7 - Hypersensitivity Flashcards
What is hypersensitivity?
Harmful immunologic reaction developing in response to an otherwise harmless specific trigger
What is an Arthus reaction? What type of hypersensitivity reaction is this?
Skin rxn when sensitized people re-exposed to specific antigen
Causes hemorrhage/edema in 4-10 hrs, necrosis of the skin
Common after vaccination in pattients recently vaccinated (with high IgG titers already)
Type III hypersensitivity rxn
What is serum sickness?
Human immunization with serum of immunized horess triggered illness a week later:
- joint pain
- swelling
- fever
- malaise
- rash
The word allergic and ____ are used interchangably.
Atopy.
What are the types of hypersensitivities as defiend by the Cell and Coombs framework? How is each mediated?
Type 1: immediate Allergy, IgE mediated
Type 2: direct antiBody mediated cytolytic
Type 3: immune Complex mediated
Type 4: Delayed type, T cell mediated
What are the two mechanisms of hypersensitivity shared by all four types of reactions?
1. Sensitization stage - development of immune response, symptoms silent, requires adaptive immnuity (antigen-specific T and B cell response)
2. Effector stage - secondary immune response, symptoms evident
What cells mediate the initial phase of anaphylaxis during a Type 1 hypersensitivity reaction?
Mast cells: tissue resident, (formed in BM)
Basophils: circulating and tissue residents
Both work as innate immune cells that wait for their trigger
What happens in a type I hypersensitivity reasion when an antigen triggers mast cells/basophils?
IgE cross-linking occurs causing rapid degranulation!
What occurs in the sensitization phase of a type 1 hypersensitivity reaction?
- BCR on naive B cell bind the venom protein
- Venom protein preocessed by APC and presented to CD4+ cell
- The naive CD4+ T helper cell matures into a Th2 oriented antigen specific cell and produces cytokines that support Bcell class switchign to IgE
- B cell and plasma cell make IgE
- Circulating IgE bind slong term onto FcgammaRI on mast cells and basopihls
*Remember this is clinically silent*
What occurs during the effector phase of a type 1 hypersensitivity reaction (after the second bee-sting)?
- Venom protein crosslinks anti-bee IgE already boudn to FCepsilonRI on mast cells/basophils
- Crosslinking triggers rapid release of preformed mediators
- Symptoms of anaphylaxis occur immediately
- Hours later, delayed phase symptoms develop
What are FCepsilonRI receptors? Where are they found?
High affinity IgE receptors constituitively expressed on mast cells and basophils.
Allergen comes in and cross-links receptors, causing phosphorylation, signal transduction, and intracellular signaling.
What results from the intracellular signaling cascade initiated by the FCepsilonRI receptor in a type 1 hypersensitivity reaction?
- Degranulation: release of preformed mediators
- Leukotrienes made: takes a little longer
- Cytokines: longest because it requires transcription
What preformed mediators are released in a type 1 hypersensitivity reaction? How long does this take and what is the result?
Histamine, neutral proteases such as tryptase, proteoglycans such as heparin
- cause vascular dilation, smooth muscle contraction, and tissue damage.
Takes seconds to minutes.
What is released in the minutes-hours during a type I hypersensitivity reaction? What is the result?
Platelet-activiting factors (PAF), prostaglandins (PGD2), and leukotrienes
- causes vascular dilation and smooth muscle contraction
**basophils don’t make tryptase or PGD2
What is released in hours-days during a type I hypersensitivity reaction? What is the result of this?
Cytokines - takes awhile becasue it relies on transcription.
Causes inflammation through leukocyte recruitment.
What is anaphylaxis and what are signs and symptoms?
Systemic Type I hypersensitivity syndrome
- swelling of conjunctive
- light headedness
- confusion
- headache
- fast or slow HR
- low BP
- hives, flushing, itchiness
- abdominal cramping
- vomiting
What physiologic changes occur during anyphylaxis (type I hypersensitivity rxn)?
Leaky/dilated blood vessels: angioedema, low BP, shock
Cardiac effects: myocardial depression, tachy/bradycardia
Smooth muscle spasm: bronchospasm, GI/GU tract spasm, coronary spasm
What is the most important preformed mediator involved in a type I hypersensitivity reaction? What are its receptors and the associated symptom when it binds?
Histamine! Short lived in the serum (gone in minutes)
Receptors:
- H1R: itching, incerased vasc. perm (edema), smooth muscle contraction
- H2R: gastric acid secretion
What releases tryptase during a type I hypersensitivity reaction? What are the different types and when are they released? How long does it last in serum?
Tryptase released from mast cells NOT basophils
Immature: constit. released (a and b protryptase)
Mature: only released when degranulation (b tryptase)
Lasts up to 4 hours in serum.
What is the best clinical indicator of mast cell activation? What is the purpose of this?
Tryptase; leads to remodeling of connective tissue matrix
Other than tryptase, what are other preformed mediator enzymes released during a type I hypersensitivity rxn? What is their function?
Proteases such as chymases, cathepsin G, and carboxypeptidases.
Degrade toxins and lead to connective tissue remodeling.
Which cytokines are rapidly synthesised during a type I reaction? What is the function of each?
