TYPE III IMMUNE COMPLEX-MEDIATED

HYPERSENSITIVITY
Antigen - soluble free antigen in excess

Antibody - IgG & IgM

Site of immune complex deposition

- vascular and glomerular basement

membranes, skin, joint & lung

Mechanism
When antibody combines with its specific
antigen, immune complexes are formed
Normally immune complexes are removed
by the reticuloendothelial system
Mechanism
Monocytes and macrophages, using Fc
receptors are very efficient at binding and
removing complexes
But are relatively inefficient at removing
those formed in Ag excess
Mechanism
The persistence of the immune complexes
and their deposition in tissue can trigger an
acute inflammatory response resulting in
immunopathological reactions
Mechanism
In persistent microbial or viral infections,
immune complexes may be deposited in
organs (e.g. kidneys), resulting in dysfunction
Mechanism
In autoimmune disorders, self antigens may
elicit antibodies that bind to organ antigens
or are deposited in organs and tissues as
complexes, especially in joints (arthritis),
kidneys (nephritis) and blood vessels
(vasculitis)
Mechanism
Finally, environmental antigens such as
fungal spores and certain drugs can cause
immune complex formation with disease
Mechanism
Immune complexes will activate a number of
defense mechanisms
Complement activation and release of
anaphylatoxins (C3a, C4a & C5a ) occur that
in turn cause cell lysis when complex is
deposited in tissues
Mechanism
Vasoactive amines produced from mast cells
and platelets will lead to vasodilatation and
increased vascular permeability due to
retraction of endothelial cells
Mechanism
Neutrophils will be attracted to the site and
try to remove the complexes, if these are
trapped in tissues, some of neutrophils will
difficult to engulf the complex and release
their granule contents, this will lead to more
tissue damage (frustrated phagocytosis)
Mechanism
Platelet aggregation, through Fc receptors,
will produce microthrombi which can lead to
tissue damage by causing local ischaemia
Mechanism
Macrophages that take up the complexes
may find them difficult to destroy and
provide a persistent activating stimulus
leading to release of the cytokines IL-1 and
TNF-α , reactive oxygen intermediates and
nitric oxide
Examples of type III hypersensitivity
Inflammatory lesions due to locally formed
complexes
Arthus reaction - necrotic dermal reaction
Farmer’s lung
Extrinsic allergic alveolitis
Autoimmune diseases - rheumatoid arthritis
Examples of type III hypersensitivity
Diseases resulting from circulating complexes
Serum sickness - systemic immune complex
Post-streptococcal glomerulonephritis
Autoimmune diseases - SLE
B Menu F
Two major forms of immune complex
mediated hypersensitivity
Local (Arthus reaction)
Typically elicited in the skin when a low dose
of antigen is injected
Immune complexes form locally IgG antibodies
are involved
Two major forms of immune complex
mediated hypersensitivity
Local (Arthus reaction)
The resulting activation of complement leads
to activation of mast cells and neutrophils,
mediator release and enhanced vascular
permeability
This typically occurs in about 12 hours
Two major forms of immune complex
mediated hypersensitivity
Systemic immune complex disease
There are several examples, including diseases
such as acute post-streptococcal
glomerulonephritis
Acute post-streptococcal glomerulonephritis
Well known immune complex disease

Occurs several weeks after group A β-

haemolytic streptococcal infection, particularly
of the skin infection due to nephritogenic types
of streptococci
TYPE IV CELL MEDIATED (DELAYED)
HYPERSENSITIVITY
Cell mediated hypersensitivity is a function
not of antibody but of specifically sensitized T
lymphocytes that activate macrophages to
cause an inflammatory response
TYPE IV CELL-MEDIATED (DELAYED)
HYPERSENSITIVITY
The response is delayed

Usually starts 2-3 days after contact with the

antigen

Lasts for days

TYPE IV CELL-MEDIATED (DELAYED)
HYPERSENSITIVITY
Slowly evolving (24-72 hours)

Reactions manifest as inflammation at the

site of antigen exposure and tissue damage
 TYPE IV CELL-MEDIATED (DELAYED)
HYPERSENSITIVITY
First exposure

