Download HYPERSENSITIVITY REACTIONS The immune system is required

HYPERSENSITIVITY REACTIONS
The immune system is required for defending the host against pathogenic microbes and
tumor cells. However, sometimes immune responses are themselves capable of causing tissue
injury and disease. Immune responses that are inadequately controlled, inappropriately
targeted to host tissues, or triggered by commensal microorganisms and harmless
environmental antigens are called hypersensitivity reactions. Hypersensitivity reactions may
occur in two situations. First, responses to foreign antigens (nonpathogenic microbes or
nonmicrobial environmental antigens) may be excessive or dysregulated, resulting in tissue
damage. Second, the immune responses may be directed against self antigens, as a result of
the failure of self-tolerance. Responses against self-antigens are termed autoimmunity, and
disorders caused by such responses are called autoimmune diseases. Hypersensitivity
reactions are classified into four types based on the principal immunologic mechanism that is
responsible for tissue injury and disease. Type I hypersensitivity reactions are caused by the
interaction of soluble allergens with specific IgE that causes the degranulation of mast cells.
Type II hypersensitivity reactions are mediated by IgG antibodies made against cell- or
amtrix-associated antigens. On binding to their specific cell-surface antigens, the antibodies
cause the modified human cells to become subject to complement activation and
phagocytosis. Type III hypersensitivity reactions are caused by IgG antibodies made against a
soluble antigen, which form immune complexes that are deposited in tissues and induce
complement fixation and phagocyte activation. Type IV hypersensitivity reactions are
mediated by T cells responding either to the epitopes of foreign proteins or to peptides derived
from chemically modified human proteins.
Type I hypersensitivity reactions
Type I or immediate hypersensitivity is a TH2 cell-, IgE antibody- and mast cellmediated reaction to nonmicrobial antigens (often referred to as allergens) that causes rapid
vascular leakage and mucosal secretions, often followed by inflammation. These IgEmediated reactions are also called allergy, or atopy, and individuals with a strong propensity
to develop these reactions are said to be atopic. Such reactions may affect various tissues and
may be of varying severity in different individuals. In most cases, people with allergies
develop mild to moderate symptoms, such as watery eyes, runny nose or rashes. But
sometimes, exposure to an allergen can cause a life-threatening allergic reaction known as
anaphylactic shock. Allergens may cause an allergic reaction when they land on the skin, in
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the eye or are inhaled, injected or ingested. Inhaled materials include plant pollens, the dander
of domesticated animals, mold spores, and proteins in the feces of house dust mites. Injected
materials include insect venoms, vaccines, and drugs. Ingested materials include some foods
(e.g. peanuts, eggs, shellfish) and orally administered drugs.
Symptoms of allergic disease are developed only after a person has made IgE antibodies
that react with the allergen and those antibodies have armed mast cells in the tissue exposed to
the allergen. In this situation, the person has become sensitized to the allergen. During
sensitization, APCs take up the allergens, migrate into secondary lymphoid organs/tissues and
activate allergen-specific naive T cells. Some of these T cells differentiate to IL4-secreting
TFH cells, which promote the activation of allergen-specific naive B cells. IL-4 secreted by the
TFH cells binds to the B cell’s IL-4 receptor, driving the B cell to switch its immunoglobulin
isotype to IgE and to become an IgE-secreting plasma cell. Allergen-specific IgE binds to
high-affinity Fc receptors (FcεRI) on mast cells. During this first exposure to the allergen, no
clinical symptoms are felt. By becoming armed, or sensitized, with allergen-specific IgE, the
mast cells become acutely sensitive to subsequent exposure to allergen. Mast cell activation
will occur as soon as allergens bind to mast-cell associated IgE. A mast cell passively acquires
IgE molecules with different specificities and made by different B cells, which bind to the
cell-surface FcεRI. A mast cell displays around half a million FcεRI molecules on its surface
and so can be armed with a variety of different IgEs at high density. By comparison, a B cell
has only 50,000–100,000 B-cell receptors. Mast cells vary in shape and their cytoplasm
contains membrane-bound granules. Activated mast cells secrete a variety of mediators that
are responsible for the development of allergic reactions. These include substances that are
stored in granules and rapidly released upon exposure to allergens, and others that are de novo
synthesized upon activation. Like mast cells, basophils and activated eosinophils also express
high-affinity FcεRI and bind IgE. Therefore, basophils and eosinophils that are recruited into
tissue sites where allergens are present may contribute to immediate hypersensitivity
reactions. Exposure to the allergen will cross-link sufficient IgE molecules to trigger mast cell
