Principles of Immunology Chapter 33

Allergy & Hypersensitivity

Hypersensitivity
Type I

Immediate
hypersensitivity

IgE, mast cells and lipid mediators

Type II

Antibody mediated

IgM and IgG against cell-bound or extracellular

matrix Ag

Type III

Immune complex

IgM and IgG immune complex deposition

Type IV

Delayed Type
Hypersensitivity

CD4 mediated delayed type hypersensitivity

Type IV is the only T cell mediated hypersensitivity, all other types are non T cell
mediated.
Immediate hypersensitivity/Type I
Allergy

immune-mediated inflammatory response to common

environmental antigens that are otherwise harmless
The enhanced tendency to produce IgE in response to
environmental antigens

Atopy atopic
individual

high levels of IgE (varies with condition)

Large numbers of Eosinophils, eosinophils being highly
potent, must be highly regulated
Large numbers of IL-4 secreting Th2 cells

Antigens/allergens
Allergens tend to share some common features: individuals are repeatedly exposed to
them via a mucosal route (they can be inhaled or ingested), they are very stable,
highly soluble in bodily fluids and usually introduced in very low doses.
Allergens induces Th2 response in low dose and at mucosal locations (respiratory,
GIT, reproductive) *lecture note details
Allergic reactions Type I hypersensitivity
Systemic anaphylaxis
- Antibiotic, venom, peanut allergies
Allergy rhinitis (Hay fever)
- Pollens, dust-mite.
Asthma (acute, chronic)
- Danders, pollens, dust-mitethunderstorm asthma pollen soaks up
moisture & bursts

 Food allergies
- Peanuts, dairy products, shellfish. Gluten intolerance, though not exactly an
allergy
Separate Type I hypersensitivity into 2 phases:
Sensitization

IgE sensitization is central to Type I hypersensitivity

Local (common) or systemic (rare)

response

Local - rhinitis, bronchoconstriction, conjunctivitis

Systemic - anaphylaxis

Responses have an immediate and a delayed phase

Type I hypersensitivity requires:

1. Generation of Th2 cells
2. Signals toward B cells for IgE class switching
Events:
B cell encounters allergen in context of its surface Ig. At the same time, there is likely
to be a T cell in the paracortical areas that has encountered the antigen also but in the
context of DC. The T cell then undergoes differentiation towards the Th2 pathway.
B cell after recognition will endocytose the antigen via receptor mediate endocytosis.
Processes it via the endosomal route and finally presents it on MHC class II.
B cell and Th2 will come together and exchange the required signals (B to T):
1. MHCII-peptide to TCR
2. CD40 to CD40L
3. IL4 Th2 produces IL4
IL-4 leads to B cell class switching to IgE. Now there is a B cell that is encouraged to
proliferate and mature, it produces IgE. The Fc portion of IgE has a very high affinity
for FcR, thus as soon as it is secreted, it quickly bind to cells with the Ig Fc receptor,
especially mast cells.
Mast cells now have IgE specific for the allergen coating them. Upon re-encounter with
the antigen/allergen, it will be recognized by IgE and binds to it leading to IgE cross
linking activating the mast cell causing mast cell degranulation and release of
molecules that leads to inflammation and type I hypersensitivity response.
Study the diagrams included in the lecture notes: Boxes read:

First exposure to allergen

Activation of Th2 cells and stimulation of IgE class switching in B cells
Production of IgE
Binding of IgE to FcR on mast cells (end of sensitization phase)
Repeated exposure to allergen

Activation of mast cell: release of mediators (vasoactive amines, lipid

mediators, cytokines
Mast cell activation
Activation of mast cells results in the:
1. Secretion of preformed mediators: histamine: present in preformed state,
release of histamine elicits mast cell to release other factors too
2. Synthesis and secretion of lipid mediators:
prostaglandins & leukotrienes, both of which have different action pathways,
but both are associate with muscle contractility. Leukotrienes are particularly
involved in sustaining the inflammatory response.
3. Synthesis and secretion of cytokines
IL-3, IL-4, IL-5, IL-13. All of these have the ability to further amplify the
inflammatory response. IL-5 recruits and activates Eosinophils.
Mast cell degranulation: physiological effects:
The location of mast cell degranulation will determine the overall response/effects

GIT

Increased fluid secretion & peristalsis

Diarrhoea, vomiting

Airways

Decrease in diameter and increased mucus

secretion IL-13 released by Th2
encourages mucus production

Wheezing, coughing,
phlegm

Blood
vessels

Increase blood flow and permeability,

increase in cell and protein, fluid in tissue,
lymph flow and effector response

anaphylaxis

Immediate and late phases

Immediate (minutes)

Redness vasodilation
Soft Swelling leakage of
plasma from venules
Dependent upon IgE

Late (hours-days)

Hard swelling - Accumulation of

leukocytes
Neutrophils, Th2 cells,
eosinophils

Type II Hypersensitivity

EARLY
due to preformed mediators
(histamines etc), which are rapidly
metabolized
Blood vessels dilate and leak plasmas
Localized swelling around site of
challenge (wheal)
Blood vessels in area further dilate and
engorge with blood (flare)
LATE: 8-12 hours
induced mediators (chemokines,
cytokines, leukotrienes)
involve cell infiltrates and sustained
edema and/or smooth muscle
contraction

 Antibody mediated
- Binding of Abs to host antigens, Ab binds to what is intrinsically own endogenous
Type II hypersensitivity can lead to 2 outcomes:
injury due to activation of effector mechanisms
-

C activation
Recruiment of inflammatory cells
Activation via Fc Receptor cross lining leads to activation resulting in local
inflammation

abnormal physiological response (nothing to do with complement activation).

