Type 1 Hypersensitivity

Question 1

Type I hypersensitivity

Answer 1

Occurs when IgE antibody is made
by atopic (allergic) individuals. IgE
binds to FcEpsilon receptors on
mast cells. Encounter with allergens
causes cross-linking of IgE
antibodies on mast cells & results in
the release of mediators into the
circulation which cause the
symptoms of allergies.

Question 2

Receptor on IgE: culprit in allergy

Answer 2

FceRI receptor binding site

Question 3

sensitization phase

Answer 3

1. Allergens are internalized by antigen-precengin cells and degraded by proteolytic enzymes in phagosomes.
2. intracellular association of allergen peptides with MHC complex (2) then move to the cell surface.
3. CD4 T cells recognize the allergens by binding to MCH and to allergen
4. IL-4 and other cytokines are secreted by TH2 cells leading to isotope switching and the resultant production of specific IgE by lymphocytes
5. IgE then attached to mast cells and basophils, completing the process.

Question 4

Th1 is associated with …

Answer 4

IL-12

Question 5

Th2 is associated with….

Answer 5

IL-4

Question 6

Proteins found in nature (allergens)

Answer 6

Tree pollen
– Grass pollen
– Weed pollen
– Molds
– Dust mite feces
– Cockroaches
– Animal danders

Question 7

T cell expansion and differentiation

Answer 7

antigen exposure of native T cells results in activation, proliferation and differentiation of T cells into th1 or th2 effector cells. Th1 differentiation is enhanced by IL-12. Th2 differentiation is enhanced by IL-4

Question 8

Effector phase of allergy activation

Answer 8

IgE receptor binding : allergens bind to Fab region on sensitized cells activating mediator release.

Question 9

early effector phase

Answer 9

mast cells release histamine, proteases, chemoattractants; causes vasodilation, smooth muscle contraction, brochochonstriction, increased vascular permeability; increased secretions.

Question 10

late effector phase

Answer 10

8-12 hours

mediators require synths IL 4,5, 10 and leukotrienes
Eosinpphils: granule contents toxic major basic protein
increases early downstream effects, prolongs inflammatory response

Epithelial damage and loss cilia
increase mucous and mucous glands

Question 11

afferent immune response

Answer 11

IgE-dependent antigen focusing and presentation in the afferent immune response.
Allergen/antigen–IgE antibody complexes are
bound to FceRII (CD23) on activated B cells and FceRI and/or FceRII on FDC, IDC and LC. This leads to antigen focusing and enhanced presentation to T cells in the initiation of an immune response which is skewed toward a Th2-like pattern and IgE production. Antigen-
specific IgE would feed back positively to
amplify the antigen-specific IgE production and allergic response while IgG would inhibit
these processes.

Question 12

inhibitor immunoglobulin

Answer 12

IgG

Question 13

Th1 and Th2 mediated inflammation

Answer 13

The introduction of an
infectious agent stimulates the release of
chemokines & TNF-a from tissue macrophages, stimulating the recruitment (up-ward arrows) of T cells and monocytes. Antigen recognition by T cells stimulates the production of Th1 cytokines. IFN-y activates macrophages, enhancing the clearance of infectious agents.

Trafficking to sites of Th2 responses is
stimulated by local chemokine expression,
leading to T-cell recruitment. Antigen recognition leads to IL-4 production by Th2 cells, which stimulates IgE class switching of antigen-specific B cells. Cross linking of FceRI molecules bound to IgE leads to the degranulation of mast cells
and eosinophils.

Question 14

effects of mast cell products
Histamine
LTC
PGD
TNF-a
proteases

Answer 14

Question 15

Disease of type 1 hypersensitivity

Answer 15

Hayfever (Allergic rhinitis), Allergic
Conjunctivitis
• Asthma
• Urticaria (hives & angioedema)
• Anaphylaxis (Systemic allergic
reaction)

Question 16

Pathogenic mechanism of anaphylaxis

Answer 16

Mast cells and basophils are activated and degranulated either through cross-linking of IgE molecules on the cell surface by antigen (classic anaphylactic pathway) or by a variety of different stimuli leading directly to activation/degranulation, independent of IgE (anaphylactoid pathway).

Upon triggering, preformed mediators such as histamine are released as a consequence of non-cytolytic extrusion and subsequent rupture of granules. Other mediators, including prostaglandins, leukotrienes, and cytokines, are synthesized in response to cellular activation. The explosive, nearly simultaneous release and synthesis of mediators from a very large number of cells initiates systemic pathophysiologic events that can lead to the signs and symptoms of an anaphylactic reaction.

Question 17

Time course of histamine release and physiologic changes after allergen challenging during early-phase response

Answer 17

There was an immediate increase in sneezing, secretion production, and histamine release with a more delayed rise in nasal airway resistance (NAR).
In contrast to the rise in sneezes & histamine levels which were of fairly short duration, production of nasal secretions & nasal congestion were more prolonged after a single-dose allergen challenge.
Histamine increased only on the side of challenge whereas secretions & NAR increased in both nostrils indicating a nasonasal reflex.