activation. Activation of mast cells results in three types of biologic response: release of the
preformed granule contents by exocytosis (degranulation), synthesis and secretion of lipid
mediators, and synthesis and secretion of cytokines. Many of the biologic effects of mast cell
activation are mediated by biogenic amines that are released during degranulation and act on
blood vessels and smooth muscle. In human mast cells, the major mediator of this class is
histamine. Histamine causes contraction of the endothelial cells, leading to increased
interendothelial spaces, increased vascular permeability, and leakage of plasma into the
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tissues. Histamine also triggers contraction of intestinal and bronchial smooth muscle. Thus,
histamine may contribute to the increased peristalsis and bronchospasm associated with
ingested and inhaled allergens, respectively. Other molecules released from mast-cell granules
include mast-cell chymotryptase, tryptase, and other neutral proteases that activate
metalloproteases in the extracellular matrix. Collectively, these enzymes break down
extracellular matrix proteins. The action of histamine is complemented by that of TNF-α,
another cytokine released from mast-cell granules. TNF-α activates endothelial cells, causing
an increased expression of adhesion molecules, thus promoting leukocyte traffic from the
blood into the inflamed tissue. Mast-cell degranulation is responsible for the immediate
allergic reactions, which are followed, to a greater or lesser extent depending on the disease,
by a more sustained inflammation, which is due to the recruitment of other effector
leukocytes, notably TH2 lymphocytes, eosinophils, and basophils (late-phase reaction). Mast
cell activation results in the rapid de novo synthesis and release of lipid mediators that have a
variety of effects on blood vessels, bronchial smooth muscle, and leukocytes. Prostaglandin
D2 promotes the dilation and increased permeability of blood vessels and also acts as a
chemoattractant for neutrophils. Prostaglandin synthesis can be prevented by cyclooxygenase
inhibitors, such as aspirin and other non-steroidal antiinflammatory agents. The leukotrienes
have activities similar to those of histamine, but are more than 100 times more potent on a
molecule-for-molecule basis. These two mediators are therefore complementary. Histamine
provides a rapid response while the more potent leukotrienes are being made. In the later
stages of allergic reactions, leukotrienes are principally responsible for inflammation, smooth
muscle contraction, the constriction of airways, and the secretion of mucus from mucosal
epithelium. A third type of lipid mediator produced by mast cells is platelet-activating factor
(PAF). PAF has direct bronchoconstricting actions. It also induces the influx and activation of
leukocytes, which contribute to allergic inflammation. Mast cells produce many different
cytokines that contribute to allergic inflammation (the late-phase reaction). These cytokines
include TNF, IL-4, IL-5, and IL-13. TH2 cells that are recruited into the sites of allergic
reactions also produce some of these cytokines.
The physical effects of IgE-mediated mast-cell degranulation vary with the tissue
exposed to allergens. Common gastrointestinal symptoms include abdominal cramps, nausea,
vomiting, and diarrhea. Cutaneous symptoms include hives, itching, and eczema or dermatitis.
Dermatitis is an especially common manifestation in early childhood. About 40% of cases of
dermatitis in young infants may involve food allergies. Mild respiratory symptoms (running
nose, sneeze, coughing) are much more likely to be encountered with exposure to
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environmental allergens such as pollens or animal danders that are airborne and inhaled
directly into the respiratory tract. A more serious IgE-mediated respiratory disease is allergic
asthma, which is triggered by allergen-induced activation of submucosal mast cells in the
lower airways. This can lead within seconds to bronchial constriction and an increased
secretion of mucus into the airways, making breathing more difficult by trapping inhaled air
in the lungs. Patients with allergic asthma usually need treatment, and severe asthmatic
attacks can be life-threatening. Some asthma patients develop airflow obstruction that is
irreversible or only partially reversible and experience an accelerated rate of lung function
decline. The structural changes in the airways of these patients are referred to as airway
remodeling. If allergen is introduced directly into the bloodstream, for example, by a bee or
wasp sting, or is rapidly absorbed into the bloodstream from the gut in a sensitized individual,
connective-tissue mast cells associated with blood vessels throughout the body can become
immediately activated, resulting in a widespread release of histamine and other mediators that
causes the systemic reaction called anaphylaxis. The symptoms of anaphylaxis can range in
severity from mild urticaria (hives) to fatal anaphylactic shock. An anaphylactic shock should
be treated immediately with an injection of epinephrine (adrenaline). Two injections may be
necessary to control symptoms.
