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Flashcards in Immunopathology Deck (36):

What is Type I hypersensitivity?



IgE, mast cells, and lipid mediators


What is Type II hypersensitivity?

antibody mediated


IgM and IgG against cell-bound or extracellular matrix antigens


What is Type III hypersensitivity?

immune complex


IgM and IgG immune complex deposition


What is Type IV hypersensitivity?

delayed type


CD4 mediated


What is an allergy?

  • Type I/immediate hypersensitivity (associated with forms of Type IV)
  • Immune-mediated inflammatory response to common environmental antigenst that are otherwise harmless


What is an atopic individual?

  • hihg levels of circulating IgE (normally barely detectible)
    • ths vaires with condition
  • elevated eosinophils in circulation in tissues
  • elevated of Th2 cells secreting IL-4


IgE is specialised to control...



What are the two phases of immediate (Type I) hypersensitivity?

  • sensitization - rapid, usually not noticed
  • response - varies
    • local (common) - rhinitis, bronchoconstriction, conjunctivitis, hives, skin rashes, hay fever
    • systemic (rare) - anaphylaxis
    • immediate and late phase (both may be occuring at once)


What are the 6 main contributors to the immediate/Type I hypersensitivity mechanism?

  • allergens (antigens)
  • Th2 cells - switch on B-cells to produce IgE
  • IgE (antibody)
  • FceRI (high affinity FceR) - IgE receptor
  • mast cells - major player, FceRI receptors
  • eosinophils


What are the features of allergens?

  • repeated exposure via mucosal route
  • inhaled: highly soluble proteins, carried by small particles
  • ingested: slowly degraded
  • not easily broken down
  • highly soluble in body fluids (causes systemic response)
  • introduced at very low doses (favours Th2 response)
  • allergens are often (not always) enzymes
    • body might mistake them for parasite enzymes


What are the acute and chronic responses to inhaled allergens?

  • acute (pollens, Der p 1)
    • rhinitis, conjunctivitis, hayfever
  • chronic (+ danders)
    • asthma
      • shares some delayed type IV features


What is the sensitization mechanism of Th2 activation?

  • Low dose Ag via mucosal route
  • APC has taken it up and presented it
  • in presence of IL-4 binds to T cell
  • Differentiates to Th2
  • Th2 produces IL-4, IL-5, and IL-13


What is the sensitization mechanism IgE secretion?

  • Th2 interacts with B-cells via CD40 ligand
  • in presence of IL-4 and IL-13
  • induces proliferation
  • induces isotype switching to IgE


How do dendritic cells contribute IL-4 to Th2 differentiation?

  • indirectly (do not produce IL-4)
  • some produce IL-33
    • basophils are activated by IL-33 (and allergens) to secrete IL-4
    • production of IgE

this is part of the sensitization phase


How do basophils contribute IL-4 to Th2 differentiation?

  • act as APCs
    • express MHC I and II, PRRs
    • interact w/Ag
    • present Ag to CD4 Th2 via MHC II - TCR (signal 1)
      • upregulation of co-stimulatory molecules (CD80/86 - CD28) (signal 2)

      • secrete IL-4 (signal 3)

      • activates Th2 cells

this is part of the sensitization phase


How do dendritic cells and basophils contribute to Th2 differentiation and IgE production in the sensitization phase?

dendritic cells

  • proudce IL-33
  • induces basophils to release IL4
  • Th2 differentiation
    • +CD40L, IL-4, IL-5, IL-13 by Th2 cell
    • binds CD40 --> IgE


  • act as APCs
  • present allergen/Ag on MHC II - binds to TCR on Th2 cell
  • upregulate CD80/86 production - binds to CD28 on Th2
  • upregulate IL-4 secretion
  • Th2 differentiation
    • +CD40L, IL-4, IL-5, IL-13 by Th2 cell

    • binds CD40 --> IgE


What are the properties of mast cells?

