Hypersensitivity Reactions

• Immune activation leads to the production

of antibody and T cell responses that are
generally protective against infections
(may cause potential damage to host tissue)

• An exquisite system of checks and

balances optimizes antigen-specific
eradication of infectious organisms .

Cont….
 Types of hypersensitivity
• Type I disease results from IgE antibody
adsorbed on mast cells or basophils
– When these IgE molecules bind their specific antigen
(allergen), they are triggered to release vasoactive
amines and other mediators that in turn affect
vascular permiability and smooth muscle contraction
in various organs
• Type II disorders are caused by humoral
antibodies that bind to fixed tissue or cell surface
antigen and cause a pathological process by
predisposing cells to phagocytosis or
complement-mediated lysis
• Type III disorders are best thought of as
“immune complex disease”; antibodies
bind antigens to form large antigen-
antibody complexes that precipitate in
various vascular beds and activate
complement
– The immune complexes and complement
activation fragments also attract neutrophils
– Ultimately, it is the activated complement and
the release of neutrophilic enzymes and other
toxic molecules (e.g., oxygen metabolites)
that cause the tissue damage in immune
complex disease
• Type IV disorders (also called”delayed
hypersensitivity”) are cell-mediated
immune responses where antigen-specific
T-lymphocytes are the ultimate cause of
the cellular and tissue injury
Feature Type 1 Type 2 Type 3 type4
Reaction type anaphylactic cytotoxic Serum Delayed
sickness hypersensitivi
Arthus ty (TB)
reaction

Cell involved Mast cell MP.Nkcell NP CD4 +CD8+

Basophil NP B cell MP
Neutrophil EP
,CD4 cells B cells
Eosinophil,
Bcell

Antibody type IgE IgG,IgM IgG,IgM None

Chemical IL-3,4,5 CS CS Lk,IL-12,2

mediators Vasoactiv IFN,TNF,TGF
amine
Feature Type-1 Type -2 Type-3 Type -4

APC Required Not required Required Required

Pre R NR R R
sensitization
 Type I Hypersensitivity
(Allergy and Anaphylaxis)
Definition :Immunological reaction,
developing within minutes after
combination of an antigen with antibody
bound on mast cells or basophils,in
already sensitized individuals.
• Depending upon the portal of entry:
– Local reaction(Ag confined to particular site )
that is merely annoying (hay fever,seaosonal
rhinitis) or severely debilitating (asthma)
• Systemic :follows parental administration
bee venom,I/V injection of
hormones,enzymes,drugs) results in
systemic anaphylaxis within minutes of
exposure.
• Examples :urticaria ,bronchoconstriction
,vomiting ,abdominal cramps ,diarrhea)
• Many localized type I reactions have two
well defined phases:
– The initial response, characterized by
vasodilation, vascular leakage, and smooth
muscle spasm, usually evident within 5-30
minutes after exposure to an allergen and
subsiding by 60 minutes
– The late phase reaction is characterized by
more intense infiltration of tissues with
eosinophils and other acute and chronic
inflammatory cells as well as by tissue
destruction in the form of mucosal epithelial
cell damage
 Mast cells
• Bone marrow derived cells
• Widely distributes in the tissues; they are found
predominantly near blood vessels and nerves and in
subepithelial sites
• Their cytoplasm contains membrane-bound granules
that possess a variety of biologically active mediators
• They are activated by cross-linking IgE bound to their
surface by high-affinity Fc receptors
• Mast cells can also be stimulated by complement
components C5a and C3a (anaphylatoxins) binding to
specific mast cell membrane receptors
• Mellitin (present in bee venom),and physical stimuli
(e.g., heat, cold, sunlight)
• Drugs (codeine ,morphine )
 Basophils
• Similar to mast cells in many respects but
are not normally present in tissues
• They circulate in blood in extremely small
numbers and, like other granulocytes, can
be recruited to inflammatory sites
 Mechanism underlying type -1
hypersensitivity
• First exposure of Ag
• APC present Ag
• Recognition of Ag by TCR on T cells
• T.cell release IL-3,IL-5 which cause
recruitment of Eosinophils
• T.cell also release IL-4 which cause
differential of IgE (B cellsIgE production)
• IgE bind to IgE Fc receptors on mast cells
• exposure 2nd to Ag
• Ag bind to IgE previously bound to mast
cells
• Multivalent Ag bind to more than one IgE
molecule leading to cross linking of IgE Fc
receptors
• Mast cell activation & release of mediators
Mast cell
 Primary Mediators
• Histamine, the most important mediator causes
increased vascular permeability, vasodilation,
bronchoconstriction, and increased secretion of
mucus
• Adenosine – causes bronchoconstriction and
inhibits platelet aggregation
• Chemotactic factors for neutrophils and
eosinophils
• The other mediators are found in granule matrix
– Heparin and neutral proteases (e.g., tryptase)
– These generate kinins and cleave complement
components to produce additional chemotactic and
inflammatory factors
 Secondary Mediators
• Lipid mediators
Leukotriens( C4, D4 are vasoactive & spasmogenic
while B4 chemotactic for NP ,EP Monocytes )
Prostaglandin :Bronchospasm & increased mucous
secretion )
PAF (platelet aggregation ,release of histamine
,bronchospasm ,vasodilation , chemotactic )
Ctokines: TNF ,IL-1, IL-3,4,5,6,
Type I Hypersensitivity
Activation of Mast cells in type I hypersensitivity & release of their mediators
Clinical Manifestations
• Systemic (parenteral) exposure (bee
venom; penicillin) results in
anaphylaxis
– Within minutes after exposure itching,
urticaria (hives), and skin erythema –
profound respiratory difficulty and
hypersecretion of mucus – musculature of
GI tract may be involved with vomiting,
diarrhea, abdominal cramps – systemic
vasodilation (anaphylactic shock)
• Local reaction
– Route of Ag – skin, ingestion, inhalation
• Genetically controlled –atopy (familial
predisposition) – cytokine gene on
chromosome regulates the expression
of IgE
 Milk & food Allergy
• Jersey cows may become allergic to the α casein of their
own milk, if milking is delayed
• Reactions ranging from mild discomfort with urticaria to
acute anaphylaxis. About 2% of ingested protein is
absorbed as peptide fragments large enough to be
recognized as foreign Ag.
• Allergic Inhalant Dermatitis – dogs and
cats
 Type II Hypersensitivity
(Antibody Dependent)
• Mediated by antibodies directed against
target antigens on the surface of cells or
other tissue components
• The antigens may be normal molecules intrinsic
to cell membranes or extra cellular matrix, or
they may be adsorbed exogenous antigens
(e.g., drug metabolites)
1)Complement activation
2)ADCC (antibody dependant cell mediated cytotoxicity )
3)AMCD (antibody mediated cellular dysfunction )
 1. Complement-Dependent Reaction