IL-1 and IL-3: associated with Th2 and promote Bcell class switching
IL-3, IL-5, and GM-CSF: promote survival and activate eosinophils
TNF-alpha: activates endothelium and leads to adhesion molecule expression.
What chemokines are rapidly synthesized during a type I reaction? What is the function of each?
MIP-1a (CCL3): chemotactic for monocytes, macrophages, neutrophils, T cells, and eosinophils
RANTES (CCL5) and Eotaxin (CCL11): chemotactic for T cells and eosinophils
What lipid mediators are rapidly synthesized during a type I reaction? What is the function of each?
Cysteinyl leukotrienes (LTC4, D4, E4): leads to eosinophil migration, smooth muscle contraction, vascular permeability, and mucus secretion
Platelet activiating factor (PAF): attracts/activates eosinophils, activates PMNs adm platements, and increases lipid mediator production
Most atopic (allergic) diseases have _______-induced recruitment and associated pathology. This cell type has crystalloid granules that contain __________.
Eosinophil
Major basic protein
What is the function of major basic protein?
MAst cell activation, helminthotoxic, and core protein.
What major mediators do eosinophils have?
- Major basic protein
- Eosinophilic cationic protein (same as MBP)
- Lysophospholipase
- Eosinophil derived neurotoxin (EDN)
- Platelet activating factor (PAF): bronchoconstriction
- LTC4 (leukotrience C4): bronchoconstriction, mucus secretion
What is the importance of IL-5 in a type I hypersensitivity reaction? Why is it important clinically?
Produced by Th2 CD4+ cells; In vivo causes hypereosinophilic syndrome and incases fluids frmo allergic late phase reactions.
Important clinically to make anti-IL5 antibodies.
What effect do corticosteroids have on eosinophils?
Binds glucocorticoid receptor which goes to nucleus to inhibit AP-1 and NFkB
Inhibits production of IL-5 via decreased release from marrow and rapid apoptosis.
**steroids seem to make eosinophils disappear!
What are three examples of type I hypersensitivity reactions?
- Allergic rhinitis
- Drug*, food, venom, and allergies
- Asthma* (reversible airway obstruction)
*not all cases are due to or triggered by teyp I hypersensitivity or allergen
What are two disorders of mast cells?
-
Urticaria/angioedema (hives/swelling)
* contact (dog licking) or chronic (autoimmune, direct activation) -
Mastocytosis (increased MC burden)
* spontaneous anaphylaxos, osteoporosis, chronic diarrhea
How do you clinically confirm sensitization for type I hypersensitivity?
- Prick/scratch test: first line that balances sensitivity/specificity
- Intradermal testing: 1000x more sensitive, never used on foods
- Serum IgE ELISA: tests serum for specific IgE
How do you clinically manage type I hypersensitivity?
- Avoid known allergies
- Suppression of mediators: nasal steroid, oral antihist, nasal mast cell inhibitors
- Immunotherapy (allergy shots): SubQ of sublingual
What is the prevelance of asthma and what are sommon symptoms?
Reversible airway obstruction that effects 5% of population
Symptoms: non-productive cough, wheezing, shortness of breath, and chest tightness.
What are basic (first choice) treatments for asthma? What doesn’t work?
- Trigger avoidance
- Corticosteroids (Apoptose eosinophils)
- Bronchodilators: short-acting B-agonists (albuterol)
Antihistamines ineffective
What are some second-line treatments for asthma?
- Anti-leukotrienes: Montelukast
- Biologics: omalizumab
- Immunotherapy: SCIT SubQ allergy shots
- Long acting B-agonists (LABA) - only given with inhaled steroids too
What are characteristics of a type II hypersensitivty reaction?
Antibody (IgG or IgM) binds cell or matrix bound antigen.
Bound Ab to antigen leads to:
- future immunologic attack and/or
- functional interference (inhibition or activation)
What are the four types of type II hypersensitivity?
- Complement activation
- Antibody dependent cellular cytotoxicity (ADCC)
- Phagocytosis (opsonization)
- Antibody alteration of normal function (anti-receptor_
Type II hypersensitivity reactions are usually _____ or ______. Name a few examples.
Infectious or autoimmune.
Exp: goodpasture syndrome, bullous pemphigold, pernicious anemia, vasculities, thrombotic phenomena, and acute rheumatic fever.
What type of hypersenvitity reaction is drug-induced hemolytic anemia/thrombocytopenia? What occurs?
Type II
Medicien becomes antigenic when bound to RBCs or platelets and IgG may target the drug-cell antigen (hapten formation)
Antibody tagged RBCs/platelets are targets for destruction (ADCC) in the spleen.
Fetal Rh incompatibilityl is an example of a type II hypersen. reaction. What occurs in this disease? How would you prevent this?
- Rh neg mother becomes sensitized againt Rh factor from fetus and developes IgG against fetal Rh antigen.
- Next pregnancy, mom anti-Rh IgG crose placenta and tags fetal RBC
- Fetal RBC destruction leads to hydrops/stillbirth from severe anemia
Treat mom with anti-Rh antibody to prevent disease
What is a type III hypersensitivity reaction? What occurs?
