|






Under some circumstances, immune response

produce damaging or fatal results.

Such deleterious reactions are known collectively

as Hypersensitivity. IR are damaging rather than
helpful to the host.

Inappropriate/overreaction/immunopathology



oombs and Gell (1960): Reactions 4 types:

Œ Ôype I > 2-30 min IgE Abs mediated

Œ Ôype II 5-8 hr Abs (IgG & IgM) +

omplement (cytotoxic)

Œ Ôype III 2-8 hr Ag/Ab Immune omplex

Œ Ôype IV 24-72 hr Ô-cell mediated (DÔ )






|


ΠMost common type of hypersensitivity reaction.

ΠMediated by IgE & causes hay fever to life

threatening (bee stings) clinical manifestations.

ΠReactions are stimulated by binding of IgE (via

its Fc region) to high affinity IgE specific
receptors (FcüRI) expressed on mast cells &
basophils.
Πhen cross linked by Ags, IgE triggers mast
cells & basophils to release inflammatory
mediators that lead to clinical features
(allergic reactions) eg. rhinitis, asthma,
allergy, hay fever, bee sting, etc.

Œ Ôhese reactions are very rapid, occur within

min after challenge-that is re-exposure to Ag.

Œ Allergic reactions are called IÔ or Ôype I

hypersensitivity.
ΠSequence of Events involved:

ΠSensitization Phase = Activation Phase =

Effector Phase
 Sensitization Phase

ΠInitial exposure to an allergen (Ag) induces IgE

formation, following the primary antibody
mediated immune response.

ΠIgE binds via Fc portion to specific receptors on

basophils (in blood) and mast cells (in tissues),
(both cell types have histamine granules)

(No effect on mast cells directly up to this stage)

Activation Phase

ΠSecond and subsequent exposure to same

allergen (specific Ag):

-allergen (specific Ag) binds to V region of

Fab and crosslinks two adjacent IgEs on
mast cell/basophil surface.
Effector Phase

Πrosslinking of two adjacent IgEs on mast

cell/basophil surface triggers these cells to
degranulate immediately and release histamine
and many other mediators.

Œ Immediate response (min after exposure) ƛ

mediators release due to an increase in cGMP
levels and/or decrease in cAMP levels
ΠLeads to clinical manifestations, allergy,
asthma, etc.
ΠSensitization-skin contact, ingestion, injection,
inhalation.
Π~50% generates IgE response to airborne
Ags but ~20% develops clinical symptoms
(those with high IL-4).
ΠLow levels of IgE in non-allergic due to
suppressor effect of IFN-ƪ (Ôh1 produced)
dowregulates Ôh2.
ë 


Œ ay Fever ƛ watery eyes, runny nose due to vascular

permeability and edema.

Œ Swelling and itchiness ƛ nasal congestion, hives,

edema.

Œ Anaphylaxis ƛ bronchoconstriction, shock, edema.

Œ Asthma ƛ smooth muscle constriction

'


|
ƛ preformed molecules in granules.
-binds receptors on target cells (lungs, skin, blood
vessels)
-causes vasodilation, capillary permeability, smooth
muscle constriction
-antihistamines block histamine receptors.

 ƛ from mast cells, causes bronchial

constriction, edema.

 ƛadhesion of leukocytes to capillary

venules, degranulation.
ë ë
ë

ë 
!

" #$
-produced after exposure to allergen, nor preformed
-slow release
-bronchoconstricton: implicated in asthma

% 

"
%"

!

" #$
-preformed in mast cell granules
-quick release
-attracts eosinophils which release Ơ"ơ and
 !
from their granules

-histaminase degrades excess histamine

Π&
'
 ƛ destructive effects
(from eosinophils granules)

Π
| 
(mast cells); superoxide,
nitric oxide, Ôumor necrosis Factor (all from
macrophages)

%"


Œ Antihistamines ƛ block histamine receptors on

target cells
Œ orticosteroids ƛ block degranulation of mast
cells
Œ romolyn sulfate ƛ blocks degranulation fast
acting but not permanent, must administer
when exposed or risk at exposure to allergen
ΠNSAIDs: Non steroid Anti Inflammatory drugs
(Aspirin)
Ôreatment Acute allergies (anaphylactic shock)

Œ Epinephrine (EpiPen) ƛ inject directly,

increases camp levels which decreases
mediator release.

-immediate action
-short effect (~20 min)
-followed by intravenous antihistamines
 Ôype-II Reactions

Πypersensitivity resulting from Abs mistakenly reacting

with normal self-Ags on body cells.