• Ag+Ab reaction involving IgM &IgG cause

activation ofg complement system
• Complement can mediate type II
hypersensitivity via two mechanisms:
– Direct lysis
– Opsonization
Clinically, antibody-mediated reactions
occur in the following situations:
• Transfusion reactions, where
red cells from an incompatible
donor are destroyed after being
coated with recipient antibodies
directed against the donor’s
blood group antigens
• Erythroblastosis fetalis due to
rhesus antigen incompatibility;
maternal antibodies against Rh
in a sensitized Rh negative
mother cross the placenta and
cause destruction of Rh-positive
fetal red cells
• Drug reactions, where antibody is directed
against a particular drug (or its metabolite)
that is nonspecifically adsorbed to cell
surfaces (hemolysis after penicillin
administration

• Pemphigus vulgaris caused by antibodies

against desmosomal proteins that lead to
disruption of epidermal intercellular
junctions
 2. Antibody-dependent Cell-
Mediated Cytotoxicity (ADCC)
• This form of antibody-mediated
injury involves killing via cell
types that bear receptors for
the Fc portion of IgG; targets
coated by antibody are lysed
without phagocytosis or
complement fixation
• ADCC may be mediated by a
variety of leukocytes, including
neutrophils, eosinophils,
macrophages, and NK cells
• Although, ADCC is typically
mediated by IgG antibodies, in
certain instances (e.g.,
eosinophil mediated killing of
parasites; IgE antibodies are
used
3. Antibody-Mediated Cellular Dysfunction

