Ch 15 - Allergy, hypersensitivities, chronic inflammation

history of allergies

toxin produced by jellyfish, single injection had no effect in dogs but second injection was lethal, called this anaphylaxis (removal of protection)

classification of hypersensitivities

type 1 - allergies

type 2 - complement/cell mediated

type 3 - formation of immune complexes

type 4 - delayed type hypersensitivities (caused by TC)

type 1 hypersensitivity

IgE Ab are responsible, atopic are people predisposed to generate IgE Ab against common environmental Ab, most allergens are proteins w/ multiple epitopes, nature of symptoms depends on route of entry/concentration of allergen/prior exposure; Ag = exogenous, histology = basophils eosinophils, transferred w/ Ab, appearance = wheel and flare

properties of type 1 allergens

have intrinsic enzymatic activity that can affect IR (ex protease disrupts cell junction), many contain potential PAMPs, many enter host via mucosal tissue at low concentration to stimulate TH2 response (triggers BC, IgE secretion)

process of type 1 hypersensitivity

first encounter w/ Ag, BCs secretes IgE, IgE docks on Fc receptors on mast cell, creates a sensitized mast cell, future encounters w/ Ag dock on IgE on mast cell and cause release of granules often histamine (heparin, proteases, other inflammatory responses cause symptoms of allergy); serotonin equivalent to histamine in rats

mediators in primary vs secondary type 1 response

primary - histamine, heparin, eosinophil/neutrophil chemotaxis, proteases

secondary - leukotrienes (ex asthma), prostaglandins, cytokines, platelet activating factor

type 1 early and late response

early - immediate, within minutes of allergen exposure, wheel and flare

late - hours after, localized inflammation (swelling), TNF-alpha and IL-1 influx of neutrophils/eosinophils (more degranulation)/ TH2

systemic anaphylaxis

worst case of type 1 hypersensitivity, shock like and often fatal state, occurs within minutes, allergen introduced directly into blood/absorbed from gut or skin, labored respiration/drop in bp/contraction of smooth muscles (bronchoconstriction), treat quickly with epinephrine to relax smooth muscles and improve CO

localized hypersensitivity reactions

atopy (dematitis, rhinitis, allergic asthma), pathology is limited to a specific target tissue/organ (where first exposure happens), allergic rhinitis (hay fever)/asthma/atopic dermatitis (eczema)/food allergies (allergen cross linking, smooth muscle contraction/vasodilation = vomiting/diarrhea, gut can increase permeability so allergen enters blood stream)

skin testing

allows screening of wide range of Ag at one time, small amts of potenatial allergens are introduced as specific sites by intradermal injection, 30 minutes later sites are reexamined for redness/swelling

hyposensitization

repeated exposure to increasing doses of allergens, also known as immunotherapy, two mechanisms - repeated exposure to low doses increases Tregs producing immunosuppressive cytokines, or may induce increase in IgG4 that competitively inhibit igE binding; hygiene hypothesis proposes exposure to pathogens in infancy benefits those by stimulating IR and making healthy TC subset

type 2 hypersensitivity

Ab mediated w/ Igs other than IgE (IgG, IgM), can induce death in 3 ways (activation of complement, Ab dependent cell mediated cytotoxicity, Ab on foreign cells serves as opsonin phagocytic killing), Ag = cell surface, response time = minutes to hours, appearance = lysis and necrosis, histology = Ab and complement

type 2 blood group reactions

you have Ag on eythrocytes then corresponding serum Ab (not known why you have these, if you have A on RBC you have anti-B in serum), wrong type of blood will be destroyed and form complexes that block vasculature; massive hemolysis, hours later free hemoglobin in plasma gets filtered through kidneys and degraded, metabolized to bilirubin which is toxic at high levels

type 2 hemolytic disease of newborn

develops when maternal Ig Abs specific for fetal group Ag cross placenta and destroy fetal RBC, fatal form is erythroblastosis fetalis (diff alleles of Rh factor, Rh- mother with Rh+ fetus), rhogam shot binds fetal RBC that may have entered mother's circulation before memory BC can be made (so mother can't make Ab against Rh+), if newborn does get disease the conversion of hemoglobin to bilirubin can cause brain damage, destroyed by exposure to UV light

type 2 drug induced hemolytic anemia

some antibiotics and drugs can adsorb nonspecifically to proteins on RBC membranes and form drug protein complex, induces production of Ab that attack drug protein complex and destroy those RBC, stop by stopping the drug use

type 3 hypersensitivity

Ag-Ab complex forms lattice structure that can bind vasculature and destroy vessels, called serum sickness, can resolve spontaneously, Ab = IgG/IgM, Ag = soluble in circulation, response time 3-8 hours, appearance = erthema/edema/ necrosis, histology = complement and neutrophils

type 3 immune complexes

can damage tissues, formation of Ag-Ab complexes and their FcR mediated recognition by phagocytes is part of adaptive IR, big lattice is hard to get rid of (deposited in blood vessel/tissue ex in joints cause joint pain) which results in type 3 rxn, complement fixation (production of anaphylatoxins, activated by immune complexes binding FcR), interact w/ plts form tiny clots; conditions that prevent immune complexes from being cleared - presence of Ag capable of generating extensive Ag-Ab lattices, high intrinsic affinity of Ag for particular tissues, presence of highly charged Ag, compromised phagocytic system

type 3 autoantigens/diseases

autoantigens - improper clearing of apoptic cells, nuclear material released, complexes form, chronic type 3 reaction develops

diseases - autoimmune (systemic lupus, rheumatoid arthritis, multiple sclerosis), infection (meningitis, hepatitis, malaria)

type 3 Arthus reaction

localized type 3 reaction, inject Ag intradermally to which circulating Ab are known to exist, inflammatory rxn will peak 4-10 hours post injection, swelling/localized bleeding/fibrin deposition; ex some people may go from type 1 to type 3 w/ insect bite; systemic Arthus includes Farmer's lung (inhalation of moldy hay), pigeon fancier disease (inhalation of serum protein from pigeon feces)

type 4 hypersensitivity (DTH)

initiation by TC, delay required for reaction to develop, recruits macrophages (not neut/eos) from intracellular pathogens, Ag = tissues/organs, response time = 48-72 hours, appearance = erythema/induration, histology = monocytes/lymphocytes, ex poison ivy

DTH process

APCs pick up Ag that enters skin, transport to regional LN where TC activated (CD4 TH1 subset), initial sensitization of Ag followed by Ag specific TC being activated; 2 phases - sensitization phase and effector phase (when macrophages participate, enhanced phagocytic killing, induced by second exposure to Ag)

DTH response (2nd exposure)

apparent response 24 hours after Ag contact, time for cytokines to induce localized influxes of macrophages, once response starts mediators amplify, prolonged DTH (if Ag can't be cleared) becomes destructive to host = granulomatous reaction, granulomas can fuse for form multinucleated giant cells which can displace and destroy normal cells

type 4 hypersensitivity examples

Mycobacterium tuberculosis, activated macrophages wall off organism in lung and contain it within granuloma type lesion, release of lytic enzymes damages lung tissue; TB test injects small amt Ag under skin, if red lesion in 48-72 hours = positive, means you've been exposed to TB before

contact dermatitis occurs when chemical cpd binds skin proteins, presented to TC, can be cosmetics/hair dyes/etc