ŒBinding of Abs to these normal cells result in immune

destruction.
 Mechanism

ΠEither IgG or IgM made against normal self-Ags as a

result of a failure in immune tolerance or a foreign Ag
resembling some molecules on the surface of host
cells enters the body and IgG or IgM made against
that Ag then cross-reacts with the host cell surface.
Binding of IgG/IgM to host cell surface leads to:

ΠOpsonization of host cell.

ΠActivation of classical complement pathway causing

MA mediated lysis of cells.

ΠAD destruction of host cells: NK cells attachment >

release pore-forming proteins Ɲperforinsƞ & proteolytic
enzymes Ɲgranzymesƞ. Granyzymes pass through
pores & activates enzymes that leads to apoptosis of
infected cell by means of destruction of its structural
cytoskelton proteins & by chromosomal degradation.
Ab & Rh blood group reactions.
Autoimmune diseases (Graves/multiple sclerosis)
Good pastureƞs disease, auto Ab to lung & kidney
basement membrane cause hemorrhage at site of
binding.

Breakdown of tolerance to self:

Abs to Ach receptors, loss of receptors, reducing or
inhibiting nerve impulses across neuro-muscular
junctions (myasthenia gravis).
 |




ΠNormally Immune complexes removed by

phagocytic cells & there is no tissue damage.

Πowever, when large amounts of I.s.

persists in tissues they activate complement
cascade and cause damage to tissues.
(Arthus reaction).

ΠAgs responsible: Microbial Ags, auto Ags,

foreign serum components.
 Removal of Ag ƛ Ab omplex

ΠAg-Ab complex binds to Fc receptors of IgG,

RBs have 3b receptors, binds to
complexes, that have fixed complement &
transport them to liver, where complexes are
removed by phagocytic kupffer cells.

ΠAg-Ag complexes are clusters of interlocking

Ags-Abs; rapidly removed by blood stream by
Macrophages (spleen), kupffer cells (liver).
Πhen large quantities of Is of a certain size
are formed in circulation, they can be
deposited in tissues and trigger a variety of
pathogenic events, called hypersensitivity
reactions- III. (Kidneys, skin, joints, eye).
ΠAg-Ab complex activates classical
complement pathway. Ôhis may cause
Massive inflammation: complement protein
5a.
ΠInflux of neutophils: Due to complement
protein 5a, neutrophils discharge their
lysosomal enzymes & cause tissue damage,
further inflammation.
ΠMA lysis of surrounding tissue cells.
ΠAggregation of platlets: Blockage of
capillaries.
ΠUnder some circumstances Is continue to
circulate, and eventually become trapped in
tissues of kidneys (glomerulonephritis), liver,
skin (skin lesions), joints (thematoid arthritis),
blood vessels & lead to inflammation & tissue
damage.
ΠLocalized: inhaled> bacterial fungal spores,
pigeons serum (farmerƞs lung disease).
Systemic: Micobes (Streptococcus)
Streptococcal nephritis. Serum sickness
(fever, skin eruption, lympadenopathy.
 
( ) 


!
|

)|

Œ Mediated by Ô-cells together with dendritic

cells, macrophages & cytokines.
Œ Ôhe normal events associated with cell-
mediated immunity are a crucial mode of
immunologic reactivity for protection against
intracellular parasites (bacteria, viruses etc).
owever, the nature of reaction and its
mediators also cause DÔ reactions.
Πhen activated by contact with an Ag presented by
antigen-presenting cell the responding Ô cells release
inappropriately large amount of cytokines, some of
which attract and activate other mononuclear cells
that are not antigen specific (such as monocytes and
macrophages).

ΠRecruitment and activation of these antigen-

nonspecific mononuclear cells are mainly responsible
for the eventual damaging outcome of the reactions.
 Major events: 3 steps

Œ Activation of antigen-specific inflammatory Ôh- 1

cells in a previously sensitized individual.

ΠElaboration of proinflammatory cytokines by the

antigen-specific Ôh-1 cells.

ΠRecruitment and activation of antigen non-specific

inflammatory leukocytes.
Œ Ôhese events typically occur over a period of
several days (24-72 hrs) ƛ hence known as DÔ
 ausative Agents

ΠSkin contact, small molecules (chemicals,

plant molecules).
Πontact Sensitivity (contact dermatitis): eg.
some cosmetics, Formaldehyde.

ΠPoison Ivy Dermatitis: Offending substance is

contained in an oil secreted by leaves of
poison-ivy vine & other plants. Ôhey
penetrate skin & cause blister formation.
 Mantoux or PPD Ôest

ΠSmall amounts of purified protein derivative

(PPD) of tuberculin derived from M.
tuberculosis organisms injected into skin &
site examined after 72 hrs. +ve skin test ƛ Ist
red swelling, maximal at 48-72 hrs post
injection. Ôhis is caused by influx of Ô-cells &
macrophages at site of injection.

ΠPPD test is useful for public health

surveillance of ÔB.