Allergies are the most frequent disorders of the immune system, estimated to affect
about 20% of people, and the incidence of allergic diseases has been increasing in
industrialized countries. Asthma and allergy are caused by the complex interplay between
genetic factors and environmental exposures. Genome-wide linkage studies have identified 18
genomic regions and more than 100 genes associated with allergy and asthma. Although
genetic predisposition is clearly evident, gene-by-environment interaction probably explains
much of the international variation in prevalence rates. Environmental factors such as
infections and exposure to endotoxins may be protective or may act as risk factors, depending
in part on the timing of exposure in infancy and childhood. The hygiene hypothesis posits that
exposure of an infant to a substantial number of infections and many types of bacteria
stimulates the developing immune system toward nonasthmatic phenotypes. This may be
exemplified in the real world by large family size, whereby later-born children in large
families would be expected to be at lower risk of asthma than first-born children, because of
exposure to their older siblings’ infections. Numerous epidemiological studies have shown
that children who grow up on traditional farms are protected from asthma, hay fever and
allergic sensitization. Early-life contact with livestock and their fodder, and consumption of
unprocessed cow’s milk have been identified as the most effective protective exposures.
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Underlying mechanisms are multiple and complex. They include decreased consumption of
homeostatic factors and immunoregulation, involving various regulatory T cell subsets and
Toll-like receptor stimulation.
When an individual who has previously encountered an allergen and produced IgE
antibodies is challenged by intradermal injection of the same antigen, the injection site
becomes red from locally dilated blood vessels and then rapidly swells as a result of leakage
of plasma from the venules. This soft swelling is called a wheal and the characteristic red rim
at the margins of the wheal, where blood vessels dilate, is called a flare. In patients with a
clinical history of allergic disease, allergists use this immediate response to help assess and
confirm sensitization, and to determine which allergens are responsible for the symptoms.
Very low amounts of potential allergens are introduced into the skin by a skin prick - one site
for each allergen - and if the individual is sensitive to any of the allergens tested, a wheal-andflare reaction will occur at the site within a few minutes. Another standard test for allergy is to
measure the circulating concentration of IgE antibody specific for a particular allergen by
means of ELISA (enzyme-linked immunosorbent assay).
Most of the current drugs that are used to treat allergic disease either treat only the
symptoms, or are general anti-inflammatory or immunosuppressive drugs such as the
corticosteroids. Treatment is largely palliative, rather than curative, and the drugs often need
to be taken throughout life. Antihistamines that target the H1 histamine receptor reduce the
symptoms that follow the release of histamine from mast cells. Anticholinergic drugs
bronchodilate constricted airways and reduce respiratory secretions. Antileukotriene drugs act
as antagonists of leukotriene receptors on smooth muscle, endothelial cells, and mucous-gland
cells. Inhaled bronchodilators that act on β-adrenergic receptors to relax constricted muscle
relieve acute asthma attacks. In a chronic allergic disease it is very important to treat and
prevent the chronic inflammatory injury to tissues, and regular use of inhaled corticosteroids
is now recommended in persistent asthma to help suppress inflammation. Topical
corticosteroids are used to suppress the chronic inflammatory changes seen in eczema. A new
type of allergy-suppressive therapy that is beginning to gain significant use is the blockade of
IgE function by treatment with monoclonal anti-IgE antibodies. These antibodies bind the Fc
portion of IgE at the same site that binds the FcεRI on basophils, mast cells and activated
eosinophils. Another, more routinely used approach that aims to permanently eliminate the
allergic response is allergen desensitization. This form of immunotherapy aims to restore the
patient’s ability to tolerate exposure to the allergen. Patients are desensitized by injection with
increasing doses of allergen, starting with tiny amounts. Successful desensitization appears to
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depend on the induction of Treg cells secreting IL-10 and/or TGF‑β, which skew the response
away from IgE production.
Type II hypersensitivity reactions
Type II hypersensitivity reactions are caused by IgG and IgM antibodies against cellular
or matrix antigens and specifically affect the cells or tissues where these antigens are present.
Antibodies against tissue antigens can cause disease by three main mechanisms.
