HYPERSENSITIVITY

Definitions
• Hypersensitivity – an exaggerated immune response
to an innocuous antigen, that results in tissue injury
• Hypersensitivity reactions occur when the immune
system mounts an excessive response to a stimulus
• Allergen – an antigen that gives rise to immediate
hypersensitivity
• Allergy – a hypersensitive response to an
environmental antigen
• Atopy – genetic predisposition to type I
hypersensitivity
 Classification
• According to Gell and Comb’s classification,
hypersensitivity reactions can be divided into 4
types (type I, II, III, and IV) depending on the
mechanism of immune recognition involved and
on the inflammatory mediator system recruited
• Types – I II, and III reactions are dependent on the
interaction of specific antibodies with the given
antigen, whereas, in type IV reactions recognition
is achieved by antigen receptors on T-cells
 Coombs and Gell classification
• Type I hypersensitivity – immediate
hypersensitivity reactions.
• Production of IgE antibodies against foreign
proteins commonly present in the
environment (e.g. pollen, animal danders,
house dust mites)
 Coombs and Gell classification
• Type II hypersensitivity – antibody mediated
reactions
• IgG or IgM antibodies produced against
surface antigens on the cells of the body
• Antibodies either activate complement or bind
NK cells
• E.g. ABO transfusion reaction
 Coombs and Gell classification
• Type III hypersensitivity – Arthus immune
complex reactions
• Formation of immune complexes in the
circulation that are not adequately cleared by
macrophages or other cells of the RES
• E.g. SLE, chronic glomerulonephritis, serum
sickness
 Coombs and Gell classification
• Type IV hypersensitivity – delayed type
hypersensitivity reactions/cell-mediated reactions
• Specific T cells are the primary effector cells
• Contact sensitivity e.g. to nickel, poison ivy
• Graft rejection
• Hypersensitivity skin responses of leprosy, TB
• Exaggerated response to viral infections e.g.
measles
 TYPE 1 HYPERSENSITIVITY
• Results in rapid clinical manifestations, and underlies
many disorders widely recognised as ‘allergies’ such as
hay fever and asthma, systemic (anaphylactic reaction)
• In individuals predisposed to Type I hypersensitivity,
antigen exposure leads to IgE production
• IgE binds Fc receptors on mast cells, packed with
granules containing histamine and other preformed
mediators
• IgE cross-linking by allergen causes degranulation of
mast cells and rapid release of mediators
 Contd …
Type 1 (immediate type) reactions have two
well-defined phases
Initial phase (response)
• Characterized by vasodilatation, vascular
leakage, and depending on the location,
smooth muscle spasm or glandular secretions
Late phase
• As it is manifested for example in allergic rhinitis and
bronchial asthma, more intense infiltration of eosinophils,
neutrophils, basophils, monocytes and CD4+ T cells are
encountered and so does tissue destruction (epithelial
mucosal cells)
• Mast cells and basophils are central to the development of
Type I reaction
• Mast cells are bone marrow driven cells widely distributed
in tissues around blood vessels, and sub epithelial sites
where type I reaction occurs
• Environmental stimuli for type 1 reactions
include
– House dust mite
– Cat dander
– Foods (peanut)
– Drugs
– Infectious triggers eg Schistosomiasis
TYPE II HYPERSENSITIVITY
REACTION
 TYPE II HYPERSENSITIVITY REACTION
• It is mediated by antibodies directed towards
antigens present on the surface of exogenous
antigens
• is caused by cytotoxic antibodies binding to
components of cells or tissues or antigen/hapten
which has become intimately associated with cells
• Three different antibody-dependent mechanisms
are involved in this type of reaction
 i. Complement-dependent reaction

Direct lysis:
• a) It is effected by complements activation,
formation of membrane attack complex (C5 – 9)
• b) Opsoinization: By C3b, fragment of the
complement to the cell surface enhances
phagocytosis
• Examples include red blood cells, leukocytes and
platelets disorders: Transfusion reaction;
haemolytic anemia; Certain drug reaction
 ii. Antibody dependent cell - mediated
cytotoxicity /ADCC/
• This type of antibody mediated Cell injury does not
involve fixation of complements
• The target cells coated with IgG antibodies are killed
by a variety of nonsensitized cells that have Fc
receptors
• The non-sensitized cells included in ADCC are
monocytes/large granular lymphocytes/ Natural killer
cells, neutrophils and eosinophils
• The cell lysis proceeds without phagocytosis Example
include graft rejection
iii. Antibody-mediated cellular dysfunction

