Hypersensitivity - Schein 4/11/16 Flashcards Preview

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Flashcards in Hypersensitivity - Schein 4/11/16 Deck (20):
1

hypersensitivity

4 types

exaggerated response of the immune system to some antigen in a damaging way

  • aka allergic reaction

 

4 types:

type I : IgE mediated hypersensitivity - ab (Th2)

type IIantibody-mediated cytotoxic hypersensitivity - ab (Th2)

type IIIimmune complex-mediated hypersensitivity - ab (Th2)

type IV : Delayed Type hypersensitivity - T cells (Th1)

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type I hypersensitivity

immediate (minutes) = allergy (atopy)

  • initial exposure: sensitization → Th2 activation → IgE made
    • IgE binds Fc receptor on mast cells and basophils, hangs out waiting for secondary exposure
  • secondary exposure: multivalent antigen causes cross-linking of surface IgEs → release of inflammatory mediators by mast cells, eosinophils, basophils
    • mast cell pdts attract eosinophils (primary defense against parasites/worms/etc)

ex. hay fever, asthma, allergy to penicillin, expulsion of worms/insect infections

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allergy mediators

primary (stored)

  • histamine, serotonin (vascular permeability, smooth muscle contraction)
  • eosinophil chemotaxis mediators
  • neutrophil chemotaxis mediators
  • protease (mucus secretion, connective tissue degradation)

secondary (synthesized)

  • leukotrienes (vascular permeability, sm muscle contraction)
  • prostaglandins (vasodilation, sm muscle contraction, platelet activation)
  • bradykinin (vascular permeability, sm muscle contraction, pain)
  • cytokines (recruit immune cells, inflammation)
  •  

4

manifestations of allergy

symptoms: sneezing, coughing, wheezing, diarrhea

local anaphylaxis: allergic rhinitis, asthma, urticaria (hives), atopic dermatitis (eczema), angioedema (swelling of soft tissues)

late phase rxn: cytokines recruit eosinoiphils, neutrophils, lymphocytes → promotes infl

systemic anaphylaxis

  • disseminated mast cell activation → increased vasc permeability, constriction of sm muscle
    • leads to extravasation of fluid ( → hypotension), constriction of airways, epiglottis swelling

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skin test for allergy

small amt of allergen introduced via intradermal injection or superficial scratching

 

local mast cells degranulate → increased permeability and fluid leakage, vasodilation and increased blood flow

  • wheal: swelling, local region of intense edema. appears white bc capillaries are occluded
  • flare: larger surrounding areas of redness due to vasodil

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RAST test for allergy

radioallergosorbant test

detects level of IgE

 

  • allergens are coupled to beads
  • patient serum is added → IgE binds beads
  • radiolabeled anti-IgE is added, measured → IgE quantified

 

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allergy shots

desensitization

introduce small amounts of antigen in increasing amounts over a period of time

goal: try to get isotype switching from IgE → IgA, IgG

  • trying to get Tregs going to suppress Th2 cells that are forming IgE
  • if it works; IgA and IgG will bind to and neutralize antigen when it's encountered, prevent it from binding IgE → prevent it from setting off allergic rxn 

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hygiene hypothesis

modern day practice of hitting everything with antiseptics and avoiding all types of microbial contact → insufficient contact leading to insufficient stimulation of Th1 reactions

  • results in imbalance of Th1/Th2 → more Th2 → processing of innocuous environmental agents as threats → allergic responses

theory: exposure to diverse environmental antigens may actually prevent sensitization to any particular one

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type II hypersensitivity

antibody-mediated cytotoxicity

hours (vs Type I minutes)

IgM or IgG dependent → bind to antigens on cell surfaces

opsonization → 

  • phagocytosis by macrophages and neutrophils
  • neutrophil recog and secretion of lytic enzymes (antibody-dependent cell-mediated cytotoxicity = ADCC)
  • complement activation (MAC attack)

 

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ADCC

antibody-dependent cell-mediated cytotoxicity

 

target cell is coated with antibodies → target cell is lysed by cytosolic effector cells

  • NK cells
  • macrophages
  • neutrophils

 

no complement required!!!

but dependent on prior antibody response

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type II hypersensitivites (rxns)

