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CHAPTER 12 – OVERREACTIONS OF THE IMMUNE SYSTEM
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Four types of hypersensitivity reactions are caused by effector mechanisms of adaptive immunity
o Type I hypersensitivity – results from the binding of antigen to antigen-specific IgE bound to its Fc receptor, principally on mast cells
; causes degranulation of mast cells and the release of inflammatory cytokines. Type I reactions are commonly caused by inhaled
particulate antigens (i.e. plant pollens)
o Type II hypersensitivity – caused by small molecules that bond covalently to cell-surface components of human cells, producing
modified structures that are perceived as foreign. The B cell response produces IgG which, on binding to the modified cells, causes
their destruction through complement activation and phagocytosis (i.e. penicillin)
o Type III hypersensitivity – due to small soluble immune complexes formed by soluble protein antigens binding to the IgG made
against them; some complexes become deposited in the walls of small blood vessel or the alveoli of the lungs and initiate and
inflammatory response that damages the tissue and impairs its physiological function
o Type IV hypersensitivity – cause by the products of antigen-specific effector T cells (specifically CD4 TH1 cells); a minority of type IV
reactions are due to cytotoxic C8 T cells that arise when small, reactive, lipid-soluble molecules pass through cell membranes and
bond covalently to intracellular human proteins. Degradation yields abnormal peptides that bind HLA class I and stimulates a
cytotoxic T cell response
TYPE I HYPERSENSITIVITY REACTIONS
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A prerequisite for a Type I hypersensitivity reaction is that IgE antibody is made when a person first encounters antigen – sensitized
IgE binding to FcεR1 provides mast cells, basophils, and activated eosinophils with antigen receptors
o IgE causes allergic reactions because of its exceptionally high affinity for its Fc receptor (generally considered irreversible) and the
cellular distribution of the receptor
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FcεR1 is expressed constitutively by mast cells and basophils, and by eosinophils after they have been activated by
cytokines
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Stable complexes of IgE and FcεR1 effectively provide mast cells, basophils and eosinophils with antigen-specific receptors
; all these cells have granules containing preformed inflammatory mediators and when antigen is encounter a second time,
these cells becomes activated and release their mediators
o Two important features distinguish the “antigen receptors” on mast cells, basophils, and eosinophils from those of B and T cells
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The cell’s effector function becomes operational immediately after antigen binds to the ‘receptor’ and does not require a
phase of cell proliferation and differentiation
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Each cell is not restricted to carrying receptors of just one antigen specificity, but can carry a range of IgE representing that
present in the circulation
o IgE-mediated activation of mast cells, basophils, and eosinophils provide protection from parasites (typically in developing countries)
o In developed countries, however, IgE responses tend to be stimulated by contact with non-threatening substances
Mast cells defend and maintain the tissues where they live
o Mast cells are resident in mucosal and epithelial tissues lining the body surfaces
o Morphologically, the defining characteristic of the mast cell is the cytoplasm, which is filled with 50 – 200 large granules containing
inflammatory mediators (typically histamine, heparin, TNF-α, chondroitin sulfate, neutral proteases and other degradative enzymes
and inflammatory mediators)
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Heparin, an acidic proteoglycan, is largely responsible for the characteristic staining of mast-cell granules with basic dyes
o IgE mediated activation of mast cells via FcεR1 is limited to degranulation and to the synthesis of small inflammatory mediators
known as eicosanoids, signaling through other receptors induces manufacture and secretion of cytokines to recruit neutrophils,
eosinophils and effector T cells to the infected tissue, and induces secretion of growth factors that promote the repair of damage.
