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49 Cards in this Set

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Definition of Hypersensitivity
Broad def. : disorder caused by immune responses (dysregulated response to foreign antigen, failure of self-tolerance)
Clinical: excessive immune response against foreign antigen
Definition: Allergy
symptoms elicited by encounter with foreign antigen in a previously sensitized individual
Type I Hypersensitivity
Allergy/ Immediate Hypersensitivity.
IgE mediated, soluble antigen, mast cell as effector mechanism. Example : peanut reaction.
Type II Hypersensitivity
Bystander Reaction.
Hypersensitivity with drug reaction, IgG and IgM monomer mediated, cell or matrix bound antigen, complement and Fc-gamma-R+ effector mechanism
Type III Hypersensitivity
Immune Complex Disease.
IgG multimer mediated, soluble antigen, complement and PMN, Macrophage effector mechanism
Type IV Hypersensitivity
Delayed-type hypersensitivity.
CD4+ or CD8+ T-cell mediated, soluble antigen (CD4) or cell bound antigen (CD8), Macrophage activation (CD4) and Cytoxicity (CD8) effector mechanisms
2 steps needed for Type I Hypersensitivity
Sensitization - antigen contact to illicit IgE production
Re-exposure - Preformed IgE is crosslinked with antigen, and triggers mast cell activation
Time frame of Type I reaction
Occurs within seconds or minutes of exposure
What are the important factors that direct Ig class switiching to IgE
IL-4, IL-13 (Th2 cytokines) and CD40L from T-cells
Half life of IgG and IgE
IgG - 30 days
IgE - 2 days

rapid take up by FceR1 on tissue mast cells and circulating basophils
Describe the critical steps in the early phase effector stage of a Type I reaction
IgE crosslinking -> degranulation of cell --> release of histamine
What is the important mediator of the early phase of Type I reaction? List its effects
Histamine.
SM contraction, mucuous secretion, vascular permeability, Gi motility, sensory nerve stimulation
Duration of the early phase of Type I reaction
1-2 hours
Describe the events that occur durin gthe late phase of the of Type I reaction
Mast cell turns on TFs and secretes newly synthesized mediators.
AA pathway activated and prostaglandins and leukotrienes are secreted.
De novo synthesis of cytokines leading to recruitment of PMNs and eosinophils
What are the critical factors released during the late phase of a Type I reaction
leukotrienes C4, D4 (SM contraction, vasodilation, mucous production)
IL4, IL13, (Th2 cytokines, more mast cell release, more T-cell polarization to Th2)
IL3, IL5, GM-CSF (eosinophil recruiting triad)
TNF-alpha (inflammation marker, adhesion activator, chemotaxic)
How do you treat Type I reactions?
Treat Early phase - with epinephrine for patients in anaphylatic crisis, and antihistamines
Treat Late phase - mediators blocking inflammation like glucocorticoids
What is the structure of the FceR1?
Alpha, Beta, and 2 gamma chains. The alpha chain binds IgE monomer the B and 2 gamma chains contain the ITAMs
How does receptor binding lead to degranulation?
Prebound IgE binds a multivalent Ag, aggregration of receptors occurs leading to the activation of the Lyn (kinase associated with Beta chain) which initiates ITAM phosphorylation. Leads to activation of phospholipase C, rise in intracellular Ca2+, and exocytosis
What are the innate responders of Type I hypersensitivites?
Eosinophils
Where are eosinophils produced and what are their important signals/factors?
Produced in the bone marrow.
IL5 (Th2 cytokine drives eos. specific production, cheotaxic)
IL3, GM-CSF (Granulocyte production)
Eotaxins 1,2,3 (chemotaxic)
How do the 3 states of eosinophils differ?
Resting state - looking for antigen in blood.
Primed State - increased FcaR, FcgR, FceR. primed for activation by IL-5, C3a, C5a
Activation State - triggered by Ig cross-linking, potentiated by IL5, GM-CSF, MBP, C3a/C5a; results in exocytosis. secrets IL3,IL5, GM-CSF, IL5, IL8 (PMN chemoattractant). LTC4, LTD4
Why does the hypersensitivity system exist?
Allows us to clear parasites quickly from our system. This is largely a evolutionary hold over from the pressure put on humans by parasitic diseases.
What proof do we see for the evolutionary explanation of hypersensitivity?
in mice that lack mast cells ther is increased susceptibility to Trichinella, Strongyloides.
when there is eosinophil depeletion mediated by antibody there is increased schistosomal infection
What are the manifestations of hypersensitivity?
Asthma and allergy in the respiratory mucosa. Vomitting, diarrhea, hives, anaphylaxis in the GI mucosa. Contact urticaria in the skin. Systemic allergic response with hives, laryngeal edema, loss of airway, hypotension due to exposure in circulation
The wheal and flare responses in a skin testing of allergens are due to what processes?
Wheal - edema
Flare - reddness, vasodilation

