Transcript Cytotoxic Hypersensitivity

Hypersensitivity Types II-IV
Type II: Cytotoxic
 Type III: Immune Complex Type
 IV: T Cell-Mediated (DTH)
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Hypersensitivity II & III
(antibody mediated diseases)
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Antibodies (other than IgE) may cause tissue
injury & diseases by binding directly to their
target organs & extracellular matrix (type II) or
by forming immune complexes that deposit
mainly in blood vessels (type III) .
Cytotoxic hypersensitivity
Characteristics of Cytotoxic
Hypersensitivity
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Antibodies directed against cell surface
or tissue antigen
Characterized by complement cascade
activation and various effector cells
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Complement
Activated C3 forms opsonin recognized by
phagocytes
Formation of membrane attack complex (lytic
enzymes
Formation of chemotactic factors
 Effector cells possess Fc and complement
receptors
macrophages/monocytes
 neutrophils
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Mechanisms of tissue injury
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Antibodies specific for cell & tissue antigens
may deposit in tissue and cause injury by
inducing local inflammation , or may interfere
with normal cellular functions.
IgG bind to neutrophil & macrophages Fc
receptors and activate these leukocytes ,
resulting in inflammation.
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The same antibodies ,as well as IgM , activate
the complement system by the classical
pathways , resulting in the production of
complement anaphylatoxins(C3a, and C5a), and
complement membrane attack complex that
recruit leukocytes and induce inflammation.
and attack cells .
If antibodies bind to cells , such as erythrocytes
& platelets ,the cells are opsonized and may
be ingested & destroyed by host phagocytes.
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Some antibodies may cause disease without
directly inducing cell injury. Some antibodies
against hormone receptors & inhibit
receptor function (Myasthenia Gravis).
Other antibodies may activate receptors
e.g.,Graves disease in which antibodies against
the receptor for the TSH will stimulate thyroid
cell even in absence of hormone.
Examples of Type II
Hypersensitivity
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Blood transfusion reactions
Hemolytic disease of the newborn (Rh disease)
Autoimmune hemolytic anemias
Drug reactions
Myasthenia gravis (acetylcholine receptor)
Pemphigus vulgaris
Goodpasture s syndrome
Graves disease (TSH receptor ,hyperthyroidism)
Pernicious anemia
Hypersensitivities
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Drug-induced cytotoxic reactions
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Some drug molecules bind larger molecules
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Stimulate the production of antibodies
Can produce various diseases
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Immune thrombocytopenic purpura
Agranulocytosis
Hemolytic anemia
Drug-Induced Reactions:
Adherence to Blood
Components
blood cell adsorbed drug
or antigen drug metabolite
antibody to drug
complement
lysis
Immune (Toxic )Complex
Hypersensitivity (Type III)
Hypersensitivities
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Type III (Immune Complex–Mediated) Hypersensitivity
 Involves immune reactions against soluble antigens
circulating in serum.
 Leads to formation of immune complexes( Ag-Ab complexes)
 Can cause localized reactions
 Hypersensitivity pneumonitis
 Post streptococcal glomerulonephritis
 Can cause systemic reactions
 Systemic lupus erythematosus
 Rheumatoid arthritis
Diseases associated with immune complexes
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Persistent infection
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Autoimmunity
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microbial antigens
deposition of immune complexes in kidneys
self antigens
deposition of immune complexes in kidneys, joints,
arteries and skin
Extrinsic factors
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environmental antigens
deposition of immune complexes in lungs
Inflammatory Mechanisms in Type III
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Complement activation
Anaphylatoxins ( C3a and C5a)
 C3b and C4b release( opsonizing and chemotactic
factors)
 MAC formation( membrane attack complex C5bC9)
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Neutrophils attracted
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difficult to phagocytoze tissue-trapped complexes
Immune Complex Mediated
Hypersensitivity
Kher
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Disease Models
Serum sickness
 Arthus reaction
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Arthus Reaction
Localized manifestation of generalized
hypersensitivity
Ag+Ab precipitates cause C activation and release of
inflammatory molecules. It Leads to ↑ vascular
permeability & neutrophil infiltrate. Leucocyte-platelet
thrombi formed which reduce blood supply leading to
necrosis.
Clinical example – Farmer’s lung & other
hypersensitivity pneumonitis following inhaled Ag like
Actinomycetes.
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Arthus reaction
Arthus reaction
Type-III
Weal & flare reaction
Type-I
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Serum Sickness
–Systemic form of Type III reaction.
