Hypersensitivity Flashcards
What is a hypersensitivity
An excessive or aberrant pathologic immune reaction
What is Gel and Coombs classification for type I sensitivity?
Immediate hypersensitivity of mast-cell derived mediators
What is the Gel and Coombs classification for type II sensitivity?
Antibody-mediated cytotoxcitity with IgM or IgG antibodies against cell surface or extracellular matrix antigens
What is Gel and Coombs classification for type II hyperssensitivities?
Immune complex-mediated diseases with deposition of immune complexes in vascular basement membranes
What is Gel and coombs classification for type IV hypersensitivities?
T-cell mediated (non-ab)
includes autoimmunity
Type I is mediated by what? what is it characterized by?
IgE on mast cells responsding to allergen, characteried allergy or atopy; rapid vascular leakage (inflammation) examples are hay fever, food allergies, asthma,or anaphylaxis
Upon activation mast cells degranualte and release what?
Mast cells are under the skin, in mucosal tissue of the airways and gut and upon activation release histamine, lipid mediators (prostagladins, leukotrienes) and secrete cytokines (TNF-alpha)
Describe the pathway of type I exposure to allergens
During first exposure there is no clinical manifestation.
- allergen binds to B cells leading to activation of TH2 cells, which then secrete IL-4 and IL-13 back to the B cells. This stimualtes the IgE class switching in the B cells and the secretion of IgE into the serum. IgE will bind with the Fc-epsilon-receptor of mast cells.
- Upon second exposure of this antigen the binding of IgE to the fc-epsilon-receptor of mast cells causes activation of the mast cell and they its mediators like TNF-alpha, histamine, and leukotrienes and prostagladins.
After mast cell activation, what does the mast cell secrete to cause the immediate hypersensitivity, and what about the late-phase reaction?
Vasoactive amines and lipid mediators like histamine, prostagladin, and leukotrienes cause immediete.
-release of cytokines like TNF-alpha cause late phase reaction 6-24 hours after repeat exposure to antigen
Upon Fc-epsilon-receptor cross linking by IgE and allergen on mast cells, what are the steps of the pathway that follows?
- FCeRI crosslinks antigen
- phosphorlaytion of Lyn kinase
- phosphorlytation of syk kinase
- phosphorylation of PLC gamma
- PLC converts phosphatidylinositol-4,5 biphosphte into IP3 (leading to Ca2+ release from ER and degranulation) and DAG (leads to transcription factors and release of cytokines)
- MAPRK is activation leads to phospholipid A activation (mediate lipid mediators)
Probably draw out the pathway for the mast cell activation
What is released by mast cells and is responsible for chemotaxis of eosinophils and neutrophils?
ECF-alpha and NCF-alpha
Release of TNF-alpha and IL-1 by mast cells leads to what?
ICAM-1 upregulation (important for diapedesis)
Release of what leads to platelet aggregation?
Release of PAF platelet aggregation factor
Release of Heparin (granules) by mast cells leads to what?
anti-coagulation
How do mast cell mediate complement activation?
Release proteases (granules) that cleave C3a, 4a, 5a the anaphylatoxins
What cytokines help the survival of mast cells?
IL-3 and IL-4
What cytokines released by mast cells stimualte Th-2 activation?
IL-4, IL-5, IL-13
What makes you itch in type I hypersens?
Mast cells release of histamine
What do mast cells release that leads to increased vascular permeabiltiy?
Histamine, PAF, prostagladin, and leukotrienes
What do mast cells secrete that works for vasodilation?
Histamine, PAH, prostagladin
What is the role of typtase release by mast cells?
Aids in mucus secretion
What is the role of histamine in the immediate reaction during type I hypersensitibity?
Histamine elads to vasodilation, vascular permeability, and the transient contration of smooth muscles
What are the roles of prostaglandins in the immediate reaction?
Vascular dilation - a product of the AA metabolite pathway
What is the role of leukotriens in type I Hypersens?
Prolonged smooth muscle contraction
What cytokines are released by mast cells that work in the late phase reaction of type I hypersensitivity?
TNF-alpha, IL-4, and IL-5
What ILs work in the late phase reaction that activate Th2 cells?
