The immune system is an integral part of human protection against disease, but the normally

protective immune mechanisms can sometimes cause detrimental reactions in the host. Such reactions
are known as hypersensitivity reactions, and the study of these is termed immunopathology. The
traditional classification for hypersensitivity reactions is that of Gell and Coombs and is currently the
most commonly known classification system.
It divides the hypersensitivity reactions into the following 4 types:

Type I reactions (ie, immediate hypersensitivity reactions) involve immunoglobulin E (IgE)–

mediated release of histamine and other mediators from mast cells and basophils.
IgE or immunoglobulin E is a type of antibody that occurs in mammals. They are the least common
type of antibody in the body. Further, plasma B cells produce them. Generally, IgE plays an essential
role in the type I hypersensitivity, manifesting various types of allergic reactions. Some examples are
allergic asthma, food allergies, most types of sinusitis, allergic rhinitis, and specific types of chronic
urticaria and atopic dermatitis. Additionally, the other environmental allergens against which IgE
reacts are anaphylactic drugs, bee stings, pollen, etc.

Anaphylaxis is a medical emergency because can lead to an acute, life-threatening respiratory failure.
It is an IgE-mediated process. It is the most severe form of an allergic reaction, where mast cells
suddenly release a large amount of histamine and later on leukotrienes. In severe cases intense
bronchospasm, laryngeal oedema, cyanosis, hypotension, and shock are present.[4]
Allergic bronchial asthma is an atopic disease, characterized by bronchospasm. It may also be a
chronic inflammatory disease. In its aetiology, and environmental factors along with a genetic
background play an important role. The diagnosis is dependent on history and examination. In allergic
bronchial asthma, IgE is elevated, Epidemiologically, a positive skin prick test or specific IgE are risk
factors for asthma.[5]
Allergic rhinitis is another atopic disease where histamine and leukotrienes are responsible for
rhinorrhoea, sneezing and nasal obstruction. Allergens are similar to those found in bronchial asthma.
[6]
Food allergy One must differentiate food allergy (IgE-mediated) from food intolerance that can be
cause for a variety of aetiology including malabsorption and celiac disease. It is more frequent in
children as seen in cow's milk allergy. Food allergy symptoms mostly affect the respiratory tract, the
skin, and the gut. Skin prick tests are helpful to test for food allergens that can trigger severe
reactions, e.g., peanuts, eggs, fish, and milk.[7]
Drug allergy .Drugs may cause allergic reactions by any mechanism of hypersensitivity. For
example, penicillin may cause anaphylaxis, which is IgE-mediated but must responses be trivial.
Penicillin cross-reacts with other semisynthetic penicillin’s including moonbeams and curableness
and may also cross-react with other antibiotics such as cephalosporin’s.[8]

On first exposure to the antigen:

  Antigen Presenting Cells (APCs) detect the antigen and neutralise it.
 APCs present to B Cells which produce specific IgE antibodies for future defence
 IgE antibodies bind to Fc receptors on the surface of mast cells – priming the mast cells.
The crucial aspect of mast cells is that they contain histamine granules and when triggered,

this histamine is released.

Upon second exposure to the antigen:

 Antigen binds to IgE on the mast cell surface

 Mast cell degranulation occurs – histamine is released, along with other chemicals
including leukotrienes.
 Histamine has multiple effects on the body including vasodilation, oedema,
bronchospasm and an urticarial rash.

Type I hypersensitivity includes things like allergies e.g. latex, peanuts etc. Management involves
avoiding the trigger, anti-histamines, corticosteroids to suppress the immune system and
adrenaline in emergencies.

Type II reactions (ie, cytotoxic hypersensitivity reactions) involve immunoglobulin G or

immunoglobulin M antibodies bound to cell surface antigens, with subsequent complement fixation.
IgG and IgM mediate cytotoxic-mediated response against cell surface and extracellular matrix
proteins. The immunoglobulins involved in this type of reaction damages cells by activating the
complement system or by phagocytosis. Type II hypersensitivity reactions can be seen in immune
thrombocytopenia, autoimmune haemolytic anemia, and autoimmune

Immune thrombocytopenia (ITP)