Opsonization and phagocytosis. Antibodies that bind to cell surface antigens may directly act
as opsonin, or they may activate the complement system, resulting in the attachment of C3b
complement protein fragments to cell surface. The opsonized cells are phagocytosed and
destroyed by phagocytes that express Fc receptors and complement receptors. This is the
primary mechanism of cell destruction in autoimmune hemolytic anemia and autoimmune
thrombocytopenic purpura, in which antibodies are produced targeting red blood cells or
platelets, respectively. Binding of autoreactive antibodies leads to the opsonization and
removal of these cells from the circulation. The same mechanism is responsible for hemolysis
in transfusion reactions. Antibodies are also able to react with chemically reactive small
molecules used for medication that become covalently bound to the surface of cells. The
chemical reaction modifies the structures of human cell surface components, which are now
sensed as foreign antigens by the adaptive immune system. Self proteins conjugated with the
drug provoke a TH1 response that activates some B cells to produce IgG antibodies against the
new epitopes. On binding to their specific cell-surface antigens, the antibodies cause the
modified human cells to become subject to phagocytosis. Penicillin is an example of a small
reactive molecule that induces type II hypersensitivity reactions in some patients who are
taking this antibiotic drug.
Inflammation. Antibodies deposited in tissues activate the complement system leading to
production of C3a and C5a fragments. These by-products recruit neutrophils and
macrophages, which bind to the antibodies, or complement proteins by Fc and complement
receptors, respectively. If recruited phagocytes bind the antigen but are unable to internalizeit
, they release lysosomal enzymes and reactive oxygen species causing tissue injury. This
action has been referred to as „frustrated phagocytosis”. The mechanism of tissue injury in
pemphigus vulgaris, Goodpasture’s syndrome and in many other diseases is inflammation and
leukocyte activation. Antibodies that cause cell- or tissue-specific diseases are usually
autoantibodies produced as part of an autoimmune reaction. Less commonly, these antibodies
may be produced against a microbial antigen that is immunologically cross-reactive with a
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component of self tissues. In a rare consequence of streptococcal infection called rheumatic
fever, antibodies produced against the bacteria cross-react with antigens in the heart, deposit
in this organ, and cause inflammation and tissue damage.
Abnormal cellular functions. Antibodies that bind to receptors or other proteins may interfere
with their functions and cause disease without inflammation or tissue damage. Antibodies
specific for thyroid stimulating hormone receptor or the nicotinic acetylcholine receptor cause
functional abnormalities leading to Graves’ disease and myasthenia gravis, respectively.
Antibodies that bind to cell surface receptors may act as agonists or antagonists. Agonist
antibodies mimick the biological activity of the natural ligand inducing sustained activation of
the receptor. Antagonist antibodies work in counteractive directions, they block or dampen
receptor signaling.
Type III hypersensitivity reactions
These reactions are caused by deposition of immune complexes of antigens and specific
IgG antibodies in particular tissues and sites. At the sites of deposition, the immune
complexes activate the complement system and induce an inflammatory response that
damages the tissue and impairs its function. Immune complexes that trigger these reactions
may be composed of antibodies bound to either self antigens or foreign antigens. The clinical
symptoms of diseases caused by immune complexes reflect the site of immune complex
deposition and are not determined by the cellular source of the antigen. Therefore, immune
complex-mediated diseases tend to be systemic and affect multiple tissues and organs,
although some are particularly susceptible, such as kidneys and joints. In the early 1900s,
before discovery of antibiotics, diphtheria infections were treated with serum from horses that
had been immunized with the diphtheria toxin. However, the antibodies from the animal
serum are also foreign proteins that can act as antigens when injected into humans. The
recipient’s immune system responds by producing antibodies that react against the animal
serum proteins resulting in the formation of immune complexes. Deposition of these immune
complexes in the tissues causes a systemic reaction known as serum sickness. Fever, rash,
arthritis, and sometimes glomerulonephritis occur 7–10 days after the first injection of horse
serum and more rapidly with each repeated injection. However, the clinical symptoms resolve
themselves after discontinuation of the horse serum treatment. Serum sickness remains a
clinical issue today in a proportion of subjects receiving therapeutic monoclonal antibodies
derived from rodents or polyclonal antisera to treat snake bites or rabies.
