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53 Cards in this Set
- Front
- Back
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What is a hypersensitivity? Describe them
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-Aberrant or excessive immune response to foreign antigens
-Primary mediator is the adaptive immune system -T and B lymphocytes -Damage is mediated by the same attack mechanisms that mediate normal immune responses to pathogen |
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What is the common term for a type I sensitivity? What is the mediator?
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Immediate type
IgE monomers |
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What is the common term for a type II sensitivity? What is the mediator?
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Cytotoxic Type
IgG/IgM monomers |
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What is the common term for a type III sensitivity? What is the mediator?
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Immune Complex Type
IgG/IgM multimers |
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What is the common term for a type IV sensitivity? What is the mediator?
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Delayed type
T cells |
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Who do hypersensitivity reactions occur in?
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Sensitized individuals
-Generally at least one prior contact with the offending agent |
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How long does sensitization last?
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Sensitization can be long lived in the absence of re-exposure (>10 years) due to immunologic memory
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What is a hapten?
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-Chemical moiety too small to elicit a T cell response alone
-Capable of tight association with self proteins -This "conjugation" creates a new (foreign) target |
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What is an example of a hapten?
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Penicillin - capable of eliciting types I-IV hypersensitivity. Penicillin will conjugate with the protein. When the protein is endocytosed at the end of its life it will no longer look like self and this particular face of the protein was not present during thymic selection so your T and B cells don’t know this as self. This will elicit an anti-hapten response by T and B cells.
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What is the sensitization in type I hypersensitivity?
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Antigen contact, typically low-dose via mucous membranes (respiratory, GI) -> IgE production
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What is the elicitation for type I hypersensitivity?
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Pre-formed IgE (allergen-specific) triggers mast cell activation -> mediator release
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Describe the reactions of type I hypersensitivity
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-Can occur within seconds-minutes of exposure
-Severity ranges from irritating to fatal |
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Describe IgE production
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-Secondary immune response (multiple or persistent exposures)
-B cell class switch to IgE requires T cell help: CD40L and IL-4 or IL-13 (Th2 cytokines) -The propensity to make an IgE response to environmental antigens varies among individuals |
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What are atopic individuals
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"Atopic" individuals are those with an inherited predisposition to form IgE responses
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What produces IgE?
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IgE is produced by plasma cells as a result of T cell help. The serum half-life of IgE is 2 day because it is taken up very rapidly by FcepsRI. Mast cells are sentinel cells underlying all the mucosal and cutaneous surfaces in our body.
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Describe the early phase of sensitization in type I hypersensitivity
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IgE crosslinking by antigen leads to the release of preformed mediators. This is followed by rapid production of arachadonic acid products.
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What are the intermediates of the early phase of type I hypersensitivity reactions? What are the effects of these intermediates?
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Histamine (also tryptase, heparin)
These lead to: -Smooth muscle constriction -Vasodilation; vascular leak -GI motility (increased) -Mucous secretion -Sensory nerve activation |
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What products are released in the early phase of type I hypersensitivity reactions? What are the effects of these products?
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Leukotrienes, prostaglandins
The effect of these is: -Smooth muscle constriction -Vasodilation; vascular leak -Mucous secretion -Neutrophil chemotaxis |
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Describe the late phase of type I hypersensitivity reactions
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Gene activation leads to new cytokine production
This occurs ~6 hours after antigen triggering Cytokines released: TNFalpha-> recruits inflammatory cells IL-3, IL-5, GM-CSF-> Eosinophil production IL-4, IL-13 -> Propagate Th2 response |
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What does IL-4 do?
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More IL-4 means more B cells making IL-4 which means more class switching to IgE.
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Describe the structure of the FcepsRI receptor
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It is alpha-beta-gamma2
alpha - binds IgE monomer gamma - shared by IgG FcR's I and III |
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Describe FcepsRI receptor aggregation
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-Pre-bound IgE binds polyvalent Ag
-Initiates ITAM phosphorylation |
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what is cyrus allergic to
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the lack of kitty
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what happens when cyrus not pet kitty enough
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she pouts lots
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What are ITAMs?
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Conserved tyrosine-containing sequence motifs within a variety of receptors (TCR, BCR, FcR's).
They serve as docking sites for downstream activating kinases. In the case of type I hypersensitivity, this is SyK. |
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What is the innate responder cell in Type I hypersensitivity?
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Eosinophils
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What drives production of eosinophils in the bone marrow?
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IL-5 (Th2 cytokine)
IL-3 CM-CSF |
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What is responsible for chemotaxis of eosinophils from blood to tissue sites?
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-IL-5
-Eotaxins (CCL11, CCL24, CCL26) |
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What primes eosinophils for activation?
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IL-5
Eotaxins C3a/C5a -Increased expression of FcR for IgG, IgAm IgE also decrease the threshold for degranulation |
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Describe eosinophil activation
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-Most potent trigger is FcR-crosslinking (IgA>IgG>IgE)
-Results in exocytosis of preformed toxic proteins -Major basic protein -Eosinophil cationic protein -Eosinophil-derived neurotoxin These are directly toxic to helminths, but also lead to collateral tissue damage |
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What propagates the eosinophil response?
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-They secrete IL-3, IL-5, and GM-CSF
-They also secrete IL-8 (PMN attractant) |
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What is the purpose of having mast cells line all subepithelial mucosa?
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-Rapid recruitment of PMN, eosinophils, monocytes to sites of pathogen entry
-Increased lymph flow from peripheral sites to lymph nodes -Increased GI motility -> favors expulsion of GI pathogens |
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Describe the role of eosinophils in parasite clearance
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-c-kit-/- mice have no mast cells. This leads to increased susceptibility to trichinella,
strongyloides. -Eosinophil depletion (Ab-mediated) leads to increased severity of schistosomal infection |
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What is anaphylaxis? What is the mechanism?