  • mucosal and epithelial tissues, near interacting areas w/infectious agents e.g. blood vessels
  • contain pre-formed granules
  • bind IgE via high-affinity FceR (only receptor that binds Ab not bound to Ag)
    • sensitizes the mast cell
    • surface-bound IgE is very stable (lasts months or years; normal Ab is 24hrs)
  • binding of IgE (Ab) to allergen induces cross-linking of FceRs
  • degranulation (immediate)
    • contain inflammatory mediators
  • synthesis of more inflammatory mediators (lipid mediators, chemokines, cytokines)


Activation of mast cells results in:

  • secretion of preformed mediators from granules (immediate, 30-45s)
    • histamine, heparin, enzymes (tryptase, chymase), TNF-a
  • synthesis and secretion of lipid mediators on mast cell activation (still immediate, 10-30mins)
    • prostaglandins and leukotrienes from arachidonic acid intermediates
  • synthesis and secretion of cytokines (slow)
    • mast cells make more mRNA for synthesis of cytokines, IL-3, IL-4, IL-13, IL-5, TNF-a


What is a wheal and flare response?

  • type I hypersensitivity (immediate)
  • immediate phase (seconds to minutes)
  • allergen introduced into skin
  • components released from granules and synthesized by mast cells (e.g. histamines)
  • blood vessels dilate, leak plasma --> swelling, pallor (wheal, squishy)
  • further dilation leads to reddened area from blood (flare)


What is the late phase of the wheal and flare response?

  • type I/immediate hypersensitivity
  • late phase (8-12 hours)
  • much bigger response by the slowly produced mediators (chemokines, cytokines, leukotrienes)
  • site is full of cells (neutrophils, Th2 cells, basophils, eosinophils)
    • sustained oedema, hard to touch
    • eosinophil presence is characteristic of atopic individuals


What are the common allergic responses induced by mast cells?

  • vasodilation
  • vasopermeability
  • smooth muscle contraction
  • fluid secretion


What is the reaction to the allergic response of mast cells in the GIT?

  • +fluid secretion and +peristalsis
  • leads to diarrhea and vomiting


What is the reaction to the allergic response of mast cells in the skin?

  • +fluid secretion (wheal) and +vasodilation (flare)
  • leads to swelling, itching, urticaria (hives)


What is the reaction to the allergic response of mast cells in the airways?

  • -broncial diameter, +mucous
  • nasal blockage, coughing, phlegm, asthma


What is the reaction to the allergic response of mast cells in the blood vessels?

  • +blood flow, +permeability
  • leads to +tissue fluid, +cell infiltrate
  • can lead to anaphylactic shock (systemic)
    • CO cannot keep up with +blood flow to hugely dilated vessels


What cell type is characteristic of the late effector phase of type I/immediate hypersensitivity?


  • normally in mucosal linings at low numbers to protect against parasites
  • when activated (late only) they produce toxic granule-derived basic proteins and free radicals responsible for tissue damage and remodelling (meant for parasites, but instead is happening to us)
  • produce chemical mediators that activate local tissues
    • epithelial cell activation, inflammatory cell recruitment and activation
  • normally, tightly controlled; bypassed in allergic responses


What happens when eosinophil control is bypassed in late allergic responses?

  • part of type I/immediate hypersensitivity late effector phase
  • IL-5 produced by early Th2 cells and by mast cells activates:
    • eosinophils
    • eosinophil production by bone marrow
  • eosinophils are then attracted to and infiltrate tissues (inflamatory chemokines from epithelial cells)
  • activation in tissues:
    • release toxic granules
    • upregulate FceRIs, boosting IgE binding and tf activation and degranulation (increased sensitivity, decreased threshold)


What are some symptomatic allergy treatements?

these are non-antigen specific treatments

  • adrenaline/epinephrine in anaphylaxis
  • inhaled B-aR agonists in asthma
  • antihistamines for hives, allergic rhinitis
  • corticosteroids


What is immunotherapy or desensitization?

