DEPARTMENT OF

MICROBIOLOGY
INDEX
INTRODUCTION

• Hypersensitivity can be defined as a state

of altered immune response against an
antigen characterized by hyper reactivity
leading to Immunopathology
• Hypersensitivity reactions require a pre-
sensitized (immune) state of the host.
• There are two categories of adaptive
hypersensitivities
a) Immediate hypersensitivities refer to
humoral immunity (antigen/antibody
reactions)
b) Delayed hypersensitivities refer to cell-
mediate immunity(cytotoxic T-lymphocytes,
macrophages, and cytokines)
CLASSIFICATION OF
HYPERSENSITIVITY

Coomb and Gell in 1963 classified

hypersensitivity reactions into the following
four types based on the mechanism
involved and time taken for the reaction.
Type-I hypersensitivity

It is also known as immediate or anaphylactic hypersensitivity

and is mediated by IgE.
• The reaction occurs on exposure to allergen second time. The
first exposure (sensitizing dose) results in sensitization of host
to allergen and subsequent exposure (s) (shocking dose) will
cause reaction
• Anaphylactic shock occurs in sensitized animals within
seconds to minutes (15-30after exposure to the allergen)
after exposure to the antigen, now called as an allergen.
Sometimes the reaction may have a delayed onset (10-12
hours).
• In type I hypersensitivity reactions, the allergens are proteins
with a molecular weight ranging from 10 to 40 kDa.
• Diagnostic tests for immediate hypersensitivity include skin
(prick and intradermal) tests resulting in wheal and flare
reaction, measurement of total IgE and specific IgE antibodies
against the suspected allergens by ELISA, Radioallergosorbent
test (RAST)
Mechanism of Type-I hypersensitivity

The mechanism of reaction involves preferential

production of IgE, in response to certain antigens
(allergens).
• Individuals prone to type-I hypersensitivity preferentially
produce IL-4 and IL-13 that favor IgE class switch.
• IgE has very high affinity for its receptor (FcεIII; CD23)
expressed on surface of mast cells and basophils; the Fc
portion of IgE binds to these receptors.
• A subsequent exposure to the same allergen cross links
the cellbound IgE and triggers the release of various
pharmacologically active substances by a process called
as ‘degranulation’ ; mast cell degranulation is preceded by
increased Ca++ influx, which is a crucial process.
• These agents cause the early phase of allergic reactions
that appears within minutes after exposure to the antigen.
•Degranulation of cells result in the synthesis and
secretion of inflammatory mediators such as platelet-
activating factor, leukotreins, bradykinins, prostaglandins,
and cytokines that contribute to inflammation.
• The reaction is amplified by PAF (platelet activation
factor) that causes platelet aggregation and release of
histamine, heparin and vasoactive amines. Eosinophil
chemotactic factor of anaphylaxis (ECF-A) and neutrophil
chemotactic factors attract eosinophils and neutrophils,
respectively, which release various hydrolytic enzymes
that cause necrosis
• These agents cause the early phase of allergic reactions
that appears within minutes after exposure to the antigen.
• Late phase allergic reactions may begin several hours
after exposure to antigen.
• Cell-bound IgE on the surface of basophils of sensitive
individuals binds a substance called histamine releasing
factor (possibly produced by macrophages and B-
lymphocytes) causing further histamine release
Type II Hypersensitivity

• Type II hypersensitivity are antibody mediated cytotoxic

reactions occurring when an antibody binds to antigens
located on the surface of cells (usually RBCs). The
reaction time is minutes to
hours.
• It is mediated, primarily, by antibodies of IgM or IgG
class.
• The bound antibody can cause cell lysis by activating the
classical complement pathway, promoting phagocytosis
(opsonization) or through ADCC.
• Many different antigens may trigger this cell destruction,
but an infection in a genetically predisposed animal
appears to be a major triggering pathway.
• Antigens are normally endogenous, although exogenous
chemicals (haptens, such as ivy or drugs) that can attach
to cell membranes can also induce type II reactions.
• Autoimmune haemolytic anaemia, Blood transfusion
reactions, Erythroblastosis fetalis, drug-induced
hemolytic anemia, granulocytopenia and
thrombocytopenia are examples
Mechanism of Type II Hypersensitivity

• IgM or IgG antibodies are made against self

antigens either as a result of failure of immune
tolerance or cross-reactive antibodies can
develop during infections, which may bind to
normal tissue antigens and trigger antibody-
mediated cytotoxicity.
• Subsequent binding of these antibodies to the
surface of host cells leads to:
–Opsonization of the host cells whereby
phagocytes stick to host cells by way of IgG,
C3b, or C4b and discharge their lysosomes.
–Activation of the classical complement
pathway causing MAC induced lysis.
–ADCC mediated destruction of the host cells
whereby NK cells attach to the Fc portion of the
antibodies.
Examples of Type II Hypersensitivity