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-Response to systemic circulation of allergen
-IgE cross-linking on mast cells in peri-vascular tissue -Circulating histamine, PG's/LT's -> vasodilation, vascular leak -High-output shock: significant decrease in BP despite increased cardiac output -Other symptoms: urticaria, wheeze, laryngeal edema with airway compromise, GI cramping, diarrhea, "feeling of dread" |
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Describe the time course of anaphylaxis
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The symptoms progress rapidly (seconds)
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Describe the treatment of anaphylaxis
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Immediate: epinephrine 0.3cc IM, followed by antihistamines (H1 and H2 blockage) IM or IV. This is for treating the early phase response. After that is subsequent administration corticosteroids -> prevent the late phase response.
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What does epinephrine do?
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Increases the blood pressure and helps to close the vascular leak and return the fluid to the vascular system
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How do you demonstrate type I hypersensitivity?
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Skin testing for allergic sensitization
-Allergen (airborne, food, venom, medication) is introduced by prick or intradermal injection -Sensitization is evident with 15 minutes as a wheal/flare at site of allergen introduction |
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What mediates damage in type II hypersensitivity?
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IgG or IgM
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What are the origins of the tissue-specific antibody response in type II hypersensitivity?
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-Hapten response
-Molecular mimicry -Idiopathic -loss of self tolerance (autoimmune) |
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What is the mechanism of sensitization of the hapten response in type II hypersensitivity?
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-A foriegn agent (typically drug) acts as a hapten
-Conjugates self protein -> modified self -> T cell/B cell response -> high affinity anti-self IgG or IgM from a germinal center reaction |
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Describe the elicitation phase in the hapten response in type II hypersensitivity
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On re-exposure
-Hapten conjugation to self -> modified self protein -Binding to IgG or IgM to modified self tissue (platelet, RBC) -Activation of normal immunoglobulin effector functions, but in the wrong place |
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Describe Molecular mimicry
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This is important in type II hypersensitivity.
-Pathogen elicits appropriate inflammatory response -High-affinity anti-pathogen IgG -Pathogen-specific antibody cross-reacts with self -Long-lived anti-pathogen IgG -> persistent tissue damage |
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Describe type III hypersensitivity
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This type III hypersensitivity reactions are mediated by antibodies, but immune complexes instead of monomers. There is a lot more antibodies than there is antigen to bind then each of the antigen will be coated and each antigen will be coated with antibody. There is not a lot of crosslinking. In the zone of excess you have one antibody per antigen and some antigen that doesn’t have any antibody. Due to the ratio there is not a lot of crosslinking. In between there is a zone of equivalence where there is a lot of crosslinking and the formation of a macromolecular network called an immune complex. This happens because the antigen has more than one binding site for antibody and the antibody has two antigen binding sites.
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What are the mechanisms of damage in type III hypersensitivity
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-Ag-Ab complexes deposit in local blood vessel walls
-Fix compement -> generate C5a -Chemoattractant for neutrophils -Mast cell activator -> histamine release -> hives, tissue edema -Bind Fc Receptors on: -Neutrophils -> release of oxygen free radicals, proteases -Platelets -> aggregation, thrombosis, necrosis Cells come in that have Fc receptors and they see the immune complex and release oxygen free radicals and proteases. Thrombosis of vessels can lead to occlusion of the vessel and necrosis of the tissue. These complexes are soluble antibody binding to soluble antibody s o they can occur anywhere. They have nothing to do with the tissue that they are damaging. We tend to accumulate immune complexes in the kidney. |
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What is the classic form of type III hypersensitivity?
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Serum sickness reaction
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What are the symptoms of serum sickness?
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Fever
Lymphadenopathy Urticaria Joint Pain Proteinuria These occur 2-3 weeks following infusion of antigen (classically an anti-serum of horse origin) |
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What causes serum sickness?
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Early therapies for immunosuppression involved giving antibodies from other species. These antibodies are fairly long lives. The host starts to make antibodies against the foreign antibody. If you end up producing antibodies against the horse antibodies before they are cleared from the system you create a zone of equivalence temporally. Your antigen if falling and your antibody is rising.
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What occurs with type IV hypersensitivity?
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Group of T cell mediates responses to antigen
-Direct killing of target cells (by CD8 T cells) -Indirect via activation of macrophages (CD4+ T cells) |
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What is necessary for a type IV hypersensitivity?
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-Sensitization is required
-T cells are necessary and sufficient -Athymic subjects do not have type IV reactions -T cell depletion (via anti-T cell Ab's) reverses sensitization -Transfer of purified memory T cells confers sensitization |
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What is the time course of type IV hypersensitivity reactions?
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On re-exposure - reactions occur over 1-3 days
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Describe sensitization in contact hypersensitivity
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-Agent (antigen) crosses epidermis
-If hapten, associates with epidermal cell proteins -> self -Langerhans cells process antigen proteins -Load antigen peptides into MHC I and MHC II. These go to the lymph node. -LC migration -> presentation to naive T cells -Expansion of CD4 to CD8 T cell response |
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Describe re-exposure in contact hypersensitivity
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-If hapten modifies extracellular proteins these will be taken up by cutaneous APC's
-> MHC II -Effector CD4 T cells respond: -Production IFN-gamma, chemokines -Recruit macrophages -> produce TNF-alpha -Inflammatory infiltration, local edema/erythema -If lipophilic, the hapten easily crosses the cell membrane, modifying cytoplasmic proteins -> MHC I -Effector CD8 T cells respond: -Targeting of haptenylated keratinocytes for cytolysis -Keratinocyte death, blistering |