IL-4, IL-5, IL-13
What leukocytes are recruited during the late phase reaction?
Eosinophils (by IL-5), and Neutrophils
What are the symtpoms of anaphylaxis?
It is a systemic reaction caused by widespread mast cell degranulation. Edema can lead to airway obstruction and a fall in blood pressure from vasodilation that can lead to shock
How do you diagnose atopy?
With a skin test, look for wheal (edema) and flare (erythema) reaction.
- there are two types Epicutaneous (first line) and intradermal (more sensitive and requires saline as a negative control and histamine as a postitive control)
- there is a risk of anaphylaxis with the intradermal test
What is the process of Immunocap to test type I hypersens?
IgE from the patient sample will bind to the allergen covalently attachted to the well. An enzyme labeled anti-IgE is added. Substate for the enzyme is added. Depending on the amount of color change will depend on the amout of enzyme that was bound
How do you treat anaphylaxis?
Epinephrine to increase cardiac output, and relax airway muscles
Asthama is treated with Beta-2 adrenergic agonist (bronchodilators), corticosteroids; reduce inflammation, leukotriene antagonists, histamine receptor antagonist (diphenhydramine)
What is type II hypersensitivity mediated by?
Antbodies against cells or extracellular matrix componenets (more common)
or
Microbrial antigens that cross-react with self tissue (less common) example is steptococcus cross reacting with cardiomyocytes to casue rheumatic fever
Type II diseases with tissue injury utilizes what mechanisms?
Complement activation, Fc receptor activation on neutropihls and macrophages (IgG1 and IgG3), opsonization of cells,
examples are transfusion reaction and rh incompatibility
What is the mechanism for Type II antibody-mediated hypersensitvity with diseases witout tissue injury?
Antibodies with specificity for a receptor (can block the receptor or be an agonist and actiate it)
- example is myastehnia gravis (antibodies block the acetylcholine receptor)
- other example is Graves disease (antibodies agasint the thyroid-stimulating hormone TSH receptor stimulate thyroid cells
What is a type III hypersensitivity?
Immune complexes deposited in vessels attract and activate leukocytes. IgG antigen-antibody aggregates
-arthus reaction is the experimental example where subcuntaneous admin of protein antigen in an immunized animal
What is the Arthus reaction?
Antigen is injected into an immune individual with IgG antibody. Local immune complexes form and activate mast cells leading to degranulation. this leads to edema, necrosis, and activation of complement. Can lead to blood vessel occulsion.
What is serum sickness?
Injection of a large amount of foreign antigen (often followed horse serum). Antibodies to foreign protein are produced and immune complexes form and are deposited in membranes where they fix complement and this leads to tissue damage.
- happens with antivenim and most common cause is penicillin
- occurs 7 to 10 days after injection and presents as chills, fever, rash, arthritis, and glomerulonephritis
How is post-steptococcal glomerulonephritis an example of a type III hypersen?
Cross-reactive anti-streptococcal antibodes can lead to nephritis
How is SLE a type III hypersens?
Antibodes against DNA and nucleoproteins leads to nephritis
How do you treat type II and III hyper sens?
Corticosteroids, IVIg, Anti-CD20 antibodies (depletes B cells, not plasma cells), CD40 ligand (CD154) antagonist, antibody blockade of cytokines important for B cell and plasma cell survival
Type IV hyper sens is mediated by what?
T-cell mediated
-directed agasint self-antigens (autoimmunity), and environmental antigens like poison ivy, also agasint microbes like TB and hepatitis
What is type III hyper sen mediated by?
CD4 t cells secrete cytokines inducing inflammation
TH1 secrete IFN-gamma activating macrophages
TH17 secretes IL-17 activating neutrophils
What are some example of type IV hypersens?
TB, contact dermatitis, and some autoimmune disease
How is DTH skin test differerent than type I skin test?
This is looking at delayed hypersensitivity in response to purified protein derivative. Type I would only take minutes while DTH takes 24-48 hours after antigen exposure. it takes time for ciculating effector T cells to home to antigen challenge site and response
How do you treat type IV hyper sens?
Corticosteroid, Anti-TNF, costimulatory blockage,