ITP is an autoimmune disorder that occurs at any age. Phagocytes destroy sensitized platelets in the
peripheral blood. Clinically, it manifests by thrombocytopenia with shortened platelet survival and
increased marrow megakaryocytes. Sudden onset of petechial and bleeding from the gums, nose,
bowel, and urinary tract occurs. Bleeding can accompany infections, drug reactions, malignancy and
other autoimmune disorders such as thyroid disease and SLE.[
Autoimmune haemolytic anemia (AIHA)
There are two types of immune haemolytic anemia: IgG-mediated (warm AIHA) and IgM-mediated
(cold AIHA). The warm type may be idiopathic autoimmune or secondary to other diseases such as
malignancy affecting the lymphoid tissues. The cold type may be idiopathic or secondary to infections
such as Epstein-Barr virus. The primary clinical sign of the two is jaundice. The laboratory diagnosis
is made by a positive Coombs test, which identifies immunoglobulins and C3 on red blood cells.

Haemolytic disease of the fetus and the new-born (erythroblasts fetalis)

The maternal immune system suffers an initial sensitization to the fetal Rh+ red blood cells during
birth, when the placenta tears away. The first child escapes disease but the mother, now sensitized,
will be capable of causing a haemolytic reaction against a second Rh+ fetus, which develops anemia
and jaundice once the maternal IgG crosses the placenta

Myasthenia gravis is an autoimmune disorder caused by antibodies to post-synaptic acetylcholine

receptors that interfere with the neuromuscular transmission. It is characterized by extreme muscular
fatigue, double vision, bilateral ptosis, DE conjugate eye movements, difficulty swallowing, and

weakness in upper arms. Babies born to myasthenia mothers can have transient muscle weakness due
to pathogenic IgG antibodies that cross the placenta.

The killing of cell can occurs by one of the three mechanisms. 

 Complement mediated cell lysis

 Antibody dependent cell mediated cytotoxicity (ADCC)

 Opsonization

1. Complement mediated lysis of cell

 Complement system is a system of lytic enzyme which are usually inactive in blood.
 Enzymes of complement system are activated by antigen-antibody complex.
  When antibody binds to antigen (microorganism or RBC) they form Ag-ab complex.
 Ag-ab complex can activate complement system by three different mechanism-classical
pathway, alternate pathway and lectin pathway.
 Activated complement proceeds in cascade mechanism
 When complement is activated on the surface of cell (RBC) it causes lysis of cell.

2. Antibody dependent cell mediated cytotoxicity (ADCC):

 Antibody binds with antigen by its Fab portion. However Fc region of antibody has receptor
on cytotoxic cells. So, antibody cross link target cell (microorganism or RBC) with cytotoxic
cells and promote killing.
 Most cytotoxic cells contain storage of hydrolytic and digestive enzymes. These enzymes are
released on the surface of target cell (MOs or RB or target cell), killing them.
 Here antibody itself does not kill or destroy cell but rather mediate killing by presenting
antigen to cytotoxic cell. Similarly cytotoxic cell depends upon antibody to bind antigen. So
this mechanism is known as Antibody dependent cell mediated cytotoxicity
3. Opsonization
 When antigen enters into host body, antibodies are produced.
 Antibody binds to antigen through Fab region. Fc region of antibody remains free
 Phagocytic cells such as Neutrophils, macrophages and monocytes have receptors that can
bind to Fc region of antibody. The receptor is known as FcR.
 In this case antibody molecule directly cross links antigen (Microorganism or RBC or target
cell) with phagocytic cells. This cross-linkage activates phagocytic cells and increases the rate
of phagocytosis.
 This increased rate of phagocytosis by binding of antibody to antigen is called Opsonization.

Type III reactions (ie, immune-complex reactions) involve circulating antigen-antibody immune
complexes that deposit in post capillary venue’s, with subsequent complement fixation. An example is
serum sickness.
These are also mediated by IgM and IgG antibodies that react with soluble antigens forming antigen-
antibody complexes. The complement system becomes activated and releases chemotactic agents that
attract neutrophils and cause inflammation and tissue damage as seen in vasculitis and
glomerulonephritis. Type III hypersensitivity reactions can classically be seen in serum sickness and
Arthus reaction.
Serum sickness can be induced with massive injections of foreign antigen. Circulating immune
complexes infiltrate the blood vessel walls and tissues, causing an increased vascular permeability and
leading to inflammatory processes such as vasculitis and arthritis. It was a complication of anti-serum
prepared in animals to which some individuals produced antibodies to the foreign protein. It was also
experienced in the treatment with antibiotics such as penicillin.

