopic response?
Fatigue
Myalgias
Asthma
In general, what is responsible for the acute atopic response?
Release of inflammatory mediators and recruitment of inflammatory cells from circulation
In general, what is responsible for the late phase chronic atopic response?
Cytokines and eosinophil products
What are the symptoms of atopic asthma?
Intermittent dyspnea, cough, and wheezing
Airway hyperresponsiveness and bronchiole hyperreactivity (BHR) leading to exaggerated constrictor response
Systemic anaphylaxis results from allergens being introduced directly into the ________, leading to systemic activation of mast cells.
There is an increase in vascular permeability and constriction of smooth muscle. Anaphylactic shock results from drastic drop in ______ _______, and death due to ___________
SA has effect on heart, vascular system, respiratory tract, GI tract
Blood
Blood pressure; asphyxiation
Epinephrine causes vascular smooth muscle contraction, increases cardiac output, and inhibits bronchial smooth muscle cell contraction. What is this used to treat?
Anaphylaxis
Corticosteroids reduce inflammation. Leukotriene antagonists relax bronchial smooth muscle and reduce inflammation. Phosphodiesterase inhibitors relax bronchial smooth muscle. What are these agents used to treat?
Bronchial asthma
Type II hypersenstivities are ______-mediated
Antibody
Which two antibodies play the biggest role in type II hypersensitivities?
IgM, IgG against cell surface or extracellular matrix
Damage due to type II hypersensitivity is localized to specific cells of tissues bearing the antigens. What are the two primary mechanisms of action?
Complement
NK cells: ADCC
Type II hypersensitivities are associated with “fixed” antigens. Based on that, which antibodies are considered pathogenic?
Abs directed against cell surface Ags are usually pathogenic
Abs directed against internal Ags are usually not pathogenic
The degree of damage associated with a type II hypersensitivity depends on what?
The amount of Ag on target cells
Type II hypersensitivity to _______ occurs because it mimics one of the bacterial wall substrates.
Covalent linkage of the drug to erythrocyte or platelets creates a foreign or non-self epitope on a self cell.
The epitope stimulates the production of _____ and some _____ directed against the drug conjugated to the cell surface component
Penicillin
IgG; IgM
Transfusion reactions are associated with what type of hypersensitivity?
Type II
Abs like IgM cause agglutination, C’ activation, adn intravascular hemolysis
Immediate reaction involves fever, hypotension, nausea/vomiting, back and chest pain
What type of hypersensitivity is associated with hemolytic disease of the newborn?
Type II
Rhesus D is most commonly involved Ag; Kell is the second most common
What are of the pathologies associated with Type II hypersensitivities?
Hemolytic anemia Pernicious anemia Goodpasture syndrome Grave's disease Myasthenia gravis Rheumatic fever
What two monoclonal antibodies are typically used to treat type II hypersensitivities?
Anti-CD20
Anti-CD52
Is the antigen fixed or soluble in type III hypersensitivities?
Soluble
Type III hypersensitivities involve soluble Ag, so what what causes the problem?
When the complexes deposit in tissues (determined by localization of Ag in tissue)
The 3 overall groups of type III hypersensitivities include:
Persistent _______, autoimmunity, and ________ of Ag
Infection; inhalation
What are the 4 primary clinical manifestations of a type III hypersensitivity?
Fever
Arthritis
Vasculitis
Nephritis
What is the difference between early, intermediate, and late stages of type III hypersensitivity responses?
Early there are small immune complexes that do not fix complement or cause much of a response
Intermediate there are comparable amounts of Ag and Ab, leading to complement fixation and clearance from circulation
Late there are large amounts of Ab and little Ag, intermediate size complexes are formed that can fix complement and are cleared from circulation
Immune complexes normally bind complement and are removed by the _____ and ____ after binding _____ on RBCs
Liver; spleen; CR1
During type III hypersensitivity reactions:
When inflamed, immune complexes act on _______ and ______ to produce vasoactive amine release.
The amines cause _______ cell retraction and increase vascular permeability, leading to complex deposition –> platelet aggregation and _______ activation
Microthrombi form on the exposed _____ of the basement membrane of endothelium. ______ are attracted to the site by C’ products. Increases in BP and vascular turbulence increase complex deposition
Basophils; platelets
Endothelial; complement
Collagen; neutrophils
What are some of the pathologies associated with type III hypersensitivities?
SLE Polyarteritis nodosa Postreptococcal glomerulonephritis Serum sickness Arthus reaction
The inflammatory pathways for type II and type III hypersensitivities are identical. What is the major difference between the two?
Where the Ags are derived from and how the complexes form:
Type II: fixed surfaces
Type III: soluble
What are the 2 overall mechanisms of cell-mediated hypersensitivities (type IV hypersensitivities)
Delayed-type hypersensitivity
T cell-mediated cytolysis
What are the 3 types of DTH?
Contact
Tuberculin
Granulomatous
Contact DTH results in an __________ reaction and occurs at the point of contact
Eczematous
Tuberculin DTH is induced by ______ antigens and is used ___________
Soluble; diagnostically
___________ DTH is clinically the most important, it results in 21-28 days, results in skin hardening (lung epithelium) due to persistent antigen or antibody complexes
Granulomatous
What are the 2 stages of DTH?
Sensitization (Ag uptake by DCs and presentation via MHC II)
Elicitation (recruitment of CD4, proinflammatory cytokines, monocytes, and macrophages)
DTH = Ag-specific _____ T cells
CD4
Contact sensitivity occurs when contact-sensitizing agent penetrates the skin and binds to self proteins, which are taken up by _________ cells.
These present self peptides haptenated with the contact-sensitizing agent to _____ cells, which secrete IFN-y and other cytokines.
Activated __________ secrete cytokines such as IL-1 and TNF-a and chemokines such as CXCL8, CXCL11, and CXCL9.
These products activate macrophages to secrete mediators of inflammation.
Langerhans
Th1
Keratinocytes
The tuberculin reaction is a type of DTH induced by _______ antigen and is used to test for _____-cell mediated responses to organisms
The tuberculin skin test is also known as _____
Functions in recall response to previously encountered Ag with an infiltrate of cells including neutrophils, monocytes, and T cells that disrupt the ______.
It is a general measure of cell-mediated immunity
Soluble; T
PPD
Dermis
The ______________ DTH usually results from persistence within macrophages of:
Intracellular microorganisms able to resist macrophage killing
Other particles the cell is unable to destroy
Granulomatous
Granulomatous DTH occurs with chronic infections associated with ____-like responses
May also occur in the absence of infection such as to _________ _______, non-immune
Th1
Foreign body
What are some of the pathologies associated with Type IV hypersensitivities?
Multiple Sclerosis Rheumatoid arthritis Type I DM Crohns disease Contact sensitivity Tuberculosis Viral hepatitis TSS