Takes place following serum therapy
e.g., Hyperimmune globulin, Anti Snake venum.
Clinical picture: Fever, lymphadenopathy,
splenomegaly, arthritis, glomerulonephritis,
endocarditis, vasculitis, urticarial rashes,
abdominal pain, nausea and vomiting.
Pathogenesis – Formation of immune
complexes, its deposition on the endothelial
lining of BVs all over the body, leads to
inflammation.
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Serum Sickness (contd)
*Plasma concentration of C3 falls due to massive
activation and fixation to Ag+Ab complexes.
*Disease is self limited.
*Can also be seen after administration of penicillin
or other antibiotics.
Immune complexes occur in many bacterial, e.g.
pos-tstreptococcal glomerulonephritis .Also in
Hepatitis B & Malaria. Also seen in disseminated
malignancies & autoimmunity.*
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Serum sickness
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T-Cell Mediated Hypersensitivity
(Type IV / Delayed-Type)
Manifestations of T-Cell Mediated
Hypersensitivity
Allergic reactions to bacteria, viruses and
fungi
 Contact dermatitis due to chemicals
 Rejection of tissue transplants
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General Characteristics of DTH
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An exaggerated interaction between antigen and normal
CMI-mechanisms
Requires prior priming to antigen
Memory T-cells recognize antigen together with class II
MHC molecules on antigen-presenting cells
Stimulated T-cells release soluble factors (cytokines)
Cytokines
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attract and activate macrophages and/or eosinophils
help cytotoxic T-cells become killer cells, which cause tissue
damage
Types of Delayed Hypersensitivity
Delayed Reaction
time
maximal reaction
Contact
tuberculin
granulomatous
48-72 hours
48-72 hours
at least 14 days
Contact Hypersensitivity
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Predominantly an epidermal reaction
Langerhans cells are the antigen presenting cells
Associated with hapten-induced eczema
 nickel salts in jewellry
 picryl chloride
 acrylates
 p-Phenylene diamine in hair dyes
 chromates
 chemicals in rubber
 poison ivy (urushiol)
Contact dermatitis
Ag possibly enters sebaceous glands
Lesions vary from macules & papules to vesicles
which subsequently breakdown leaving weeping
surface typical of acute eczematous dermatitis.
Detected by patch test
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Contact dermatitis reaction
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Allergic Contact Dermatitis Response to
Poison Ivy Hapten
Kher
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Atopy Patch Tests
Atopy Patch Tests (APT) on the skin can detect delayed
hypersensitivity reactions to foods, but are usually employed to
identify trigger contact allergens such as nickel, rubber,
dyes and cosmetics
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The food allergen is applied to the skin under an occlusive
cover (called a Finn chamber) and the skin is assessed after
48 and 72 hours for a wheal reaction. Any redness or microblistering is then measured and graded as a positive reaction.
Kher
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Tuberculin Hypersensitivity
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Maximum at 48-72 hours
Inflitration of lesion with mononuclear
cells
Responsible for lesions associated with
bacterial allergy
 cavitation, caseation, general toxemia
seen in TB
May progress to granulomatous reaction
in unresolved infection
Granulomatous Hypersensitivity
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Clinically, the most important form of DTH, since it
causes many of the pathological effects in diseases
which involve T cell-mediated immunity
Maximal at 14 days
Continual release of cytokines
Leads to accumulation of large numbers of
macrophages
Granulomas can also arise from persistence of
“indigestible” antigen such as talc (absence of
lymphocytes in lesion)
Granuloma in a leprosy patient
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Examples of Microbial-Induced DTH
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Viruses (destructive skin rashes)
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Fungi
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smallpox
measles
herpes simplex
candidiasis
dematomycosis
coccidioidomycosis
histoplasmosis
Parasites (against enzymes from the eggs lodged in liver)
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leishmaniasis
schistosomiasis
Comparison of hypersensitivity reactions
characteristic
Type-I
Type-II
Type-III
Type-IV
antibody
IgE
IgG, IgM
IgG, IgM
none
antigen
exogenous
cell surface
soluble
intracellular
15-30 min.
Min.-hrs
3-8 hours
48-72 hours
or longer
appearance
Weal & flare
Lysis &
necrosis
Erythema &
edema
Erythema &
induration
histology
baso- and
eosinophils
Ab and
complement
PMN and
complement
Monocytes &
lymphocytes
transfer with
antibody
antibody
antibody
T-cells
examples
hay fever,
asthma
response
time
pemphigus,
Goodpasture
farmers’
lung, SLE
TB test, poison
ivy, granuloma
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