  • administration of increasing doses of allergen to achieve tolerance
  • induces T-cell tolerance by:
    • -allergen-induced proliferation
    • switch from Th2 response to Th1 response (leads to deviation of secreted cytokines)
    • switch T cells to kill themselves
    • production of Treg cells to control Th2 cells
  • new research is targeting basophils and eosinophils


What are the feautres of delayed type/type IV hypersensitivity?

  • cell mediated: ++T-cells (particularly Th1, sometimes Th8) and macrophages
  • it is a normal immune response


What elicits delayed type/IV hypersensitivity?

Persistent antigenic stimulation, e.g.

  • mycobacterium TB
  • mycobacterium perae
  • actinomyces 
  • leishmania sp
  • schistosoma sp
  • hep B & C viruses
  • picrylchloride
  • hair dyes
  • nickel salts
  • poison ivy
  • thiomersol


What is the mechanism of the sensitization phase in delayed type/IV hypersensitivity?

priming of the adaptive response

  • allergen/Ag in skin or mucosa taken up by APCs
  • APCs take it to lymph nodes
  • APCs produce +IL-12:
    • --> T-cell differentiation to Th1
    • --> switches on CD8 T cells
  • CD8 T cells & Th1--> site of allergen/Ag but cannot remove it
  • allergen/Ag persists
  • this process continues on and on


What are the 3 main kinds of type IV/delayed type hypersensitivity?

  • contact sensitivity (poison ivy, adhesives, tuberculin skin test)
    • usually caused by chemicals
    • previous sensitization, upon re-exposure central and effector memory cells are triggered
  • infection (mycobacterium tuberculosis)
    • inability to clear organism results in persistent activation of Th1 cells
  • non-infectious disease: celiac disease
    • exposure to wheat products induces Th1 dependent immunopathology of intestinal wall


What is the mechanism of contact hypersensitivity?

sensitization (e.g. poison ivy, pentacdecatechol = Ag)

  • Ag picked up by DCs in skin
  • broken down, displayed on MHC
  • DC drains to local lymph node
  • activates naive T cells
  • T cells migrate back to skin as memory T cells (normal)


  • on re-exposure more DCs are activated (as above) AND activation of memory T cells in skin
  • huge increase in T cells at infection site = hard swelling (cells, not fluid)
  • cells produce lots of IFNy (Th1s)
    • massive macrophage activation at inflammatory site
    • v. problematic



What is the mechanism of delayed type hypersensitivity responses in TB?

  • inhaled in droplets --> alveoli
  • TB (facultative intracellular pathogen) survives in the alveolar macrophages
  • some break down by macrophages, cytokines released (IL-12)
  • DCs take bits of TB to lymph nodes --> Th and CD + IL-12 --> Th1

  • TH1 stimualtes more macrophages via IFNy --> cycle persists

  • prolonged macrophage by IFNy activation produces:

    • IL-8, Il-1, TNFa --> endothelial activation, phagocyte and lymphocyte migration

    • IL-1 --> fever

    • TNFa --> weight loss, granuloma formation

      • contains MNG cells, epithelioid cells, monocytes, CD4s, CD8s

      • normal response, controls infection (90%)
      • can interrupt respiratory/alvelolar function (10%)
        • can burst BVs, cause hemoptysis (bloody sputum)


What is the mechanism of delayed type/IV hypersensitivity in celiac disease?

  • gliadin, breakdown product of gluten (wheat, barley, rye)
    • consists of glutamine & proline
    • +ve glutamine cannot bind gliadin to +ve HLA peptide binding cleft
    • tissue transglutaminase 2 (tTg2) in endomysial cells of intestinal lamina propria deamidate glutamine --> glutamate (-ve)
    • -ve glutamate binds HLA-DQ2 (& DQ-8)
      • >90% CD have HLA-DQ2 MHC
    • APCs under mucosa can bind gliadin
    • APCs --> T cells in MALT --> Th1
    • Th1 --> lamina propria --> ++ IFNy --> activate mø
    • mø release toxic contents, damage villi
      • elongated clefts, ablated villi, +immune cells


  • **we produce Abs to gliadin and tissue transglutaminase
    • used for diagnosis (not involved in disease)