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Antigen-antibody complexes are produced during normal adaptive immune responses,
and cause disease only when they are produced in excessive amounts, not efficiently cleared,
and become deposited in tissues. Large complexes are usually cleared by phagocytes, whereas
intermediate-sized ones are tend to be deposited in vessels. Capillaries in the renal glomeruli
and synovia are sites where plasma is ultrafiltered (to form urine and synovial fluid,
respectively) by passing through specialized basement membranes. These locations are among
the most common sites of immune complex deposition; however, antigen-antibody complexes
may be deposited in small vessels in virtually any tissue. The immune complexes activate the
complement system and can bind to and activate leukocytes bearing Fc and complement
receptors; these leukocytes in turn cause widespread tissue damage. If complement cascade is
activated, the C5a chemotactic factor will be generated leading to an influx of neutrophils,
which begin the phagocytosis of the immune complexes. Clearance of immune complexes in
turn may result in the extracellular release of the neutrophil granule contents, particularly
when the complex is deposited on a basement membrane and cannot be phagocytosed (so called “ frustrated phagocytosis ”). The released proteolytic enzymes, polycationic proteins
and reactive oxygen and nitrogen species induce damage to local tissues and intensify the
inflammation. The anaphylatoxins C3a and C5a produced during complement activation will
cause release of mast cell mediators resulting in increased vascular permeability and blood
flow.
Many systemic autoimmune diseases are caused by the deposition of immune
complexes in blood vessels. In systemic lupus erythematosus (SLE), complexes consisting of
nuclear antigens and antibodies are deposit in the kidneys, blood vessels, skin, and other
tissues. In almost half of cases of one type of immune complex–mediated vasculitis involving
medium-size muscular arteries, called polyarteritis nodosa, the complexes are made up of
viral antigens and antibodies. This disease is a late complication of viral infection, most often
with hepatitis B virus. In rare cases, post-streptococcal glomerulonephritis develops after
streptococcal infection and is caused by complexes of streptococcal antigens and antibodies
depositing in the renal glomeruli.
The local hypersensitivity reaction, which can be triggered by repeated injections of
antigen into the same skin site of sensitized individuals who possess IgG antibodies against
the sensitizing antigen, called Arthus reaction. The immune complexes formed in the skin
bind Fc receptors such as FcγRIII on mast cells and other leukocytes, generating a local
inflammatory response and increased vascular permeability. The clinical relevance of the
Arthus reaction is limited; occasionally, a subject receiving a booster dose of a vaccine may
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develop inflammation at the site of injection because of local accumulation of immune
complexes.
Immune-complex disease also occurs when inhaled materials (hay dust or mold spores)
provoke IgG antibody responses, perhaps because they are present at relatively high levels in
the air. When a person is reexposed to high doses of such antigens, immune complexes are
formed in the walls of alveoli in the lungs. This type of reaction is more likely to occur in
occupations such as farming, in which there is repeated exposure to hay dust or mold spores,
and the resulting disease is known as farmer’s lung. Similar situations arise in pigeon breeder’s disease, where the antigen is probably serum protein present in the dust from dried
feces of birds.
Type IV hypersensitivity reactions
In these reactions, tissue injury is caused by T cells, either by triggering inflammation or
killing of target cells. Activated TH1 and TH17 cells secrete cytokines that activate phagocytes
and induce local inflammation. The actual tissue damage in these reactions is caused mainly
by the macrophages and neutrophils. TH2 cells and the cytokines they produce may also play
a role in some type IV hypersensitivity reactions, e.g. in those chronic diseases (chronic
allergic rhinitis and asthma), which are initiated by IgE-mediated allergic reactions. Excessive
responses by TH2 cells can damage tissues through activation of eosinophils. In some type IV
hypersensitivity reactions CD8+ T cells can also be activated. If effector CD8+ T cells
recognize MHC-I-peptide complexes, they respond with the secretion of IFN-γ and
destruction of the target cells. The T cells that cause tissue damage may be autoreactive ones,
or they may be specific for foreign protein antigens that are present in or bound to cells or
tissues. Type IV hypersensitivity is often called delayed-type hypersensitivity. The term
“delayed” refers to the cellular responses that generally become apparent 24-72 h after antigen
exposure.
One of the typical delayed-type hypersensitivity reactions is the tuberculin skin test or
Mantoux test. This test is used to determine whether an individual has Mycobacterium
tuberculosis-specific CD4+ memory helper cells. Mycobacterium tuberculosis is an obligate
pathogenic bacterial species, which is the causative agent of tuberculosis. In the test, small
amounts of tuberculin, a purified protein derivative from M. tuberculosis, are injected
intradermally. In people who have been previously exposed to the bacterium, either by
infection or by immunization with the BCG vaccine (a vaccine primarily used against
tuberculosis), a local T-cell-mediated inflammatory reaction evolves over 24–72 h. When
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antigen from M. tuberculosis is introduced into subcutaneous tissue, antigen-specific memory
T cells produced during previous exposure to the antigen migrate into the site of injection and
become activated. Because these antigen-specific cells are rare, and there is no inflammation
to attract them into the site, it can take several hours for a T cell of the correct specificity to
arrive. Activated TH1 cells release mediators that activate local endothelial cells, recruiting an
inflammatory cell infiltrate dominated by macrophages and causing the accumulation of fluid
and protein. At this point, the lesion becomes apparent.
