Anaphylaxis (page 311)

• An acute, potentially fatal Type I hypersensitivity disorder & medical emergency.

• “Anaphylactoid reactions” are clinically nearly identical to anaphylaxis, but do NOT involve IgE.

• Anaphylaxis: Rapid onset after exposure to offending agent in previously sensitized person (but how does one know the sensitization status?).

• Life-threatening (with: pruritus, urticaria, angioedema, bronchospasm, laryngeal edema, hyper-peristalsis, hypotension) and REQUIRES IMMEDIATE TREATMENT.

• Mediated by IgE, with cross-linking of FcRI on mast cells & basophils, that release preformed and newly sensitized mediators.

Anaphylaxis (pages 311-312)

The most common offending agents include: • Foods (peanuts, tree nuts, shellfish, etc.)

• Horse serum, rabbit serum, monoclonal antibodies

• Insect venom

• Enzymes – aspariginase, chymopapain

• Latex (a big problem for health care workers)

• “Allergy injections” for treatment ( ~ 1 / 10 million)

Fig. 1 (10.19 Parham)Fig. 1 (10.19 Parham). Systemic anaphylaxis is caused by allergens that reach . Systemic anaphylaxis is caused by allergens that reach the bloodstream and activate mast cells (and basophils) throughout the body.the bloodstream and activate mast cells (and basophils) throughout the body.

Page 312

Fig. 4 (10.9 Parham)Fig. 4 (10.9 Parham). Activated eosinophils secrete toxic proteins contained in . Activated eosinophils secrete toxic proteins contained in

their granules and also produce cytokines and inflammatory mediators. their granules and also produce cytokines and inflammatory mediators.

Page 317

Fig. 5 (10.24 Parham)Fig. 5 (10.24 Parham). Allergen-induced release of histamine . Allergen-induced release of histamine by mast cells in skin causes localized swelling.by mast cells in skin causes localized swelling.

Basis of “allergy testing” in sensitized individuals. But what about individuals who may not have been suspected

of being sensitized: e.g., Case 2 (page 319)?

Page 318

Fig. 6 (10.15 Parham)Fig. 6 (10.15 Parham). Sensitization to an inhaled allergen.. Sensitization to an inhaled allergen. Antigens that are leached from inhaled pollen are taken up by

antigen-presenting cells (APC) in the mucosa of the airway. These activate naïve T cells to become TH2 effector cells, which secrete IL-4 and IL-13. Isotype switching by B cells in the presence of TH2 help and IL-4/IL-13 leads to the development of plasma cells that secrete IgE. The IgE binds to FcRI on mast cells and basophils.

Page 319

Fig. 9 (10.22 Parham)Fig. 9 (10.22 Parham). The acute response in allergic asthma . The acute response in allergic asthma leads to Tleads to T

HH2-mediated chronic airway inflammation.2-mediated chronic airway inflammation.

Concept behind current therapy: allergic (“atopic”) asthma is a disorder of “chronic allergic inflammation”.

Corticosteroids become a mainstay of therapy (see page 329 of notes). But….

Page 323

Mary Hewitt Loveless, MDStanford University: AB, 1921; MD, 1925

M. H. Loveless & W. R.Fackler. Wasp venomallergy and immunity.Annals of Allergy 14:347-366 (Sept.-Oct.) 1956.[Dept. of Medicine of New York Hospital & CornellUniversity Medical College]

Mary Hewitt Loveless, MDStanford University: AB, 1921; MD, 1925

M. H. Loveless & W. R.Fackler. Wasp venomallergy and immunity.Annals of Allergy 14:347-366 (Sept.-Oct.) 1956.[Dept. of Medicine of New York Hospital & CornellUniversity Medical College]

Her experimental subjectswere her patients.

* D.Zhu, C. L. Kepley, K. Zhang, T. Terada, T. Yamada & A. Saxon. Nat. Med. 11:446-9, 2005. (Their experimental subjects were mice.)

A chimeric human-cat fusion protein blocks cat-induced allergy *

* Figure from: Janet Kalesnikoff & S. J. Galli. Nipping cat allergy with fusion proteins. Nat. Med. 11:381-2, 2005.

Disclosure of conflict-of-

interest: I am a

member of the Scientific Advisory Board of Tunitas

Therapeutics, Inc., a start up

company seeking to

develop fusion proteins and

other products for treating

allergic disorders.

Fig. 1 (10.2 Parham)Fig. 1 (10.2 Parham). There are four types of immune-mediated . There are four types of immune-mediated hypersensitivity reactions that can cause tissue damage.hypersensitivity reactions that can cause tissue damage.

Review: Slide from lecture I

Fig. 1 (10.2 Parham)Fig. 1 (10.2 Parham). There are four types of immune-mediated . There are four types of immune-mediated hypersensitivity reactions that can cause tissue damage.hypersensitivity reactions that can cause tissue damage. These These basic immunological mechanisms can be directed against basic immunological mechanisms can be directed against

exogenous or endogenous antigens (or “autoantigens”)-in the exogenous or endogenous antigens (or “autoantigens”)-in the latter case, this can result in autoimmune disorders (Bill Robinson latter case, this can result in autoimmune disorders (Bill Robinson

lectures and see Parham chapter on lectures and see Parham chapter on Autoimmune diseasesAutoimmune diseases).).

AutoImm.D.: AHA MG, GD SLE IDDM, RA, MS

 

Fig. 15 (7.26 Parham)Fig. 15 (7.26 Parham). IgE crosslinking on mast cell surfaces leads to the . IgE crosslinking on mast cell surfaces leads to the rapid release of mast-cell granules containing inflammatory mediators.rapid release of mast-cell granules containing inflammatory mediators.

Review:Slidefrom

lecture I

 

Fig. 15 (7.26 Parham)Fig. 15 (7.26 Parham). IgE crosslinking on mast cell surfaces leads to the . IgE crosslinking on mast cell surfaces leads to the rapid release of mast-cell granules containing inflammatory mediators.rapid release of mast-cell granules containing inflammatory mediators.

As IgE levels

increase,so doesSurface

expressionof FcRI, making

mast cells &

basophils“better” effector

cells

Fig. 16 (10.5 Parham)Fig. 16 (10.5 Parham). Molecules synthesized and released by mast cells on . Molecules synthesized and released by mast cells on stimulation by antigen binding to IgE.stimulation by antigen binding to IgE.

Review:Slide from

lecture I