Hypersensitivity reactions are immune disorders caused by an inappropriate response to antigens that are not pathogens. There are four main types of hypersensitivity reactions: Type I are rapid IgE-mediated allergic reactions; Type II involve IgG/IgM antibodies binding to cells and recruiting complement; Type III occur when immune complexes are not cleared and deposit in tissues, inducing inflammation; Type IV are delayed T cell-mediated reactions like contact dermatitis.

1. Hypersensitivity Reactions
A state of altered reactivity in which
the body reacts with an exaggerated
immune response to a foreign agent.

2. • Some immune-mediated disorders are caused by an inappropriately vigorous
innate and/or adaptive response to antigens.
• Two French scientists, Paul Portier and Charles Richet, were the first to recognize
and describe hypersensitivities.
• In the early twentieth century, as part of their studies of the responses of bathers
in the Mediterranean to the stings of Portuguese man-o’-war jellyfish (Physalia
physalis), they demonstrated that the toxic agent in the sting was a small protein.
• They reasoned that eliciting an antibody response that could neutralize the toxin
may serve to protect the host. Therefore, they injected low doses of the toxin into
dogs to elicit an immune response, and followed with a booster injection a few
weeks later.
• However, instead of generating a protective antibody response, the unfortunate
dogs responded immediately to the second injection with vomiting, diarrhea,
asphyxia, and death.
• Richet coined the term “anaphylaxis ,” derived from the Greek and translated
loosely as “against protection” to describe this overreaction of the immune
system, the first description of a hypersensitivity reaction.
• Richet was subsequently awarded the Nobel Prize in Physiology or Medicine in
1913.

3. • There are multiple types of hypersensitivity reactions.
• Immediate hypersensitivity reactions result in symptoms that
manifest themselves within very short time periods after the
immune stimulus.
• Other types of hypersensitivity reactions take hours or days to
manifest themselves, and are referred to as delayed- type
hypersensitivity (DTH) reactions.
• In general, immediate hypersensitivity reactions result from
antibody-antigen reactions, whereas DTH is caused by T-cell
reactions.
• Two immunologists, P. G. H. Gell and R. R. A. Coombs,
proposed a classification scheme to discriminate among the
various types of hypersensitivity .

4. Four Types of Hypersensitivity Reactions:
• Type I (Anaphylactic) Reactions
• Type II (Cytotoxic) Reactions
• Type III (Immune Complex) Reactions
• Type IV (Cell-Mediated) Reactions

5. • Type I hypersensitivity reactions are mediated by IgE
antibodies, and include many of the most common allergies
to respiratory allergens, such as pollen and dust mites.
• Type II hypersensitivity reactions result from the binding of
IgG or IgM to the surface of host cells, which are then
destroyed by complement- or cell-mediated mechanisms.
• In type III hypersensitivity reactions, antigen-antibody
complexes deposited on host cells induce complement
fixation and an ensuing inflammatory response.
• Type lV hypersensitivity reactions result from inappropriate
T-cell activation.

6. • The term allergy first appeared in the medical literature in
1906, when the pediatrician Clemens von Pirquet noted that
the response to some antigens resulted in damage to the
host, rather than in a protective response.
• Although most familiar respiratory allergies result from the
generation of IgE antibodies toward the eliciting agent, and
therefore are type I hypersensitivity reactions, other
common reactions that are associated with allergy, such as
the response to poison ivy, result from T-cell-mediated, type
IV responses.

7. Hypersensitivity Reactions

8. • Hypersensitivities are immune disorders caused by an inappropriate
response to antigens that are not pathogens.
• Hypersensitivities are classically divided into four categories (types I–IV)
that differ by the immune molecules and cells that cause them and the
way they induce damage.
• Allergy is a type I hypersensitivity reaction that is mediated by IgE
antibodies.
• IgE antibodies bind to antigen via their variable regions and to one of two
types of Fc receptors via their constant regions.
• Mast cells, basophils, and to a lesser extent eosinophils express Fc RI
receptors, and are the main mediators of allergy symptoms.
• Cross-linking of Fc RI receptors by allergen/IgE complexes initiates
multiple signaling cascades that resemble those initiated by antigen
receptors.

9. • Mast cells, basophils, and eosinophils that are stimulated by Fc cross-linking
release their granular contents (including histamine, proteases) in a process called
degranulation. They also generate and secrete inflammatory cytokines and lipid
inflammatory molecules (leukotrienes and prostaglandins).
• Degranulation releases both non-protein (histamine) and protein (protease)
molecules that induce rapid inflammatory responses (e.g., vasodilation and
edema, smooth muscle constriction).
• Allergy symptoms vary depending on where the IgE response occurs and whether
it is local or systemic. Asthma, atopic dermatitis, and food allergies are examples of
local allergic responses. Anaphylaxis refers to a systemic IgE response and can be
caused by systemic (e.g., intravenous) introduction of the same allergen that
induces local responses.
• Individuals predisposed to allergic responses are referred to as atopic. Both
genetic and environmental factors contribute to allergy susceptibility.
• Why some antigens induce allergy and others do not is still not fully understood.
Some antigens that cause allergy appear to have intrinsic protease activity.
• Skin tests are an effective way to diagnose allergies.

10. • Type II hypersensitivities are caused by IgG and IgM antibodies binding to
an antigen on red blood cells and inducing cell destruction by recruiting
complement or by ADCC (antibody dependent cell mediated cytotoxicity).
• Transfusion reactions are caused by antibodies that bind to A, B, or H
carbohydrate antigens, which are expressed on the surface of red blood
cells. Individuals with different blood types (A, B, or O) express different
carbohydrate antigens. They are tolerant to their own antigens, but
generate antibodies against the antigen (A or B) that they do not express.
All individuals express antigen H, so no antibodies are generated to this
carbohydrate.
• Hemolytic disease of the newborn is caused by maternal antibody
reaction to the Rh antigen, which can happen if mother is Rh negative and
father is Rh positive .
• Drug-induced hemolytic anemia is caused by antibody responses to red
blood cells that have bound drug molecules or metabolites.

11.  Immune complexes of antibody and antigen can cause type III
hypersensitivities when they cannot be cleared by
phagocytes. This may be due to peculiarities of the antigen
itself, or disorders in phagocytic machinery.
 Uncleared immune complexes can induce degranulation of
mast cells and inflammation, and can be deposited in tissues
and capillary beds where they induce more innate immune
activity, blood vessel inflammation (vasculitis), and tissue
damage.
 Arthus reactions are examples of immune complex (type III)
hypersensitivity reactions and can be induced by insect bites,
as well as inhalation of fungal or animal protein. They are
characterized by local and sometimes severe inflammation of
blood vessels.

12. • Delayed-type hypersensitivity (type IV hypersensitivity) is cell
mediated, not antibody mediated.
• Examples include contact dermatitis caused by poison ivy, as
well as the tuberculin reaction. DTH responses are responsible
for granulomas associated with tuberculosis.
• DTH requires T cells to be sensitized to antigen. Subsequent
reexposure to antigen results in cytokine generation,
inflammation, and the recruitment of macrophages, which
produce DTH symptoms 2 to 4 days after reexposure.
• TH 1 cells are classically associated with DTH, but other helper
cell subsets have also been implicated recently.