• In some cases, antibodies directed against cell surface

receptors impair or dysregulate function without causing
cell injury or inflammation e.g.
• In Myasthenia Gravis, antibodies reactive with
acetylcholine receptors in the motor end plates of
skeletal muscles impair neuromuscular transmission and
cause muscle weakness
• The converse is noted in Graves disease where
antibodies against the thyroid stimulating hormone
receptor on thyroid epithelial cells stimulate the cells to
produce more thyroid hormones
Graves disease Myasthenia gravis
 Clinical conditions
• Incompatible blood transfusions – recipient
becomes sensitized to antigens on the surface
of the donor’s red blood cells
• Haemolytic disease of the newborn – a
pregnant woman becomes sensitized to fetal
red blood cells
• Autoimmune haemolytic anaemias – patient
becomes sensitized to his or her own red blood
cells
 TYPE III HYPERSENSITIVITY REACTION
• It is induced by antigen-antibody complex that produces tissue
damage as a result of their capacity to activate the complement
system
• The Abs involved in this reaction are IgG, IgM or IgA
• Immune complexes (Ics) may be formed in the blood and trapped in
tissues, or may be formed in situ if soluble antigen binds autoantibody
• When antigen binds antibody, complement is activated and
neutrophils and other inflammatory cells are attracted
• Phagocytic cells ingest the ICs, however, when the capacity to clear
complexes is exceeded, inflammation may occur
• IC formation occurs in healthy individuals during infections and even
after eating, However, in health ICs are cleared and do not cause
inflammation
 Sources of antigens
a.Exogenous origin
• Bacteria –streptococcus (infective endocarditis)
• Viruses –Hepatitis B virus (Polyarteritis nodosa)
• Fungi – Actinomycetes (farmer’s lung)
• Parasites - plasmodium species
(glomerulonephritis)
• Drugs – quinidin (hemolytic anemia)
• Foreign serum (serum sickness)
b. Endogeneous origin
• Nuclear components (systemic lupus
erythematosis)
• Immunoglobulins (rheumatoid arthritis)
• Tumour antigen (glomerulonephritis)
• Therefore, autoimmune diseases are
hypersensitivity diseases in which the exaggerated
immune response is directed against the self
antigens as exemplified by the above three diseases
 The pathogenesis of systemic immune
complex diseases has three phases
a. Formation of Ag-Ab complex
• Introduction of an Ag into the circulation, then
production of specific Abs by immuno-
competent cells and subsequent Ag-Ab
complex formation
b. Deposition of immune complexes
• The mere formation of ICs in the circulation
does not imply presence of disease
• Immune deposition depends on:
i) Size of immune complexes
• Large complexes in great antibody excess are rapidly removed
by mononuclear phagocytic system (MPS)
• Most pathogenic ones are of small or intermediate size /
formed in slight Ag excess/
ii) Functional status of MPS
• MPS clears circulating ICs however, its overload or dysfunction
increase the persistence of immune complexes in circulation
and resulting in tissue depositions
• Read on other factors for immune deposition
Sites of immune complex deposition include:
• Renal glomeruli, joints, skin, heart, serosal
surfaces, & small blood vessels
• c. Inflammatory reaction
• After ICs are deposited in tissues acute
inflammatory reactions ensues and the damage is
similar despite the nature and location of tissues
• Due to this inflammatory phase two mechanisms
operate:
i) Activation of complement cascades
ii) Activation of neutrophils and macrophages
through their Fc receptors
Classification of immune complex-mediated diseases:
• Systemic immune complexes diseases (e.g. serum
sickness)
• Localized diseases (e.g.Arthus reaction)
Clinical examples of systemic immune complex diseases:
• Various types of glomerulonephritis
• Rheumatic fever
• Various vasculitides
• Quartan nephropathy
• Systemic lupus erythromatosis
 TYPE IV HYPERSENSITIVITY (CMI)
• It’s due to activation of cellular immunity and the onset of clinical
manifestations is typically delayed by 48–72 hours
• Ag is taken up by APCs, which then migrate to regional lymph
nodes
• Following Ag processing, APCs present antigen to responsive T
cells, which proliferate and mature
• Antigen specific TH1 cells then migrate to the periphery and when
they encounter antigen are further stimulated
• They secrete IFN- which activates macrophages, and both T cells
and macrophages contribute to the inflammatory process
• When Ag is persistent, this process can result in granulomatous
inflammation
The two forms of type IV hypersensitivity are:
1. Delayed type hypersensitivity
• Typically seen in tuberculin reaction, which is
produced by the intra-cutaneous injection of
tuberculin, a protein lipopolysaccharide
component of the tubercle bacilli
• Steps involved in type IV reaction include
a. First the individual is exposed to an antigen e.g. to the
tubercle bacilli where dendritic (Langhan’s) cells engulf
the bacilli and present it to naïve CD4+ T-cells through
MHC type ll antigens found on surfaces of APCs
b. The initial macrophage (APC) and lymphocytes interactions
result in differentiation of CD4+TH type one cells
c. Some of these activated cells so formed enter into the
circulation and remain in the memory pool of T cells for
long period of time
d. A subcutaneous injection of the tuberculin
e.g. to a person previously exposed to the
tubercle bacilli , the memory TH1 cells interact
with the antigen on the surface of APC and are
activated with formation of granulomatous
inflammation
2. T-cell mediated cytotoxicity
• In this variant of type IV reaction, sensitized
CD8+T cells kill antigen-bearing cells
• Such effector cells are called cytotoxic T
lymphocytes (CTLs)
• CTLs are directed against cell surface of MHC
type l antigens and it plays an important role in
graft rejection and in resistance to viral infections
• Two mechanisms by which CTLs work are:
• Perforin-Granzyme dependant killing where
perforin drill a hole into the cell membrane
with resultant osmotic lysis and granzyme
activates apoptosis of the target cells
• FAS-FAS ligand dependant killing which induce
apoptosis of the target cells
 Conclusion
• The Gell and Coombs classification of
hypersensitivity is a useful framework to use
when considering many aspects of
immunopathology, however, more than one
mechanism may be relevant to a single
disease
• Additionally other methods of tissue injury
may occur.