HYPERSENSITIVITY REACTIONS 

 
Type III and Type IV hypersensitivity

SHASHI ANAND
Type III hypersensitivity reactions are caused by
antibody-antigen complexes.
Type III hypersenstivity is also called
immunecomplex disease
Type IV is also called Delayed hypersenstivity or
(DTH)

When large amounts of immune complexes are

formed they deposit in tissues and lead to tissue
reaction which is initiated by complement activation
further leading to mast cell degranulation neutrophils
chemo taxis and inflammatory reactions' caused by
the activation of these cells .
Mechanism of damage in immune
complex hypersensitivity
The principal mechanism responsible for tissue damage as
a result of deposition of immune complexes is mediated by
complement components, mainly the C3a and C5a
anaphylotoxins, that attract phagocytes and mast cells
and, following binding to complement receptors on the
surface of such cells, lead to degranulation causing a local
inflammatory reaction (vasodilation, increased vascular
permeability, etc).
 Type III hypersensitivity – immune complex
formation and deposition occurs In sensitized
individuals, allergen (antigen) combined with
antibody leads to the formation of immune
complexes, which activate complement and the
inflammatory response.
The location of the inflammation depends on the
location of the antigen - inhaled, under skin,
systemic.
Onset is usually within 2-6 hours.
In type 3 hypersensitivity reactions, insoluble immune complexes (aggregations
of antigens and IgG and IgM antibodies) form in the blood and are deposited in
various tissues (typically the skin, kidney and joints) .
There are systemic forms of type III hypersensitivity
reactions, such as serum sickness

There are also local forms of immune complex diseases,

such as the Arthus phenomenon .

In both systemic and local forms of type III

hypersensitivity reactions, the emergence as well as the
resolution of the tissue lesions and clinical symptoms
follow strictly the formation of the immune complexes,
the cause of tissue damage.
In Type III hypersensitivity, soluble immune
complexes (aggregations of antigens and IgG and IgM
antibodies) form in the blood and are deposited in
various tissues such as the skin, the kidneys and the
joints.
 They then trigger an immune response according to
the classical pathway of complement activation.
There are two stages relating to the development of the
complexes.
 Firstly the complex forms when IgG and IgM
antibodies are bound to an antigen, thereafter the
complexes form larger complexes.
 It is at the first stage of this formation where clearance
is not possible and the antigen-antibody complex
spreads and deposits as stated above.
The affinity of antibody and size of immune complexes are
important in production of disease and determining the
tissue involved.
 Diagnosis involves examination of tissue biopsies for
deposits of Ig and complement by immunofluorescence.
The immunofluorescent staining in type III hypersensitivity
is granular (as opposed to linear in type II such as seen in
Goodpasture's syndrome).
 The presence of immune complexes in serum and depletion
in the level of complement are also diagnostic.
Polyethylene glycol-mediated turbidity (nephelometry),
binding of C1q and Raji cell test are utilized to detect
immune complexes. Treatment includes anti-inflammatory
agents.
 
This deposition of the antibodies may trigger an
immune response according to the 
classical pathway of complement activation - for
eliminating cells presenting foreign antigens. There
are two stages relating to the development of the
complexes, firstly the complex forms when IgG and
IgM antibodies are bound to an antigen, after this, the
complexes can form larger ones which can be cleared
by the body. It is at the first stage of this formation
where clearance is not possible and the antigen-
antibody complex will spread and deposit as stated
above. The reaction takes hours to days to develop
 For diagnosis immuncomplexes have to
be verified in
Tissue biopsy.
Granular staining is characteristic.
Immuncomplexes and low complement
concentration
in the serum.
Arthus-reaction: immuncomplex-mediated
vasculitis
Tissue damage results at the site of the immune complex
with the influx of phagocytes and granuloctyes and the
release of inflammatory mediators (
Some examples of type III reactions
Immune complex glomerulonephritis
Rheumatoid arthritis
Serum sickness
Subacute bacterial endocarditis
Symptoms of malaria
Systemic lupus erythematosus
Arthus reaction
Farmer's Lung (Arthus-type reaction)
Type III
hypersensitivity

Local
inflammation

vasculitis
 Type 4 hypersensitivity is called the delayed type as the reaction
takes two to three days to develop. Unlike the first three types, this
reaction is not antibody mediated but rather a type of cell-
mediated response.
 CD8+ cytotoxic T cells and CD4+ helper T cells recognise antigen
in a complex with either type 1 or 2 major histocompatibility
complex.
 The antigen-presenting cells in this case are macrophages which
secrete IL-1, which stimulates the proliferation of further CD4+ T
cells.