Very similar reactions are observed in contact dermatitis (also called contact
hypersensitivity), which is an immune-mediated local inflammatory reaction in the skin
caused by direct skin contact with certain antigens. Contact hypersensitivity may result from
sensitization to chemicals in plastic items or in hair dyes, nickel in jewelry and drugs such as
neomycin and bacitracin used in topical applications. Typical molecules that cause contact
dermatitis are highly reactive small molecules that can easily penetrate intact skin. In the skin
these chemicals react with extracellular self proteins, creating haptenated proteins (proteins to
which a small molecule /the hapten/ is bound covalently) that can be proteolytically processed
in professional APCs to haptenated peptides. The modified self peptides are presented by
MHC-II molecules and recognized by T helper cells as „foreign” antigens. During the first
exposure, professional APCs in the epidermis and dermis take up and process haptenated
proteins, and migrate to regional lymph nodes, where they activate naive T cells with the
consequent production of memory T cells. A subsequent exposure to the sensitizing chemical
leads to antigen presentation to memory T cells in the dermis. Activated memory T cells
release of IFN-γ and other cytokines. This stimulates the keratinocytes of the epidermis to
release IL-1, IL-6, TNF-α, the chemokine IL-8, and the interferon-inducible chemokines
CXCL11 (IP-9), CXCL10 (IP-10), and CXCL9 (MIG). These cytokines and chemokines
enhance the inflammatory response by inducing the migration of monocytes into the lesion
and their maturation into macrophages, and by attracting more T cells.
Contact with the poison ivy plant induces very severe skin symptoms in sensitized
persons. Pentadecacatechols, a group of lipid-soluble chemicals found in these plants, can
cross the cell membrane easily; therefore, these substances attach not only to exracellular
proteins but also to intracellular ones. In this way, peptides from modified proteins can be
presented by both MHC-II and MHC-I molecules. CD8+ T cells, which recognize the
modified peptides, cause damage either by killing the eliciting cell or by secreting IFN-γ.
Activation of cytotoxic T cells is responsible for the outbreak of small or large blisters, often
forming streaks or lines.
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Celiac disease or gluten-sensitive enteropathy is an inflammatory disease of the gut
mucosa caused by an immune response directed at gluten, a complex of proteins present in
wheat, oats, and barley, all of which are major components of Western diets. Celiac disease
shows an extremely strong genetic predisposition, because more than 95% of patients express
the HLA-DQ2 or HLA-DQ8 allotype. The key step in the immune recognition of gluten is the
deamidation of its peptides by the enzyme tissue transglutaminase, which converts selected
glutamine residues to negatively charged glutamic acid. Only peptides containing negatively
charged residues in certain positions bind strongly to HLA-DQ2, and thus the transamination
reaction promotes the formation of peptide:HLA-DQ2 complexes, which can activate antigenspecific CD4+ T cells. CD4+ T cells that respond to gluten-derived peptides in the gutassociated lymphoid tissues activate tissue macrophages, which secrete pro-inflammatory
cytokines that produce inflammation and tissue damage in the small intestine. With persistent
intake of gluten, the inflammation becomes chronic and eventually causes atrophy of the
intestinal villi, malabsorption of nutrients, and diarrhea. Elimination of gluten from the diet
restores normal gut function, but to date no approach for desensitization to gluten has been
developed, so gluten ingestion must be avoided throughout life. Celiac disease is not a
classical autoimmune disease; however, it does have some features of autoimmunity.
Autoantibodies against tissue transglutaminase are found in all patients with celiac disease.
Presence of serum IgA antibodies against this enzyme is used as a sensitive and specific test
for the disease. Interestingly, no tissue transglutaminase-specific T cells have been found, and
it has been proposed that gluten-reactive T cells provide help to B cells that are reactive to
tissue transglutaminase. In support of this hypothesis, gluten can complex with the enzyme
and therefore could be taken up and presented by tissue transglutaminase-reactive B cells.
There is no evidence, however, that these autoantibodies contribute directly to tissue damage.
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