Immunology 15

Broad def. : disorder caused by immune responses (dysregulated response to foreign antigen, failure of self-tolerance)
Clinical: excessive immune response against foreign antigen

symptoms elicited by encounter with foreign antigen in a previously sensitized individual

Allergy/ Immediate Hypersensitivity.
IgE mediated, soluble antigen, mast cell as effector mechanism. Example : peanut reaction.

Bystander Reaction.
Hypersensitivity with drug reaction, IgG and IgM monomer mediated, cell or matrix bound antigen, complement and Fc-gamma-R+ effector mechanism

Immune Complex Disease.
IgG multimer mediated, soluble antigen, complement and PMN, Macrophage effector mechanism

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

Sensitization - antigen contact to illicit IgE production
Re-exposure - Preformed IgE is crosslinked with antigen, and triggers mast cell activation

Occurs within seconds or minutes of exposure

IL-4, IL-13 (Th2 cytokines) and CD40L from T-cells

IgG - 30 days
IgE - 2 days

rapid take up by FceR1 on tissue mast cells and circulating basophils

IgE crosslinking -> degranulation of cell --> release of histamine

Histamine.
SM contraction, mucuous secretion, vascular permeability, Gi motility, sensory nerve stimulation

1-2 hours

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

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)

Treat Early phase - with epinephrine for patients in anaphylatic crisis, and antihistamines
Treat Late phase - mediators blocking inflammation like glucocorticoids

Alpha, Beta, and 2 gamma chains. The alpha chain binds IgE monomer the B and 2 gamma chains contain the ITAMs

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

Eosinophils

Produced in the bone marrow.
IL5 (Th2 cytokine drives eos. specific production, cheotaxic)
IL3, GM-CSF (Granulocyte production)
Eotaxins 1,2,3 (chemotaxic)

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

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.

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

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

Wheal - edema
Flare - reddness, vasodilation

- both caused by histamine release

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

Epinephrine IM, antihistamines, and subsequent corticosteroids.

Typically manifests as a drug reaction

Target specific IgM and IgG

Reaction to foreign substance acting as a hapten is the classic manifestation. The second form is autoimmunity through the process of molecular mimicry

organic molecule too small to elicit an immune response, but is capable of covalent conjugation to self proteins (penicillin--> penicilloyl binding to RBCs)

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)

Same as normal Ab Function mechanisms. Opsonization, neutralization, ADCC, complement mediated lysis, and non-physiologic

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

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

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

Only seen in animal models as local erythema, tenderness with edema, necrosis, and hemorrhage which develops within hours.

Serum sickness: rash, fever, lymphadenopathy, joint pain, proteinuria. 2-3 wks after infusion of protein antigen.

Complement/C5a receptor and FcgR. Most of the damage following immunce complex deposit is Fc receptor-mediated.

Type IV reactions are dependent on T-cell mediated immunity not antibodies.

Prior sensitization is required in both Type I and Type IV

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.

Contact dermatitis. Erythematous, papular, scaling, and blistering. Posion ivy, latex, metals

Tuberculin - occurs in dermis, local induration (MMR, PPD, Candida)

CD4 mostly, but also CD8 (poison ivy).
Macrophages and monocytes are activated by T-cells. Basophils are also present.

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

1. Urushiol (poison ivy) - CD8, small and lipophilic toxin, diffuses into keratinocytes)
2. Analine (component of brown/black dye
3. Chromates (leather tanning)

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

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)