- both caused by histamine release
What occurs during anaphylaxis?
a response to systemic circulation antigen. Triggering of peri-vascular tissue mast cells, results in circulating histamine, prostaglandins, leukotrienes. This leads to vasodilation, vascular leakage and high-ouput shock. Laryngeal edema causes airway compromise
Treatment for anaphylaxis
Epinephrine IM, antihistamines, and subsequent corticosteroids.
How does Type II reaction typically manifest?
Typically manifests as a drug reaction
The immune effectors for Type II
Target specific IgM and IgG
What are the two major subtypes for Type II reactions
Reaction to foreign substance acting as a hapten is the classic manifestation. The second form is autoimmunity through the process of molecular mimicry
What is a hapten?
organic molecule too small to elicit an immune response, but is capable of covalent conjugation to self proteins (penicillin--> penicilloyl binding to RBCs)
How does molecular mimicry play a role in hypersensitivity?
when a pathogen that is able to elicit an Ab response is structularly similar to self proetin, it can cause an excessive and inappropriate immune response to self (Group A Strep--> Rheumatic Heart Disease)
Mechanisms of Type II
Same as normal Ab Function mechanisms. Opsonization, neutralization, ADCC, complement mediated lysis, and non-physiologic
Give an example of the targets, results, and syndromes found in Type II reactions
Opsonization-Platelet surface-Splenic Clearance-drug induced thrombocytopenia
Neutralization-AchR-receptor block-Myastenia gravis
ADCC-glom. basement mem. proteins-glom. destruction- post-streptococcal renal failure
Complement-PCN-RBC conjugate- RBC destruction - hemolytic anemia
Non-physio-TSHR-activation-Grave's
What mediates Type III reactions
Immune Complexes
What conditions allow for the formation of immune complexes?
need equivalence which occurs when there is equal amounts of antigen and antibody allowing for the formation of a large multimolecular lattice network
Describe the Arthus reaction
Caused by antibody-antigen complexes forming within small vessel walls. Fcs of complex fix complement and generate C5a. Neutrophil activation, platelet aggregation, and macrophage release of inflammatory mediators
How does the Arthus reaction clinically present?
Only seen in animal models as local erythema, tenderness with edema, necrosis, and hemorrhage which develops within hours.
In humans what is the Type III response often seen?
Serum sickness: rash, fever, lymphadenopathy, joint pain, proteinuria. 2-3 wks after infusion of protein antigen.
What are the two important mediators of Immune complex disease?
Complement/C5a receptor and FcgR. Most of the damage following immunce complex deposit is Fc receptor-mediated.
What makes type IV different from types I, II, III?
Type IV reactions are dependent on T-cell mediated immunity not antibodies.
Is prior sensitization required?
Prior sensitization is required in both Type I and Type IV
How do we know that T-cells are neccessary and sufficient for DTH?
without T-cells you do not get DTH. If you deplete T-cells you reverse sensitization and if you transfer back memory T-cells you can confer sensitization.
What are the manifestations of DTH reactions?
Contact dermatitis. Erythematous, papular, scaling, and blistering. Posion ivy, latex, metals

Tuberculin - occurs in dermis, local induration (MMR, PPD, Candida)
Which cells are mediators of type IV reactions?
CD4 mostly, but also CD8 (poison ivy).
Macrophages and monocytes are activated by T-cells. Basophils are also present.
What cytokines are present at the site of DTH reaction?
IL2 (T-cell proliferation)
IFN-gamma (T-cell signal to acivate macs)
TNF-alpha (macrophage released, upregulates adhesion molecules)
CCL2 - chemokine made by T-cells to attract macrophages
Give three examples of contact dematitits
1. Urushiol (poison ivy) - CD8, small and lipophilic toxin, diffuses into keratinocytes)
2. Analine (component of brown/black dye
3. Chromates (leather tanning)
Describe the important features of phase one in DTH
lipophilic molecule crosses epidermal barrier, haptenylation occurs with epidermal proteins, haptenylated proteins are processed loaded on to MHC I or MHC II, presented by APCs to naive T-cells
Describe the important features of phase two of DTH
re-exposure (elicitation). hapten specific memory T-cells bearing CLA1 continously migrate between lymphatics and skin. Re-exposure with langerhans cell MHC II-->CD4+ activation-->IFN-gamma, MCP1 (recruit macrophages) or MHC I --> CD8+ CTL activation -->perforins and granzymes (local tissue damage, sep of epidermal layer)