Question 18

migration of eosinophils

Answer 18

Migration of eosinophils from the vascular lumen to tissue sites of inflammation. The cells first roll along the endothelium 1 and eventually adhere to it 2. The cells then migrate into tissue sites of inflammation 3.

These different steps are coordinated by interactions between adhesion molecules on the endothelium and counterligands on inflammatory cells with orchestrating influences by cytokines and chemokines.

Question 19

chronic inflammation

Answer 19

Deposition of reticulin, fibronectin,
collagen I & III, extracellular matrix

• Hyperplasia of airway smooth
muscle

• Hyperplasia of mucous glands

Question 20

detection of allergy

Answer 20

Allergy skin tests

RAST (radioallergosorbent) assay for
specific IgE

Question 21

Allergy skin test

Answer 21

Immediate reactions:
– Wheal size & erythema read at 15-30 min •

Late Phase Cutaneous Reactions (LPCR)
– Develop 6-12 hrs later
– No standard way of grading.
– Inhibited by corticosteroids but not
antihistamines – Uncertain if they are relevant to delayed
clinical responses

Question 22

treatment of allergy

Answer 22

Avoidance • Medications
– Beta Agonists (adrenaline/epinephrine)
• Injected, inhaled – Steroids (topical, oral) – Antihistamines – Leukotriene antagonists – Immunosuppresants (Tacrolimus)
• Hyposensitization (Allergy shots) • Monoclonal Ab to IgE

Question 23

Monoclonal antibody to IgE

Answer 23

IgE binds to mast cell FcεRI
– IgE triggers release of inflammatory mediators
– Released by FDA in 2003 (Xolair=omalizumab)

Question 24

soluble IL-4 receptors

Answer 24

IL-4 necessary for IgE synthesis by B cells
– IL-4 involved in eosinophil recruitment to airways
etc – Studies show some clinical benefit in asthma

Question 25

monoclonal antibody to IIL-5

Answer 25

IL-5 essential for eosinophil maturationI – IL-5 activates eosinophils, prolongs eosinophil survival – Clinical effect not striking

Question 26

R112

Answer 26

R112, is an intranasal inhibitor to Syk, or spleen tyrosine kinase, a novel drug target for allergic rhinitis (or allergy) and asthma. Syk is involved in IgE signaling in mast cells. : Initial clinical studies demonstrated underwhelming efficacy

Question 27

Genetics

Answer 27

Multigenic – One parent w asthma 25% asthma risk – Two parents w asthma 50% asthma risk

Question 28

hygiene hypothesis

Answer 28

fewer infections, exposure to antibiotics, small family size = th2 preponderance

Question 29

prevention practices

Answer 29

Breast feeding • Avoid tobacco smoke • Good home ventilation • Avoid dampness in home • Families following precautions 14.5% asthma among children. • Families not following precautions 35.5%

Question 30

Penicillin allergy

Answer 30

Penicillin functions as a hapten • Reaction with self protein or • Reaction with MHC peptide complexes on APCs. • Covalently bound. • Haptens in combination with protein or MHC peptide complexes  many antigenic epitopes. Humoral and cellular immune responses.

Question 31

B cell isotype switch; 2 signals required for IgE synthesis

Answer 31

Signal 1: Lymphokines e.g. IL-4, IL-13 (from Th cells, Basophils & Mast cells)  germ line mrna germ line transcription  Signal 2: B cell CD40 engages with T cell CD40 ligand  There is further amplification of IgE production if allergen is presented with IgE as complexes on FcR(CD23)

Question 32

TH1 cells

Answer 32

Antigen: infectious agent Lympohkins: IL-2, TNFa, INF Ig: IgM, IgG Effector cells: macrophages

Question 33

Th2

Answer 33

antigen: allergen lymphokines: IL4, IL13 IG: IgE effector cells: mast cells, eosinophils

Question 34

Histamine

Answer 34

This mediator acts on histamine 1 (H1) and histamine 2 (H2) receptors to cause contraction of smooth muscles of the airway and GI tract, increased vascular permeability and vasodilatation, nasal mucus production, airway mucus production, pruritus, cutaneous vasodilatation and gastric acid secretion.

Question 35

tryptase

Answer 35

Tryptase is a major protease released by mast cells. It can cleave C3 and C3a. It is found in all human mast cells but in few other cells and thus is a good marker of mast cell activation.

Question 36

carboxypeptidase

Answer 36

(Recently 3/06 carboxypeptidase was reported to be preferentially released by mast cells and measurement of levels capable of detecting anaphylaxis, when tryptase levels were not elevated, and within 8 hours of the onset of an allergic reaction.)

Question 37

proteoglycans

Answer 37

Proteoglycans: Heparin & chondroitin sulfate. Heparin may play role in production of alpha-tryptase.

Question 38

chemotactic factors

Answer 38

Chemotactic factors: An eosinophilic factor of anaphylaxis causes eosinophil chemotaxis; an inflammatory factor of anaphylaxis results in neutrophil chemotaxis. Eosinophils release major basic protein and, together with the activity of neutrophils, can cause significant tissue damage in the later phases of allergic reactions.