Basic Immunology MLS364

Mr. Monsi, T.P.

Department of Medical Laboratory Science
Rivers State University
[email protected]

HYPERSENSITIVITY

When an immunologically sensitized individual comes in contact with same antigen the second time it
leads to secondary boosting of the immune response. This secondary immune response may be
excessive leading to tissue damage. Excessive or inappropriate immune responses sometimes lead to
host tissue damage resulting from prolonged or repeated antigen exposure.

Hypersensitivity refers to an excessive or exaggerated immune response to an antigen due to

prolonged or repeated exposure. This antigen could be an allergen (nonself antigen) or self-antigens
(autoimmunity). There are four types of hypersensitivity, which differ in their pathogenesis,
effector mechanisms, clinical and pathological manifestations.

Type 1 Hypersensitivity

This is also called immediate hypersensitivity or allergy or atopy as it is rapid. This type of
hypersensitivity is mediated by IgE antibody and mast cell. This results in vascular and muscular
reactions due to the cytokines production from mast cells and granulocytes. These reactions take
place on a second exposure. Examples of type 1 hypersensitivity are:

❖ Hay fever
❖ Asthma
❖ Anaphylaxis

During the first exposure to an allergen (antigen that elicits type 1 hypersensitive reaction), an
individual prone to this allergen respond by producing antibody to this antigen. A sensitized B cell
binds to the TH2 and becomes activated. TH2 produces IL-4 and IL-13 which activate B cells to
differentiate to IgE producing plasma cells.

IgE antibody has a high affinity to the Fcε receptors on the mast cells. Hence the IgE antibody
binds to the FcεR on the mast cells and becomes sensitized to that particular allergen. Upon a
second encounter with the same antigen, the IgE antibodies on the mast cell crosslink with the
antigen. This activates the mast cells, thereby secreting their mediators:

❖ Granules (vasoactive amines, histamine, and protease): vascular dilation and tissue damage
❖ Lipid mediators (prostaglandins and leukotrienes): vascular dilation and smooth muscle
contraction
❖ Cytokines (TNF): inflammation through leukocyte recruitment

Symptoms
Peristalsis: This occurs when there is an ingestion of food allergens.
Mucus production: produced by histamine and IL-13
Vasodilation: caused by the loosening of the endothelial cell junctions
Vasoconstriction: caused by smooth muscle contraction in arterial and arteriole walls

Type 1 hypersensitivity

Type 2 Hypersensitivity

Type II hypersensitivity is also known as cytotoxic hypersensitivity. It is initiated when antibodies

interact with antigens on cells membrane or extracellular matrix. This may lead to the activation of
complements. These antibodies are produced against the body’s own antigens (auto-antibodies) or
nonself molecules such as drugs. This can occur due to a mutation in self-antigens. This results in
the formation of the membrane attack complex through the activation of complement pathways. In
addition to lysis of the cells, complements attract phagocytes. Phagocytes engulf and remove the
dead cells. It is primarily mediated by IgG and IgM.

Examples of this type of hypersensitivity are Drug-induced haemolytic anaemia, Erythroblastosis

fetalis, granulocytopenia, blood transfusion reaction and thrombocytopenia.

There are three different mechanisms via which this can occur:

a) Interaction of antibodies with cells

Blood group antibodies: Transfusion of incompatible blood leads to antibodies binding to

carbohydrate molecules on RBC (blood group antigens). This may either cause phagocytosis or
activation of complements that causes lysis (haemolytic anaemia). Antibodies to Rhesus factor do
not activate complement, hence RBC are destroyed by phagocytes.

Complement: Complements are activated by IgM and IgG antibodies and generate C3b and C4b.
These are deposited on the surface of antibody-coated cells as opsonins. Phagocytes recognise
bound antibody using FcRs and bound complements using complement receptor. This occurs in drug-
induced haemolytic anaemia (e.g. penicillin).

