Hypersensitivity- Introduction, Causes, Mechanism and Types

Synopsis
 Introduction
 Causes of Hypersensitivity
 Mechanism of Hypersensitivity
 Types of Hypersensitivity Reactions
 Type I: Immediate reaction
 Type II: Antibody-mediated cytotoxic reaction
 Type III: Immune complex-mediated reaction
 Type IV: Delayed-type hypersensitivity reaction

Introduction
 Hypersensitivity is increased reactivity or increased sensitivity by the animal body to an
antigen to which it has been previously exposed.
 The term is often used as a synonym for allergy, which describes a state of altered
reactivity to an antigen.
 Hypersensitivity has been divided into categories based upon whether it can be passively
transferred by antibodies or by specifically immune lymphoid cells.
 The most widely adopted current classification is that of Coombs and Gell that
designates immunoglobulin-mediated (immediate) hypersensitivity reactions as types I,
II, and III, and lymphoid cell-mediated (delayed-type) hypersensitivity/cell-mediated
immunity as a type IV reaction.
 “Hypersensitivity” generally represents the “dark side,” signifying the undesirable
aspects of an immune reaction, whereas the term “immunity” implies a desirable effect.
Causes of Hypersensitivity
Immune responses that are the cause of hypersensitivity diseases may be specific for antigens
from different sources:
 Autoimmunity: reactions against self-antigens.
 Reactions against microbes.
 Reactions against non-microbial environmental antigens.
Mechanism of Hypersensitivity
Hypersensitivity diseases are commonly classified according to the type of immune response
and the effector mechanism responsible for cell and tissue injury. These mechanisms include
some that are predominantly dependent on antibodies and others predominantly dependent on
T cells, although a role for both humoral and cell-mediated immunity is often found in many
hypersensitivity diseases.
Immediate (type I) hypersensitivity
It is caused by IgE antibodies specific for environmental antigens and is the most prevalent
type of hypersensitivity disease. Immediate hypersensitivity diseases, commonly grouped
under allergy or atopy, are often caused by activation of interleukin-4 (IL-4), IL-5, and IL-13
producing Th2 cells and the production of IgE antibodies, which activate mast cells and
eosinophils and induce inflammation.
Antibody-mediated (type II) hypersensitivity
IgG and IgM antibodies specific for cell surface or extracellular matrix antigens can cause
tissue injury by activating the complement system, by recruiting inflammatory cells, and by
interfering with normal cellular functions.
Immune complex-mediated (type III) hypersensitivity
IgM and IgG antibodies specific for soluble antigens in the blood form complexes with the
antigens, and the immune complexes may deposit in blood vessel walls in various tissues,
causing inflammation, thrombosis, and tissue injury.
T cell-mediated (type IV) hypersensitivity
In these disorders, tissue injury may be due to T lymphocytes that induce inflammation or
directly kill target cells. In most of these diseases, the major mechanism involves the
activation of CD4+ helper T cells, which secrete cytokines that promote inflammation and
activate leukocytes, mainly neutrophils and macrophages. CTLs contribute to tissue injury in
some diseases.
Types of Hypersensitivity Reactions
The Gell’s and Coombs’ classification of hypersensitivity reactions considers four types of
reactions. Type I, II, and III reactions are basically mediated by antibodies with or without
participation of the complement system; type IV reactions are cell-mediated. While in many
pathological processes mechanisms classified in more than one of these types of
hypersensitivity reactions may be operative, the subdivision of hypersensitivity states into
four broad types aids considerably in the understanding of their pathogenesis.
Type I: Immediate reaction

Some antigens (allergens), such as insect venom, foods, pollen, and dust mite, can induce the
formation of IgE antibodies in individuals with a corresponding predisposition. The IgE
antibodies bind via Fc receptors to mast cells (sensitization). If the individual is re-exposed to
the allergen, cross-linkage of the membrane-bound IgE occurs. This results in the immediate
release of mediators (e.g., histamine, kininogen), which induce vasodilation, smooth-muscle
contraction, mucus secretion, edema, and/or skin blisters. Most allergens are small proteins
that can easily diffuse through the skin or mucosa. They are frequently proteases and are
active at very low doses. IL-4 favors differentiation of TH2 cells. The exact mechanism that
leads B cells to produce IgE is not known
Type II: Antibody-mediated cytotoxic reaction

The immunization of individuals to erythrocyte antigens during pregnancy is a typical

example of a type II reaction. Children who inherit the RhD erythrocyte antigen from their
father can induce immunization against the RhD+ antigen in their RhD-mother. Sensitization
usually occurs at birth when fetal blood cells come into contact with the maternal immune
system. In any subsequent pregnancies, maternal anti-RhD antibodies of the IgG type can
pass into the placenta and cause severe hemolysis of fetal RhD+ erythrocytes.
Other examples: Drugs (e.g., penicillin) can passively bind to erythrocytes. Antibodies
directed against penicillin then lead to lysis of the erythrocytes. The formation of antibodies
directed against the basement membrane (BM) of the glomerulus can develop during the
course of kidney inflammation. Lung damage accompanied by pulmonary hemorrhage and
renal inflammation (glomerulonephritis) may occur due to cross-reaction of these antibodies
with the basement membrane of the lung (Good-pasture’s syndrome).

Type III: Immune complex-mediated reaction

Antibody-antigen complexes (immune complexes) can form during an immune response.
Immune complexes can settle in vessel walls, the basement membrane of the lungs and/or
kidneys, and in the joints (synovia). They can induce inflammatory processes in these
structures by binding complement factors C3a and C5a (anaphylatoxins). A particular type III
reaction is the Arthus reaction: when an antigen has penetrated the skin of an individual who
has performed IgG antibodies, the immune complexes can bind to Fc receptors of most cells
inducing degranulation inflammatory cells are recruited and complement is activated, leading
to the release of C5a and local inflammation, platelet accumulation, and eventually to blood
vessel occlusion with necrosis.
 Type IV: Delayed-type hypersensitivity reaction

Haptens are molecules of very small molecular weight (often < 1 kDa). They are too small to
function as antigens, but they can penetrate the epidermis and bind to certain proteins in the
skin (carrier proteins). Hapten-carrier complexes are bound by antigen-presenting cells of the
skin (Langerhans cells), which then migrate to regional lymph nodes. T-cell stimulation then
occurs at the lymph node. The so-called sensitization phase lasts ca. 10-14 days. If the
individual is reexposed to the hapten, antigen-specific T cells migrate to the skin, where they
accumulate and proliferate. They also cause edema formation and local inflammation with
the help of cytokines. Compounds containing nickel or chrome and chemicals such as those
found in rubber are typical triggers of type IV hypersensitivity reactions.