Type 1 hypersensitivity reaction

(allergy)

Dr. Prathyusha

PG in ENT Narayana Medical College

NELLORE

once upon a time………• Menes, the first

Egyptian pharaoh ruled

about 3100 BC.

• The plate of his empty

tomb appears to show a

wasp or hornet

• suggest that Menes died

from a wasp sting ?.

100 yrs ago…..

• An young paediatrician understood that the function of the immune system should be rationalized

• NOT in terms of exemption of disease

• but in terms of change of reactivity.

• He coined a new word to represent such an idea….ALLERGY (“unfortunately used as a slang in our day today life”)

• In his own words….

• “the first contact of the immune system with an antigen changes the reactivity of the individual on the second and subsequent contacts, this change (or allergy) can induce a spectrum of responses from protective

• Clemens Peter von Pirquet

(May 12, 1874 – February 28, 1929)

• Austrian scientist and pediatrician

• Patients who were injected with horse serum or

smallpox vaccine had quicker, severe reactions

to second injections.

• The collection of symptoms resulting from

serum injections, he gave the name serum

sickness

He is none other than ….

Pirquet during those

days……

Meanwhile…..

• Two French scientists, Paul Portier and Charles Richet,

investigated the violent stings of jellyfish.

• concluded that the reaction was the result of toxins.

• Used isolated jellyfish toxins as vaccines and injected to

dogs.

• with subsequent booster doses dogs had asphyxia and

vomiting and diarrheas

• This overreaction was termed as anaphylaxis by them

• Anaphylaxis (opposite to prophylaxis )

• Richet was subsequently awarded the Nobel Prize in

Physiology or Medicine in 1913 for his work on

First of all hypersensitivity

• Exaggerated or misdirected immune response

• Results in tissue injury or other pathophysiological

changes

• Occurs when an already sensitized individual is re-exposed

to the same foreign substance

• May be immediate or delayed

Gell and Coomb classification

Components of type 1

hypersensitivity

• Antigens

• Antibody IgE (Reagenic antibody)

• Antigen presenting cells

• Basophil

• Mast cell

• Eosinophil

• Helper 2 Th2Cells

• B cells

• Inflammatory molecules

Antigens

Characteristics of an antigen

• Small 15-40,000 MW proteins.

• Specific protein components

• Often enzymes.

• Low dose of allergen

• Mucosal exposure.

• Most allergens promote a Th2 immune response

Prior Sensitization

required…………..• the allergen stimulates the production of allergen-

specific IgE antibodies by

plasma cells in susceptible individuals.

• The allergen-specific IgE attaches itself to the surface of

mast cells in various

tissues and basophils in the blood in a process known

as sensitization.

Macrophage and exposure of an

antigen• Antigen-presenting cells fall into two categories:

• professional

• non-professional.

• Those that express MHC class II molecules

Co-stimulatory molecules

Pattern recognition receptors are

• The non-professional APCs express MHC class I molecules.

Professional APCs

Activation of T helper cell

• T cells cannot recognize and DO NOT respond to, 'free' or soluble antigen.

• The APC involved in activating T cells is usually a macrophage

• the T cells recognize and respond to antigen that has been processed and

presented by cells via carrier molecules like MHC molecules.

• Helper T cells (CD4 cells) can recognize exogenous antigen presented on MHC class II

Activated T cell

• Stimulate B cells and their proliferation to plasma

cells

• Stimulates other T helper cells

Isotype switching of plasma cell

Isotype switching requires

• B cell class switch to IgE requires T cell help:

• CD40L and IL-4 or IL-13 (Th2 cytokines)

• The propensity to make an IgE response to

• environmental antigens varies among individuals

After Ig E production

• IgE produced by plasma cells is rapidly taken up

• by FcεRI

• Tissue mast cells and

• Circulating basophils

• (serum τ½~2 days; compare to IgG~21 days)

IgE receptor

• The high-affinity IgE receptor, also known as FcεRI,

• FcεRI is a tetrameric receptor complex consisting of

• one alpha (FcεRIα - antibody binding site),

• one beta (FcεRIβ - which amplifies the downstream signal),

• and two gamma chains (FcεRIγ - the site where the downstream signal initiates) connected by two disulfide bridges.

• It is expressed on mast cells and basophils

Secondary exposure to allergen

• Mast cells are primed with IgE on surface.