 CD4+ T cells secrete IL-2 and interferon gamma, further inducing

the release of other Type 1 cytokines, thus mediating the immune
response.

 Activated CD8+ T cells destroy target cells on contact while

activated macrophages produce hydrolytic enzymes and, on
presentation with certain intracellular pathogens, transform into
multinucleated giant cells.
CD8+ cytotoxic T cells and CD4+ helper T cells recognise antigen in a complex
with either type 1 or type 2 major histocompatibility complex. The antigen-
presenting cells in this case are macrophages which secrete IL-1, which
stimulates the proliferation of further CD4+ T cells
CD8+ cytotoxic T cells and CD4+ helper T cells
recognise antigen in a complex with either type 1 or
type 2 major histocompatibility complex. The
antigen-presenting cells in this case are macrophages
which secrete IL-1, which stimulates the proliferation
of further CD4+ T cells
Re-exposure to the allergen results in a Th1 mediated
response which stimulates the proliferation of the
allergen-specific memory Th1 CD4+ T
helper lymphocyte via recognition of complexes of
peptide on antigen presenting cells (APCs)
 Re-exposure to the allergen results in a Th1 mediated response which stimulates the
proliferation of the allergen-specific memory Th1 CD4+ T helper lymphocyte via
recognition of complexes of peptide on antigen presenting cells (APCs
CD4+ T cells secrete IL-2 and interferon gamma,
further inducing the release of other Type 1 cytokines,
thus mediating the immune response.
 Activated CD8+ T cells destroy target cells on
contact while activated macrophages produce
hydrolytic enzymes and, on presentation with certain
intracellular pathogens, transform into
multinucleated giant cells
CD4+ T cells secrete IL-2 and interferon gamma, further inducing the
release of other Type 1 cytokines, thus mediating the immune response.
Activated CD8+ T cells destroy target cells on contact while activated
macrophages produce hydrolytic enzymes and, on presentation with
certain intracellular pathogens, transform into multinucleated giant cells
 Some examples:

Contact dermatitis (poison ivy rash, for example)

Temporal arteritis
Symptoms of leprosy
Symptoms of tuberculosis
Transplant rejection
Coeliac disease
Caused by dissolved immuncomplexes the
outcome of the disease is influenced by the size of
the immuncomplexes might be general (eg. serum
sickness) or organspecific:
Skin (SLE, Arthus-reaction)
Lung (Aspergillosis, Farmer‘s lung)
Blood vessels (Polyarteritis)
Limbs (RA)
Kidneys (lupus Nephritis)
3-10 hours needed for the development
 Phases of DTH

Sensibilisation: 1-2 weeks after the first antigen contact.

APC
(Langerhans-cells, endothelial cells or macrophages)
produce
IL-12 and induce Th1-cell differentiation.
• Activation: Th1-activation, proliferation, rarely CD8+ CT
L activation.
• Effector phase: 2. antigen stimulus leads to Th1-cell
aktivation,
citokin secretion (24 h), recruitment of macrophages and
other
non-specific inflammatory cells (48-72 h). From the
infiltrating
cells only 5% is T cell, 95% is non-specific.
Contact with the antigen
4TH phase of DTH

Granulomatous-reaction: if
the intravascular pathogen
survives in the cells it induces
a prolonged DTH response –
chronic infection
 continuous macrophage
activation leads to cytokine-
and growth factor production
and granuloma formation
 Giant cells, epitheloid cells,
tissue damage, necrosis, and
fibrosis.
Formation of a granuloma requires the combined
activation of
Macrophages, thorough the MHC II receptor, and
CD4 lymphocytes, through their T-cell receptor,
with the M. tuberculosis peptide serving as the
joining element.
Here we see the evolution of the granuloma,
eventually with central caseous necrosis.
Type IV. hypersensitivity
 Diseases of Type IV Hypersensitivity

Infections: intracellular bacteria e.g.. Mycobacterium

tuberculosis, M. leprae; Viruses: Herpes simplex
• Contact dermatitis, atopic eczema
• Autoimmune diseases: Type 1 Diabetes Mellitus,
Arthritis,
Inflammatory bowel disease (IBD)
• Transplant rejection: allogène tissue transplantation