Normal cell mediated immune response

 TYPE IV CELL-MEDIATED (DELAYED)
HYPERSENSITIVITY
Second exposure
Memory T cells recognize Ag together with
class II MHC molecules on an APC
Stimulated T cells
Release mediators that attract and activate
macrophages or eosinophils & also cytotoxic T
cells
Inflammatory mediators
Monokines
IL 1, IL 6, TNF α
Lymphokines
IL 2, IL 3, IL 4, IL 5, IL 16, Interferon Ƴ, TNF α,
GM-CSF
Persistent or recurrent infection or when
macrophages cannot destroy an antigen
Continual release of lymphokines from
sensitized T lymphocytes
Accumulation of large numbers of
macrophages → gives rise to epitheloid cells
→ giant cells → granuloma formation occurs
Macrophages bearing antigen on their
surface become targets for killer cells and
are destroyed
Tc cell activation → damage to host cells
Examples of type IV hypersensitivity
Contact hypersensitivity
Contact hypersensitivity occurs after
sensitization with simple chemicals (e.g.
nickel, formaldehyde), plant materials
(poison ivy, poison oak), topically applied
drugs (e.g. sulfonamides, neomycin), some
cosmetics, soaps and other substances
Examples of type IV hypersensitivity
Contact hypersensitivity
In all cases, small molecules enter the skin,
and then, acting as haptens, attach to body
proteins to serve as complete antigen
Cell mediated hypersensitivity is induced,
particularly in skin
Examples of type IV hypersensitivity
Contact hypersensitivity
When the skin again comes in contact with
the offending agent, the sensitized person
develops erythema, itching, vesication,
eczema or necrosis of skin within 12-48
hours
Examples of type IV hypersensitivity
Contact hypersensitivity
Antigen presenting cell in contact sensitivity
is probably the Langerhans cell in the
epidermis, which interacts with CD4 TH1
cells that drive the response
Examples of type IV hypersensitivity
Tuberculin type hypersensitivity
Delayed hypersensitivity to antigens of
microorganisms occurs in many infectious
diseases and has been used as an aid in
diagnosis
Examples of type IV hypersensitivity
Tuberculin type hypersensitivity
It is typified by the tuberculin reaction
Small amount of tuberculin is injected into
the epidermis of a patient previously
exposed to Mycobacterium tuberculosis
Examples of type IV hypersensitivity
Tuberculin type hypersensitivity
There is little immediate reaction
Gradually, however, induration and redness
develop and reach a peak in 24-72 hours
Examples of type IV hypersensitivity
Tuberculin type hypersensitivity
Mononuclear cells accumulate in the
subcutaneous tissue
There are CD4 TH1 cells in abundance
Examples of type IV hypersensitivity
Tuberculin type hypersensitivity
A positive skin test indicates that the person
has been infected with the agent but does
not imply the presence of current disease
Examples of type IV hypersensitivity
Tuberculin type hypersensitivity
However, a recent change of skin test
response from negative to positive suggests
recent infection and possible current activity
A positive skin test response assists in
diagnosis
Examples of type IV hypersensitivity
Granulomas
Form in response to continued stimulation by
the intracellular growth of M. tuberculosis
Consist of epithelioid cells created from
chronically activated macrophages
Examples of type IV hypersensitivity
Granulomas
Fused epithelioid cells (multinucleated giant
cells) surrounded by lymphocytes and fibrosis
caused by the deposition of collagen from
fibroblasts
Examples of type IV hypersensitivity
Granulomas
Granulomas restrict spread of M. tuberculosis as
long as long as CD4 T cells can provide IFN-Ƴ
Granulomatous hypersensitivity occurs with
tuberculosis, leprosy, schistosomiasis,
sarcoidosis and Crohn disease
Important characteristics of four types of
delayed type hypersensitivity reactions
 To Study

Defination

Classifications

Immunological mechanisms of Type III and

Type IV with examples.
 Example to study
Examples of immune complex mediated
reactions include

A . Post streptococcal glomerulonephritis T

B. Goodpasture’s syndrome F

C. Rheumatoid arthritis T

D. Extrinsic allergic alveolitis T

E. Graft rejection F
Cell mediated hypersensivity

A. is transferable T

B. is typified by tuberculin reactions T

C. is mediated by cytokines and monokines T

D. can occur in atopic person F

E. involved B lymphocytes and macrophages F