Erythroblastosis fetalis

Drug-induced hypersensitivity

b) Interaction of antibody with extracellular matrix

Some autoreactive antibodies produced in certain individuals bind to the extracellular matrix
proteins (basement membrane). This triggers the classical pathway of complement activation. This
generates anaphylotoxins (e.g. C5a, C4a and C3a) that recruits neutrophils and monocytes.

c) Antibody-mediated disruption of cellular function

Some autoreactive antibodies bind to cell surface receptors without activating complement or
binding to FcRs. Examples are seen in: Graves’ disease (stimulatory: autoreactive antibodies
recognize and bind to the thyrotropin receptor (TSH receptor) which stimulates the secretion of
thyroxine (T4) and triiodothyronine (T3)) or inhibitory (insulin-resistant diabetes and myasthenia
gravis – autoantibody bind to acetylcholine receptor blocking its normal ligand [acetylcholine]
leading to muscle weakness. This occurs at the junction between neuron and skeletal muscles).

(Penicillin)

Penicillin allergy

Fig 2. Type 2 Hypersensitivity

Type 3 Hypersensitivity

Type III hypersensitivity is also known as immune complex (antigen-antibody complexes)

hypersensitivity. The reaction may be general (e.g., serum sickness) or may involve individual organs
including skin (e.g., systemic lupus erythematosus, Arthus reaction), kidneys (e.g., lupus nephritis),
lungs (e.g., aspergillosis), blood vessels (e.g., polyarteritis), joints (e.g., rheumatoid arthritis) or
other organs.

The key players in this type of hypersensitivity are antigen-antibody complex and complement. They
are mostly of the IgG class, although IgM may also be involved. 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.
It begins by the deposition of immune complexes on the wall of endothelium due to the presence of
a gap in between the endothelium. The antibody are bound to the antigen on the surface of the
endothelium or to other self-molecules and deposited on the wall of the endothelium. These
antibodies are usually autoantibodies.

Immune complexes activate complements proteins forming anaphylatoxins (C5a). There are two key
things that can occur in type 3 hypersensitivity:

1. Anaphylatoxins damage the vascular endothelial cells

2. Anaphylatoxins also recruits macrophages, neutrophils and dendritic cells to the site of the
infection.

The reaction may take 3 - 10 hours after exposure to the antigen (as in Arthus reaction).

Fig 3. Type 3 Hypersensitivity

Type 4 Hypersensitivity

It is delayed type of hypersensitivity as antigens need to be processed by antigen presenting cells

and presented to T cells. The key players in this type of hypersensitivity are: antigen presenting
cells (such as macrophages) and T lymphocytes. It is caused by dust, animal furs. Some examples
are: Hashimoto thyroiditis (caused by thyroglobulin antigens), Type-1 diabetes (pancreatic Beta cell
antigens attack Beta cells). A seen in the diagram below, antigen presenting cells such as
macrophages phagocytose antigens conjugated to a hapten molecule, process it and present it on
MHC II molecule to T helper- 1 cells. This activates the Th-1 cells to produce cytokines such as IL-
6, IL-8 and IL-2.

Hapten

IL6, IL8,
IL2

Fig 4. Type 4 initiation stage

In type IV hypersensitivity, Lymphocytes destroy tissues by two principal mechanisms:

A. Delayed-type hypersensitivity

CD4+ T lymphocytes of the Th1 subset produce cytokines that activate macrophages which produce
mainly IFN-γ (interferon-γ) and recruit inflammatory cells that produce TNF (tumour necrosis
factor). Th17 cells secrete cytokines that also recruit leukocytes, such as neutrophils. These
reactions are called Delayed type hypersensitivity; because they take 24-48 hours to develop after
antigen challenge (the classical example is a tuberculin skin test). Th1 and/or Th17 reactions against
self-antigens or against persistent microbes are responsible for many chronic disorders that you
will hear about (Crohn’s disease, type-1 diabetes, multiple sclerosis). (See diagram below for
schematic explanation).

A. T cell-mediated cytolysis

IL2 produced by the Th-1 cells activates CD8+ cells. CD8+ is called cytotoxic T cells. Upon
activation they directly kill host cells through the production of perforin and granzyme. CTL-
mediated cell injury contributes to some Th1-mediated disease such as type-1 diabetes.
Fig. 5. Type 4 Hypersensitivity pathogenesis