A) AB and Rh blood group reactions (blood

transfusion reactions, erythroblastosis foetalis)
B) Autoimmune diseases like
• Rheumatic fever where antibodies result in joint
and heart valve damage
• Idiopathic thrombocytopenia purpura where
antibodies result in the destruction of platelets;
• Myasthenia gravis where antibodies bind to the
acetylcholine receptors on muscle cells causing
faulty enervation of muscles
• Goodpasture's syndrome where antibodies lead to
destruction of cells in the kidney
Type III Hypersensitivity

• In type III hypersensitivity, soluble immune

complexes are formed in blood and are deposited in
various tissues (typically the skin, kidney and joints),
activate classical complement pathway and cause
inflammatory damage.
• It is mediated by soluble immune complexes. They
are mostly of IgG class, although IgM may also be
involved.
• The reaction takes hours to days (3-10 hours) to
develop.
• The antigen may be exogenous (chronic bacterial,
viral or parasitic infections), or endogenous (non-
organ specific autoimmunity: e.g., Systemic Lupus
Erythematosus-SLE).
• The antigen is soluble and not attached to the
organ involved.
• The prerequisite for the development of immune-
complex disease is the persistent presence of
soluble antigen and antibody.
Mechanism of Type III Hypersensitivity

• Soluble antigen-antibody (IgG or IgM) complexes are

normally removed by macrophages in the spleen and liver.
• On formation of excessive amount or large immune
complexes these gets lodged in capillaries, pass between
endothelial cells of blood vessels – specially those in the
skin, joints, and kidneys - and become trapped on the
surrounding basement membrane beneath these cells.
• The Ag-Ab complexes then activate the classical
complement pathway; the damage being caused by
platelets and neutrophils
a) massive inflammation, due to complement protein C5a;
b)influx of neutrophils, due to complement protein C5a ,
resulting in neutrophils discharging their lysosomes and
causing tissue destruction and further inflammation
c) MAC induced lysis of surrounding tissue cells; and
d) aggregation of platelets, resulting in more inflammation
and the formation of microthrombin that block capillaries.
Examples of Type III Hypersensitivity

• Examples in human beings are: serum sickness,

Arthus reaction, polyarteritis, rheumatoid arthritis,
Glomerulonephritis, SLE, allergies to penicillin and
sulfonamides, poststreptococcal
glomerulonephritis, meningitis, hepatitis,
mononucleosis.
• Examples in animals include:
– Membranoproliferative Glomerulonephritisin dogs
– Hypersensitivity Pneumonitis in large animals
(Extrinsic allergic alveolitis, Farmer’s lung disease)
– Vasculitis
– Periarteritis Nodosa (Polyarteritis Nodosa,
Necrotizing Polyarteritis)
– Canine Rheumatoid Arthritis
– Plasmacytic-Lymphocytic Synovitis
Type IV Hypersensitivity

Type IV hypersensitivity is often called delayed type

hypersensitivity as the reaction takes more than 12
hours to develop. Typically the maximal reaction
time occurs between 48 to 72 hours
• It is mediated by cells that cause an inflammatory
reaction to either exogenous or autoantigens
• The major cells involved are T lymphocytes and
monocytes/macrophages.
• This reaction to exogenous antigens involves T
cells and also antigen-presenting cells (APC), all
produce cytokines that stimulate a local
inflammatory response in a sensitized individual.
• DHR cannot be transferred from an animal to
another by means of antibodies or serum. However,
it can be transferred by T cells, particularly CD4 Th1
cells.
Mechanism of Type IV Hypersensitivity

• CD8 cytotoxic T cells and CD4 helper T cells

recognize antigen in a complex with either type I or II
MHC antigens
• The antigen-presenting cells in this case are
macrophages and they release interleukin 1, which
further stimulates the proliferation of CD4 cells.
• These cells release IL-2 and IFN-λ, which together
regulate the immune reaction; other lymphokines
involved in delayed hypersensitivity reaction include
monocyte chemotactic factor, TNF α etc.
• Cytokines produced by keratinocytes, APC, and T
cells recruit antigen-nonspecific T cells and
macrophages to participate in a local inflammatory
reaction.
• Activated CD8 cells destroy target cells on
contact, while activated macrophages produce
hydrolytic enzymes and, transform into
multinucleated giant cells.
CONCLUSION
REFERENCE