Type 1 Hypersensitivity Flashcards
Type I hypersensitivity
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.
Receptor on IgE: culprit in allergy
FceRI receptor binding site
sensitization phase
- Allergens are internalized by antigen-precengin cells and degraded by proteolytic enzymes in phagosomes.
- intracellular association of allergen peptides with MHC complex (2) then move to the cell surface.
- CD4 T cells recognize the allergens by binding to MCH and to allergen
- IL-4 and other cytokines are secreted by TH2 cells leading to isotope switching and the resultant production of specific IgE by lymphocytes
- IgE then attached to mast cells and basophils, completing the process.
Th1 is associated with …
IL-12
Th2 is associated with….
IL-4
Proteins found in nature (allergens)
Tree pollen
– Grass pollen
– Weed pollen
– Molds
– Dust mite feces
– Cockroaches
– Animal danders
T cell expansion and differentiation
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
Effector phase of allergy activation
IgE receptor binding : allergens bind to Fab region on sensitized cells activating mediator release.
early effector phase
mast cells release histamine, proteases, chemoattractants; causes vasodilation, smooth muscle contraction, brochochonstriction, increased vascular permeability; increased secretions.
late effector phase
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
afferent immune response
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.
inhibitor immunoglobulin
IgG
Th1 and Th2 mediated inflammation
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.
effects of mast cell products
Histamine
LTC
PGD
TNF-a
proteases
Disease of type 1 hypersensitivity
Hayfever (Allergic rhinitis), Allergic
Conjunctivitis
• Asthma
• Urticaria (hives & angioedema)
• Anaphylaxis (Systemic allergic
reaction)
Pathogenic mechanism of anaphylaxis
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.
Time course of histamine release and physiologic changes after allergen challenging during early-phase response
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.
migration of eosinophils
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.
chronic inflammation
Deposition of reticulin, fibronectin,
collagen I & III, extracellular matrix
• Hyperplasia of airway smooth
muscle
• Hyperplasia of mucous glands
detection of allergy
Allergy skin tests
RAST (radioallergosorbent) assay for
specific IgE
Allergy skin test
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
treatment of allergy
Avoidance • Medications
– Beta Agonists (adrenaline/epinephrine)
• Injected, inhaled – Steroids (topical, oral) – Antihistamines – Leukotriene antagonists – Immunosuppresants (Tacrolimus)
• Hyposensitization (Allergy shots) • Monoclonal Ab to IgE
Monoclonal antibody to IgE
IgE binds to mast cell FcεRI
– IgE triggers release of inflammatory mediators
– Released by FDA in 2003 (Xolair=omalizumab)
soluble IL-4 receptors
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
monoclonal antibody to IIL-5
IL-5 essential for eosinophil maturationI
– IL-5 activates eosinophils, prolongs eosinophil survival
– Clinical effect not striking
R112
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
Genetics
Multigenic
– One parent w asthma 25% asthma risk
– Two parents w asthma 50% asthma risk
hygiene hypothesis
fewer infections, exposure to antibiotics, small family size = th2 preponderance
prevention practices
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%
Penicillin allergy
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.
B cell isotype switch; 2 signals required for IgE synthesis
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 FcR(CD23)
TH1 cells
Antigen: infectious agent
Lympohkins: IL-2, TNFa, INF
Ig: IgM, IgG
Effector cells: macrophages
Th2
antigen: allergen
lymphokines: IL4, IL13
IG: IgE
effector cells: mast cells, eosinophils
Histamine
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.
tryptase
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.
carboxypeptidase
(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.)
proteoglycans
Proteoglycans: Heparin & chondroitin sulfate. Heparin may play role in
production of alpha-tryptase.
chemotactic factors
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.