Immune complex mediated reaction.
IgG targeted against a soluble foreign antigen forms a large polymeric immune complex
- may be cleared by mononuclear-phagocyte system.
- Certain cases can trigger self injury
What is the “zone of equivalence” for type III hypersensitivity reactions?
Immune complex formation is promoted in a range where the ratio of antigen to antibody is closer to 1:1. This is the “perfect storm” scenario.
In type III reactions, how do immune complexes trigger injury?
- Activate FcYR expressing phagocytic cells (proinflammatory)
- Activating complement at sites of deposition
IC deposit in preferential sites where they get stuck and cause inflammation
- kidneys, vessels, joints, skin
- sites of high antigen concentration
What is serum sickness? What type of reaction is this?
Type III hypersensitivity rxn
Systemic reaction following large quant. of foreign protein usually from animals.
- Flu like symptoms with rash, arthritic, and glomerulonephritis
- Onset 7-10 days, with more rapid onset with subsequent exposure
NAme some exogenous and endogenous sources of “foregin” antiben in type III hypersensitivity reactions?
Exogenous: infectious agents like streptocicci, hepB, or plasmodium; drugs or chemicals like foreign serum or heroin.
Endogenous: nuclear antigens, immunolglobulins, tumor antigens
What type of immune response does SLE represent? Why would someone with systemic lupus erythematosus (SLE) develop disease in the lungs and kidneys?
SLE represents a type III immune response due to the antibody complex and complement activation (with some type IV components too).
These sites are favorable for immune complex deposition.
What are the characteristics of a type IV hypersensitivity reaction?
Cell-mediated, delayed type involved T cells (CD4+ and/or CD8+)
Antigen binds to self-proteins to create haptenated self-protein (which then looks foreign to the immune system) and is processed by APCs and presented to T cells.
When happens in a type IV reaction when a haptenated protein is presented to a T cell by an APC?
T cells proliferate and secrete mediators:
- IFNg: induces expression of adhesion molecules and activates mø
- TNFa and LT (lymphotoxin): causes local tissue destruction and induces expression of adhesion molecules
- IL-3 and GM-CSF
- Chemokines that recruit macrophages
What is allergic contact dermatitis an example of? What occurs?
Type IV hypersensitivity
Haptens bind to self-proteins (haptenization) creting a foreign protein presented to APC and recognized by TCRs.
Triggers mø mediated inflammation
What are some common sensitizers that cause allergic contact dermatitis (type IV hypersensitivity rxn)?
Poison ivy (rhus dematitis) caused by allergen pentadecacatechol (urushiol)
- Formaldehyde
- Methacrylates
- Nickel, gold, cobalt
- Fragrances
- preservatives
- Rubber accelerators
How are sensitizers to allergic contact dermatitis confirmed? How are they treated?
Confirmed by patch testing
Treated with topical corticosteroids.
What is an example of intradermal diagnostic testing for a type IV hypersensitivity? What is the speed of this?
Tubreculin (PPD) skin test: screening for sensitization to TB
Slow to test positive: 24-72 hours
How does patch testing work for type IV hypersensitivities? How long does it take?
Adhesive patches with sensitizer applied to skin, interpreted after 2-3 days and 1 week.
Slow to test positive.
Descibe the reactor, antigen, and effector mechanism of a type I hypersensitivity? What are examples?
Reactor: IgE
Antigen: soluble
Effector: mast cell activation
Examples: allergic rhinitis, asthma, anaphylaxis
Descibe the reactor, antigen, and effector mechanism of a type II hypersensitivity? What are examples?
Reactor: IgG or IgM
Antigen: cell or matric associated
Effector mechanism: FcR+ cells (phagocytes and NK)
Examples: penicillin induced thrombocytopenia
Descibe the reactor, antigen, and effector mechanism of a type III hypersensitivity? What are examples?
Reactor: IgG
Antigen: soluble, large quantities in a 1:1 ratio
Effector mechanism: macrophage activation
Examples: serum sickness, arthus reactoin
Descibe the antigen and effector mechanism of a type IV hypersensitivity that uses Th1 cells as a reactor? What are examples?
Antigen: soluble
Effector mechanism: macrophage activation
Examples: contact dermatitis, tuberculin skin test
Descibe the antigen and effector mechanism of a type IV hypersensitivity that uses CD8+ cells as a reactor? What are examples?
Antigen: cell associated
Effector mechanism: cytotoxicity
Examples: contact dermatitis
What is the mechanism of allergic contact sensitivity (type IV)?
- Sensitizing agent penetrates skin and binds self-protein to be taken up by cells.
- Cells present self peptides hapenated with contact-sensitiving agent to Th1 cells which secrete IFN-Y
- Activated keratinocytes secrete cytokines (IL-1, TNFa) and chemokines (IL-8, IP-9, and MIG) which activate macrophages to secrete mediators of inflammation
What is anergy? What are examples?
Ignorance or failure to clear harmful self/foreign antigens
Examples: cancer, HIV, TB
What is autoimmunity and what are examples?
Reactivity to self antigens
Examples: lupus, rheumatoic arthritis, thyroiditis, MS