Not necessarily triggering an inflammatory response, but by binding/inhibiting
the receptor, the normal physiological response is altered/influenced
-

Binding to receptors or proteins interfering with function

Activation or inhibition.

Haemolytic disease of the newborn

Due to preformed maternal IgG antibodies which react against the child's Rh antigens
on their RBCs in utero removal of RBC via complement activation, thus the mothers
antibodies will start attacking the fetal RBC.
During birth, fetal blood enters maternal circulation, the mother generates an antibody
response again the Rhesus Ag. In subsequent pregnancies, there will be targeted
destruction of foetal RBC.
In address this problem, anti-RH antibodies are administered to the mother within 24
hours of delivery to remove fetal RBCs in maternal circulation so that she does not
form anti-Rh antibodies and so there can be survival of subsequent RH+ pregnancies.
We are beating the adaptive immune response, ridding the antigen before a response
is mounted.
Type III hypersensitivity
Complexes composed of self antigen or foreign antigen
Occurs if complexes are excessively produced, and inefficiently cleared
Pathology depends entirely upon where these complexes deposit
-

eg. Cationic antigen complexes bind to blood vessels and kidney glomeruli
(SLE)

normally immune complexes are removed in the spleen by resident macrophages. RBC
coats the complex and takes them to spleen where they can be cleared. IgG1 and IgG3
(both high affinity IgG) are required to fix the complexes.

Type III Hypersensitivity mechanism

Immune complexes not cleared

Ag excess
Low affinity Ab
Inefficient C activation, this may lead to a lack of high affinity antibody or an
intrinsic problem with the C.C.

Get deposition on vessel walls and there will be an increase in immune complex
concentration over time results in eventual C activation.
Generate anaphylotoxins (C5a, C3a) - neutrophil, mast cell degranulation
Induce macrophage cytokine release
Immune complexes directly activate platelets, basophils and mast cells
Vasoactive amines increased vascular permeability

Immune complex mediated damage

Location of complex deposition will determine the clinical pathology
Immune complexes deposit on basement membranes and blood vessel walls
- Narrow (turbulence interrupts fluid flow)
Vasculitis
- deposition in blood vessel walls
Glomerulonephritis
- deposition in kidney basement membranes
Arthritis
- deposition in joint synovium and vessels

Delayed type hypersensitivity Type IV

Cell mediated, heavy involvement of T cells (and macrophages, which produce large
quantities of IFN) Classically Th1 but sometimes CTL. This type of hypersensitivity
has T cell involvement.
Type IV hypersensitivity is elicited by:

Microbial infection
Intradermal injection of protein antigens
Contact with chemicals etc absorbed through skin

When the organism, or stimulating agent persists, T cells and macrophages

accumulate at the antigen site in large numbers and result in pathology
Type IV hypersensitivity/DTH; T cell mediated

Cell mediated inflammation due to persistent antigen

E.g. poison ivy, adhesives, TB test
Contact sensitivity

M. Tuberculosis

Previous sensitization, upon re-exposure central and

effector memory cells are triggered
Normally, macrophages which have engulfed
microorganisms are stimulated to kill them by helper T
cells (CD4 T cells), which produce - interferon (CD8 T
cells also produce IFN)

***lecture slides for examples of antigens and pathogens that induce delayed type
hypersensitivity
Sensitization phase of DTH priming of the adaptive response
** lecture slide diagram
Mechanisms of contact hypersensitivity

Skin DC, exposure to allerge/antigen, migrates to draining LN when they

activate nave T cells which after activation, migrate back to the skin

Re-exposure to the antigen in the skin reactivates the effector memory T cells
and central memory T cells. This results in production if IFN, activation of
macrophages and excessive inflammation.

Reactivation of effector memory T cells gives rise to an immediate and faster release
of mediators than the initial encounter. Effector cells move to the site of infection. This
is normal but because the antigen cant be cleared, the effector cells continue to
accumulate and lead to pathology. The antigen may be our own.
Diagnostic test for exposure (not immunity) to M. tb utilizes the DTH
response
Tuberculin skin test (Mantoux test)
Inject purified protein derivative (PPD, tuberculin) from M. tb intradermally
After 48 - 72 hrs, activated / memory T cells have migrated to injection site
inflammation, induration
Test does not determine whether or not you are immune to TB but rather, whether or
not you have exposed to TB. Relying on assumption that if there has been previous
exposure, then there will be memory cells. Thus try to reactivate those memory cells
and get them to mirate to the site of infection. If there is a lump, then there is believed
to have been previous encounter to TB antigen and have generated memory cells to
the antigen.
Granuloma: wall of cells, mixture of immune and stromal cells. granulomas appear to
barricade TB pathogen from rest of the body. Thus an inability to form granulomas
individual will succumb to TB very quickly. Whilst granulomas trap the antigen, it also

makes it difficult for immune cells to attack the microbe. We are unable to rid our
bodies of TB, thus immune cells continue to migrate to site of infection leading to
formation of a granuloma persistence of mycobacteria leads to prolonged infection.
***lecture details