The diagram above demonstrates Type III hypersensitivity. The deposition of immune complexes
triggers inflammation, complement binding and platelet aggregation. Part of the sequence triggers
vascular permeability which then stimulates further immune complex deposition. Neutrophils fail to
remove the complexes but release damaging chemicals in the process. An example of this includes
erythema multiforme.

Arthus reaction is a local reaction seen when a small quantity of antigens is injected into the skin
repeatedly until detectable levels of antibodies (IgG) are present. If the same antigen is inoculated,
immune complexes develop at the mentioned local site and in the endothelium of small vessels. This
reaction is characterized by the presence of marked edema and haemorrhage, depending on the
administered dose of the foreign antigen.

Mechanism of Type III hypersensitivity reaction:

 Type III hypersensitivity reaction develops when immune complex activates C3a and C5a
components of complement system.

 C3a and C5a are lymph toxin (anaphylaxis) that causes localized mast cell degranulation.
  Degranulation of mast cell releases histamine which increases vascular permeability of blood
capillaries. This facilitates deposition of immune complexes on wall of blood vessel.

 C5a, C3a and C5b67 also acts as chemotactic factors for neutrophils, So it attracts neutrophils
at the site of immune complex deposition.

 C3b acts as opsonic by binding with immune complex. Neutrophil binds to C3b coated
immune complex by means of type I complement receptor which is specific for C3b.

 The neutrophils attempt to phagocytosis the immune complex but phagocytosis is not possible
because immune complexes are deposited on basement membrane, so the neutrophil releases
lytic enzymes to destroy immune complex.

 The lytic enzymes cause tissue damage surrounding of immune complex deposits, resulting
hypersensitivity reaction. Furthermore complement proteins can also contribute to tissue
destruction.

Type IV reactions (ie, delayed hypersensitivity reactions, cell-mediated immunity) are mediated
by T cells rather than by antibodies. An example is contact dermatitis from poison ivy or nickel
allergy.

Type IV hypersensitivity reactions, also known as cell-mediated immunity, are facilitated by T

lymphocytes, rather than merely antibodies. This inflammatory cell-driven reaction is also referred to
as delayed-type hypersensitivity, since its onset is generally after 48 hours, in contrast to the type I
reaction, which is an immediate hypersensitivity.

In the first type IV subcategory, CD4 T H1-mediated reactions are described as delayed-type
hypersensitivities (DTH). The sensitization step involves the introduction of antigen into the skin and
phagocytosis by local antigen presenting cells (APCs). The APCs activate helper T cells, stimulating
clonal proliferation and differentiation into memory T H1 cells. Upon subsequent exposure to the
antigen, these sensitized memory T H1 cells release cytokines that activate macrophages, and activated
macrophages are responsible for much of the tissue damage. Examples of this T H1-mediated
hypersensitivity are observed in tuberculin the Mantoux skin test and contact dermatitis, such as
occurs in latex allergy reactions.

In the second type IV subcategory, CD4 TH2-mediated reactions result in chronic asthma or

chronic allergic rhinitis. In these cases, the soluble antigen is first inhaled, resulting
in eosinophil recruitment and activation with the release of cytokines and inflammatory mediators.

cases, the soluble antigen is first inhaled, resulting in eosinophil recruitment and

activation with the release of cytokines and inflammatory mediators.
In the third type IV subcategory, CD8 cytotoxic T lymphocyte (CTL)-mediated reactions are
associated with tissue transplant rejection and contact dermatitis. For this form of cell-mediated
hypersensitivity, APCs process and present the antigen with MHC I to naïve CD8 T cells. When these
naïve CD8 T cells are activated, they proliferate and differentiate into CTLs. Activated T H1 cells can
also enhance the activation of the CTLs. The activated CTLs then target and induce granzyme-
mediated apoptosis in cells presenting the same antigen with MHC I. These target cells could be
“self” cells that have absorbed the foreign antigen (such as with contact dermatitis due to poison ivy),
or they could be transplanted tissue cells displaying foreign antigen from the donor.
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