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S ECTION 2

HYPERSENSITIVITY DISEASES

To understand the sequence of reactions in

different types of hypersensitivity, with
particular emphasis on the roles of the
following:
T H 2 cells, IgE and eosinophils in immediate
hypersensitivity

C ONTACT I NFORMATION

Anthony DeFranco, PhD (Email)

R EADING
Basic Immunology: Functions
and Disorders of the Immune
System. Abbas, Abul K., and Andrew
H. Lichtman. -- Chapter 11

O BJECTIVES
To understand the types of diseases caused by
abnormal immune responses, and the meaning
of the term hypersensitivity

Antibodies, complement and Fc receptors in

antibody- and immune complex-mediated
diseases
T cells and cytokines in T cell-mediated
diseases.
To list selected examples of diseases in which
these mechanisms of tissue injury have been
defined and established.
To understand the principles underlying
rational, targeted therapies for immunemediated diseases

To describe the nature of the immune response

and the mechanisms of tissue damage in the
four major types of hypersensitivity reactions
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K EY WORDS :

HYPERSENSITIVITY
IMMEDIATE HYPERSENSITIVITY
ALLERGY
ANTIGEN-ANTIBODY COMPLEXES
DELAYED TYPE HYPERSENSITIVITY (DTH)
AUTOIMMUNITY

M AIN IDEAS :
Abnormal immune responses are causes of
many important diseases. Hypersensitivity
refers to pathologic immune responses
(responses capable of causing tissue injury and
disease).
The underlying mechanism of many of these
diseases is failure of tolerance and other control
mechanisms.
Abnormal immune responses may be directed
against self antigens (autoimmune diseases),
normally harmless environmental antigens

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(allergies and some types of contact sensitivity),
or microbial antigens.
Tissue injury may be caused by antibodies: IgE
antibodies that bind to mast cells, IgM or IgG
antibodies against tissue antigens, or antibodies
that form immune complexes and deposit in
vessels. In the latter two cases, tissue injury is
the result of antibodies binding to Fc receptors
on phagocytes and activating complement
proteins, leading to phagocytosis and
inflammation. IgM and IgG antibodies against
cell surface antigens cause depletion of these
red cells and platelets.
Tissue injury may also be caused by T cells
CD4+ T cells secrete cytokines that induce
inflammation, and CD8+ CTLs kill host cells.
H YPERSENSITIVITY DISEASES : DISORDERS
CAUSED BY IMMUNE RESPONSES

These diseases are classified on the basis of pathogenic

mechanisms and clinico-pathologic manifestations.
The four types of hypersensitivity are well recognized
and useful for understanding immunological mecha-

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nisms, but in any disease, more than one of these

mechanisms may be operative.

small individual effects. Some of these allelic variants

are in immune components related to TH2 immunity.

In general, the mechanisms of tissue injury are the

same as the mechanisms used by normal immune responses to combat microbes. The reason why immune
responses are injurious is that the responses are inappropriately directed against normally harmless antigens (self antigens in autoimmune diseases, environmental antigens in allergies), or the responses are
against microbes that are difficult to eradicate, or the
tissue injury is because of an immune response that is
not appropriately regulated. We will discuss examples
illustrating each of these in the lecture.

Sequence of events: antigens induce TH2 responses

production of IgE antibody
IgE sensitizes mast
cells (IgE binds to FcRI on mast cells)
mast cell degranulation upon antigen encounter
mast cell mediators are released and act on target tissues.

Details about specific disorders will be covered in later

lectures; here we will emphasize general principles.
Immediate hypersensitivity (allergy): the classical TH2 diseases
IgE- and mast cell-mediated rapid (immediate) vascular and smooth muscle reaction, usually in response to environmental antigens; may be followed by
late-phase reaction (inflammation); develops in genetically susceptible individuals. Genetic susceptibility is
multigenic, involving many allelic variants each with

Mast cell mediators: histamine and other vasoactive

amines; prostaglandins and leukotrienes (two classes
of lipid mediators generated from the fatty acid arachidonic acid, as described in the Pharmacology lecture
on anti-inflammatory drugs, later in I-3); proteases; cytokines.
Clinico-pathologic manifestations vary according
to site of reaction. Some allergic diseases are dominated by the acute vascular and smooth muscle reactions (anaphylaxis, acute asthmatic attacks), and others by inflammation and tissue destruction (chronic
asthma, allergic rhinitis).
Treatments: antidotes against mediators (antihistamines, epinephrine, theophylline); steroids (antiinflammatory); desensitization (immunotherapy).
Immune complex-mediated diseases
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Antigen-antibody complexes form in the circulation
and deposit in vessels, joints, kidney glomeruli or are
formed locally
activate complement and engage Fc
receptors on leukocytes
recruitment and activation
of inflammatory cells
tissue injury.
Antigens may be self-antigens (e.g. in lupus) or foreign
antigens (post-streptococcal glomerulonephritis, HBVassociated polyarteritis).
Diseases caused by antibodies against cell or tissue antigens (fixed antigens)
Antibodies bind to cells or tissues and cause disease by
any of several mechanisms: phagocytic destruction of
cells (autoimmune hemolytic anemia, thrombocytopenic purpura); inflammation (anti-glomerular basement membrane antibody-mediated nephritis); interference with normal function (antibodies against hormone and other receptors, e.g. in Graves' disease and
myasthenia gravis).
Antibodies are usually autoantibodies; less commonly,
they may be antibodies against microbes that crossreact with self antigens. One clearly established example of the latter are antibodies against a type of food
poisoning bacteria called Campylobacter, which cross-

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react with glycolipids found on peripheral myelinated
nerves, resulting in a peripheral neuropathy called
Guillain-Barre syndrome.
T cell-mediated diseases
Tissue injury caused by immune inflammation
(CD4+ TH17 cells secrete cytokines that recruit leukocytes, CD4+ TH1 cells secrete cytokines that activate
macrophages) and/or CTL-mediated killing of target cells.
Delayed type hypersensitivity (DTH) is an inflammatory reaction of a previously immunized (sensitized)
individual to challenge with the immunizing antigen.
The reaction is mediated mainly by CD4+ T cells and
their cytokines (particularly TH1 and TH17 cells), takes
24-48 hours to develop (time for migration of T cells to
site of antigen challenge, synthesis and secretion of cytokines, recruitment and activation of other leukocytes). Note that DTH is fundamentally different from
immediate hypersensitivity in terms of kinetics, mechanisms and manifestations.
T cell-mediated diseases may be caused by T cell reactions against self-antigens (type 1 diabetes, MS), or

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against normally harmless microbes (probably Crohns

disease).
Protective T cell reactions against microbial antigens
may also cause tissue injury and disease (granulomatous inflammation in TB, since the bacteria are difficult
to eradicate and elicit strong, persistent immune reactions; killing of infected hepatocytes in viral hepatitis
even though the virus is not cytopathic). This type of
hypersensitivity is often referred to as immunopathology.
Hypersensitivity diseases tend to be chronic and selfperpetuating, because the eliciting agents are difficult
to get rid of and the immune response contains many
positive feedback loops that tend to amplify the reaction and keep it going in some individuals. Since inflammation is a common and fundamental feature of most
of these diseases, they are now sometimes grouped under immune-mediated inflammatory diseases.
Therapies are often directed towards disrupting the cellular communications that underlie the immune reactions and inflammation (e.g. drugs that block cytokines
such as TNF).

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