• Allergen binds IgE and cross-links to activate

• signal with tyrosine phosphorylation,

• Ca++ influx,

• degranulation

• release of mediators

• Secondary mediators

• Mediators formed after activation

• Leukotrienes

• Prostaglandins

• Th2 cytokines- IL-4, IL-5, IL-13, GM-CSF

LOCAL ANAPHYLAXIS

• Two phases:

• Initial response

• Vasodilation, vascular leakage, smooth

muscle spasm or glandular secretions

• 5-30 min. after exposure

• subside in 60 minutes

• Late-phase reaction

• 2-8 hrs. later without additional exposure to antigen

• More intense infiltration of tissues with

• eosinophils,

• neutrophils,

• Basophils,

• monocytes &

• CD4+ T cells

• With mucosal epithelial damage

SYSTEMIC ANAPHYLAXIS

• Occur after administration of

• heterologous proteins (e.g. antisera),

• hormones,

• enzymes,

• polysaccharides & drugs

• itching, hives & skin erythema

• contraction of resp. bronchioles + resp. distress

laryngeal edema

• Continuation of sensitization cycle

• Mast cells control the immediate response.

• Eosinophils and neutrophils drive late or chronic

response.

• More IgE production further driven by

• Activated Mast cells, Basophils, Eosinophils.

Role of eosinophils

• Continuation of sensitization cycle

• Eosinophils

• Eosinophils play key role in late phase reaction.

• Eosinophils make – enzymes,

• cytokines (IL-3, IL-5, GM-CSF),

• Lipid mediators (LTC4, LTD4, PAF)

• Eosinophils can provide CD40L and IL-4 for B cell

activation.

To summarize……………..

Atopy

• Preponderance of certain individuals for

allergies

genetic mapping of atopy individuals

• One locus, on chromosome 5q,

• linked to a region that encodes a variety of

cytokines, including IL-3, IL-4, IL-5, IL-9, IL-13,

and GM-CSF.

• A second locus, on chromosome 11q

• linked to a region that encodes the chain of the

high-affinity IgE receptor.

• atopy is multigenic

• other loci to be identified

Lab Diagnosis of Allergy

• Skin Prick Test

• Liquid with allergen are injected with tiny needle either directly or by affixing a patch

• after 24 to 72 hours to see if a reaction occurs.

• If the skin reacts, a red, raised area (called a wheal) can be observed, indicating sensitization to that allergen.

• The panel chosen should be based on the patient's clinical

history, as with skin testing.

Ig E blood levels

• IgE Blood Test

• specific immunoglobulin E (IgE) antibodies in the blood

that are produced by the body’s immune system when an

allergen is present

In Vitro Testing

• patients with affected skin, such as dermatographism or

atopic dermatitis.

• safer option if the patient is at risk for anaphylaxis

• Immunoassays are often referred to as radioallergosorbent

(RAST) testing, but that term is outdated because radiation

is rarely used today.

• Current methods include enzyme-linked immunosorbent

assay (ELISA)

• fluorescent enzyme immunoassays (FEIA)

• Chemiluminescent immunoassays,

A solid-phase immunoassay

• allergen bound to a matrix. The patient’s serum is added

and the antibodies bind to the allergen.

• All serotypes (IgG, IgM, IgA, and IgE) will bind if they

recognize the allergen.

• A secondary anti-IgE antibody is used to identify if IgE is

bound.

• The report is a quantitative value in kIUA/L or in arbitrary

divisions into classes I-VI. Asymptomatic sensitization is

common below class III (< 3.5 kIUA/L).[7]

• The accuracy of immunoassays varies

with the system used and the quality of

the allergen.

• There is good predictive value (>90%) for

pollens of grass, trees, dust mites, and

cats, whereas

• less accurate results may be obtained from

venoms, weeds, latex, dogs, and molds

• If results are equivocal, further evaluation

can be done by means of skin testing and,

if indicated, a challenge to the allergen.

Patch Testing

• chronic eczematous conditions contributing to a delayed-

type hypersensitivity reaction.

• contact dermatitis to jewelry containing nickel.

• food allergies in eosinophilic esophagitis and some drug

allergies

• The most common patch techniques are the individual Finn

chamber or the thin-layer rapid-use epicutaneous (TRUE)

test.

Other tests with no clinical significance

• cytotoxic tests,

• provocation-neutralization,

• electrodermal testing,

• applied kinesiology,

• iridology, and hair analysis.

Bibliography

• The Pathophysiology, Diagnosis and Treatment of

Allergic Rhinitis Allergy Asthma Immunol Res.

2010 April;2(2):65-76.

• The history of the idea of allergy J. M. Igea Allergy

2013; 68: 966–973.

• Hypersensitivity Mechanisms: An Overview

www.columbia.edu/itc/hs/medical/pathophys/immun

ology/2009/lecture13

Thank you