• In some cases, antibodies

directed against cell surface
receptors impair or dys-regulate
function without causing cell
injury or inflammation
• In Myasthenia gravis, antibodies
against acetylcholine receptors in
motor end-plates of skeletal
muscles impair neuromuscular
transmission with resultant
weakness
• In Graves disease, antibodies
against the TSH receptor
stimulate thyroid epithelial cells
and result in hyperthyroidism
 Type III Hypersensitivity
(Immune Complex-Mediated)
• Mediated by the deposition of antigen-antibody
complexes, followed by complement activation and
accumulation of polymorphoneuclear leukocytes that
produce tissue demage.
• Immune complexes can involve exogenous antigens
such as bacteria and viruses or endogenous antigens
such as DNA
• Ag+Ab complexes may be:
• Circulating or in situ
• Exogenous
• Endogenous
• Systemic(serum sickness ) or local (arthus reaction )
 Pathogensis
• 1st phase :Ag+Ab complex formation
• 2nd phase : deposition of immune
complexes in various tissue
• 3rd phase :initiation of an inflammatory
reaction in dispersed sites throughout
body
 Systemic Immune
Complex Disease
1. Formation of antigen
antibody complexes
in the circulation
2. Deposition of the
immune complexes
in tissues
3. Initiation of
inflammatory
reaction in various
sites throughout the
body
• Two important factors determine whether
immune complex formation leads to tissue
deposition and disease:
– Size of immune complex
• Very large complexes formed in antibody excess are rapidly
removed from the circulation by mononuclear phagocytic
cells and are therefore relatively harmless.
• The most pathogenic complexes are formed during antigen
excess and are small or of intermediate size, and are cleared
less avidly by phagocytotic cells, and therefore circulate
longer
– Status of mononuclear phagocyte system (Overload
or dysfunction)
 Additional factors
• Charge of complexes
• Valency of antigen
• Avidity of antibody
• Affinity of the antigen for various tissues
• Three dimensional architecture of the
complexes
• Homodynamics of given vascular bed
• Morphology :Necrotising vasculitis
• Swelling & proliferation of mesengial and
endothelial cell
• Neutrophilic monocyte infiltration
• Favored site of deposition: Renal
glomeruli ,joints ,skin, heart ,small blood
vessels
 Serum sickness
• Acute serum sickness is the prototype of
systemic immune complex disease
(injection of horse anti tetanus serum)
 Local Immune Complex Disease
localized area of tissue necrois resulting from
immune complex vasculitis involving IgG & IgM

• Acute arthus reaction

 Type IV Hypersensitivity
(Cell Mediated)
It is immunologic response to variety of intracellular microbe e.g
mycobacterium,virus,protozoa,fungi,as well as condition like contact
dermatitis ,graft rejection
• Principal mechanism of
response to:
– Intracellular bacteria
(Mycobacterium) and
viruses
– Extra cellular agents –
protozoa, fungi, and
parasites
– Contact skin sensitivity
(poison ivy)
– Transplant rejection and
tumor immunity
• Reaction mediated by
sensitized T cells
Type IV Hypersensitivity can be subdivided
into
• Delayed type hypersensitivity initiated by
CD4+ T cells (tuberculine reaction ,grnulomatous
inflamation)
• T-cell mediated cytotoxicity
Granulomatous inflammation
• A granuloma is a special type of DTH
(delayed type hypersensitivity) occurring in
the setting of persistent or/and
nondegradable antigens
• The initial perivascular CD4 T-cell
infilterate is progressively replaced by
macrophages over a period of 2-3 weeks
• These accumulated macrophages typically
exhibit morphological evidence of
activation i.e., they become large, flat, and
eosinophilic (denoted epitheliod cells)
Cont…..
• The epitheliod cells occasionally fuse under the
influence of certain cytokines (e.g., IFN-γ) to
form multinucleated giant cells
• A microscopic aggregate of epitheliod cells,
typically surrounded by a collar of lymphocytes,
is called granuloma, and the pattern is referred
to as granulomatous inflammation
• Older granulomas develop an enclosing rim of
fibroblasts and CT
 Tuberculin reaction
• A classical example is tuberculine
reaction, elicited in an individual already
sensitized to tubercule bacillus
• 8-12 hrs after intradermal injection of
tuberculine (protein-lipoprotein injection), a
local area of erythemia and induration
appears, reaching a peak (typically 1-2
cm) in 24-72 hrs, and there after subsides
• Histologically, the DTH reaction is characterized
by the perivascular presence of CD4 cells and to
lesser extent macrophages(perivascular cuffing )
• Local secretion of cytokines by these
mononuclear inflammtory cells leads to
increased microvascular permeability, giving rise
to dermal edema and fibrin deposition; the latter
is main cause of induration in these responses
 The sequence of events
• Exposure of individual to tubercle bacilli
• CD4 lymphoctes recognize peptide
antigens in association with MHC class II
antigens on the surface of macrophage or
dendritic cells
• This process leads to the formation of
sensitized CD4 cells of the TH1 type that
remain in the circulation for years
 T-Cell-Mediated Cytotoxicity
• Sensitized CD8 T cells kill antigen-bearing target
cells
• Class I MHC molecules bind to intracellular viral
peptides and present them to CD8 T
lymphocytes
• The CD8 effector cells, called cytotoxic T
lymphocytes play a critical role to virus infections
• The lysis of infected cells, before viral replication
is completed, leads ultimately to elimination of
the infection.
• It is believed that many tumor associated
peptides may also be involved in tumor immunity
• Example : tissue rejection during tissue
transplantation