  • transfusion reactions
  • hemolytic disease of newborn (HDN)
  • autoimmune diseases
  • drug-induced hemolytic anemia
    • antibiotics (cephalosporin, penicillin, streptomycin
    • cell membrane is carrier for hapten-carrier complexes

*hapten: small molecule that can bind an antibody but is not immunogenic in and of itself

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type III hypersentitivity

4-12 hours

immune complex disease : caused by circulating antigen-antibody complexes that can lodge in small vessels and filtering organs

  • complexes = antigen + high-affinity IgG (lower affinity IgM)

mechanisms

1. large complexes are insoluble

  • fix complement → phagocytosed

2. small complexes can get into tissues where they can cause probs

  • not cleared as readily, can accumulate in blood, get deposited in vessels

3. complement C3a and C5a (anaphylatoxins) 

  • induce mast cell degranulation (IgG, not IgE)
  • mediate inflammation response
    • release cytokines, attracts neutrophils to come through and phagocytose and release lytic enzymes (tissue injury)

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Arthus reaction

type III rxn

  • acute response initiated by local deposition of Ag/Ab complexes
  • 4-12 hours to develop
    • immune complexes must form in situ → activate mast cells and neutrophils, activate complement
  • develops more slowly than type I hypersensitivity, more quickly than type IV hypersensitivity

looks like wheal and flare! BUT takes hours to form

  • pay attn to time course!

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localized vs. systemic type III rxns

localized

  • local vasculitis: deposition of immune complexes in dermal blood vessels
  • insect bites
  • drugs/vaccines
  • intrapulmonary (inhaled bacterial spores, fungi (Farmer's Lung), fecal proteins)

systemic

  • serum sickness
  • autoimmune diseases (rheumatoid arthritis, systemic lupus erythematosus) 

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example of arthus rxn

drunk pt who gets a laceration, needs a tetanus booster (no need for antiserum, bc already got vaccine 5 yrs ago)

pt struggles, shot thats supposed to be intramuscular is given intradermal

12 hours later → painful lesion.

what happened?

point of intramuscular protocol: let booster diffuse into lymphoid system so that antigen therein can trigger antibody-generation

 

intradermally injected shot cant diffuse out quickly → end up reacting with the antibody already present  → localized type III hypersensitivity rxn

16

type IV hypersensitivity

delayed type hypersensitivity (DTH)

48-72 hours (symptoms start 24h after second exposure, peak in this window)

antibody independent : mediated by antigen-specific Th1 cells

  • recruit monocytes/macrophages, granuloma formation
  • activate CTLs → cell killing

process

  • Th1 cells are sensitized : APCs presented to Th1 by APC-MHC/antigen presentation → activated Th1 cells undergo clonal expansion
  • subsequent exposures? 
    • memory T cells recognize antigens, go to work → secrete cytokines, recruit macrophages (main players, over 80% of infiltrate) and other nonspecific infl cells (neutrophils - secondary players)

ex. TB skin test

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type IV reactions

  • TB skin test
  • allergy to metal salts or other small reactive chemicals (haptens)
    • bind to proteins → create new epitopes
    • contact dermatitis to coins, jewelry
  • organ rejection
  • skin contact to poison ivy

18

example of type IV rxn:

bone marrow transplant recipient gets transplant, presents soon after with skin rash, diarrhea, jaundice, 

progressive worsening and indication of pneumonia and kidney failure

 

what happened?

gravt vs host disease!

 

graft contained some immunocompetent T cells that are active → recognize host MHC as foreign → attack whole host body as foreign :(

 

issue: donor cells have never seen foreign MHC before - read it as MHC+peptide, which is a target for attack

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hypersensitivity types

ABCD

I: anaphylactic: IgE mediated hypersensitivity

  • Allergic Anaphylaxis and Atopy 

II: cytotoxic: antibody-mediated cytotoxic hypersensitivity

  • antiBody

III: ImmuneComplex: immune complex mediated hypersensitivity

  • immune Complex

IV: DTH: delayed type hypersensitivity

  • Delayed

 

or, ACID (anaphylaxis/atopy, cytotoxic, immunecomplex, delayed)

A image thumb
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atopic

predisposed to v severe allergic rxns