o Two kind of human mast cell have been distinguished
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Mucosal mast cell – produces the protease tryptase
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Connective tissue mast cells- which produces chymotryptase
Tissue mast cells orchestrate IgE-mediated allergic reactions through the release of inflammatory mediators
o
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Mast cell activation occurs in the presence of any antigen that can cross-link the IgE molecules bound to FcεR1 on the cell surface ;
once a mast cell’s receptor has been cross-linked, degranulation occurs in seconds
o Histamine, an amine derivative of the amino acid histidine, exerts a variety of physiological effects through three kinds of histamine
receptors (H1, H2, and H3)
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Acute allergic reactions involve binding of histamine to H1 receptor on nearby smooth muscle cells and on endothelial cells
of blood vessels ; stimulation of H1 on endothelial cells induces vessel permeability and the entry of other cells and
molecules into the allergen-containing tissue, causing inflammation ; smooth muscle are induced to contract on binding
histamine
o TNF-α activates endothelial cells, causing an increased expression of adhesion molecules, thus promoting leukocyte traffic from the
blood into the increasingly inflamed tissue.
o Activated mast cells synthesize and secrete other mediators including chemokines, cytokines, and eicosanoids (prostaglandins and
leukotrienes)
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Leukotrienes have activities similar to histamine, however they are more than 100 times more potent on a molecule by
molecule basis
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Prostaglandin D2 promotes dilation and increased permeability of blood vessels, and also acts a chemoattractant for
neutrophils
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Aspirin inactivates prostaglandin synthase, thereby reducing inflammation. (this is irreversible, because aspirin
binds covalently to the active site of the enzyme)
o For allergens that pervade the environment and provide a continual stimulation, the allergic response will gather in strength as
increasing numbers of mast cells and eosinophils are recruited to the affected tissue and join in the frustrated attempts to eliminate
the ‘pathogen’
Eosinophils are specialized granulocytes that release toxic mediators in IgE mediated responses
o Eosinophil granules contain arginine-rich basic proteins ; activation leads to staged release of toxic molecules and inflammatory
mediators
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Preformed chemical mediators are released first – the normal function of these highly toxic molecules is to kill invading
microorganisms and parasites directly
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Next is the secretion of prostaglandins, leukotrienes and cytokines, which amplify the inflammatory response
o Eosinophil response is highly toxic and potentially damaging to the host; limiting damge are various control mechanisms:
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When the body is healthy, there are a low number of eosinophils due to restriction of their production in the bone marrow
; in the presence of stimulation, TH2 cells stimulate the bone marrow to increase eosinophil production and their release
into circulation
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Migration of eosinophils is controlled by chemokines CCL5, CCL7, CCL11, and CCL13, which bind to CCR3 receptor
on eosinophils
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CCL11 (eotaxin) is particularly important in the migration of eosinophils and is produced by activated endothelial
cells, T cells and monocytes
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Eosinophil activity is further controlled by modulation of their sensitivity to external stimuli; achieved through regulated
expression of FcεR1
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In the resting state, eosinophils do not express FcεR1, do not bind IgE, and cannot be induced to degranulate by
antigen
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Once an inflammatory response has been set in motion, eosinophils are induced to express FcεR1 by cytokines
and chemokines in the inflammatory site; expression of Fcϒ receptors and compliment receptors on eosinophil
surface also increases, facilitating binding to pathogen surfaces coated with IgG and complement
o Eosinophils are considered the principle cause of airway damage that occurs in chronic asthma
Basophils are rare granulocytes that initiate TH2 responses and the production of IgE
o Basophils resemble mast cells in some ways, but are developmentally more closely related to eosinophils ; they have a common
stem-cell precursor and require similar growth factors including IL-3, IL-5 and GM-CSF
o Basophils are the key cell that initiates the TH2 response through its unique capacity to secrete IL-4 and IL-13, at the beginning of an
immune response
o During an innate immune response, basophils are recruited to infected tissue, where they are activated through their toll-like
receptors and other receptors of innate immunity; at the beginning of an adaptive immune response, basophils are also recruited to
the secondary lymphoid tissues, where their secretion of IL-4 and IL-13 initiates the polarization of antigen-stimulated T cells
towards a TH2 response
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Basophils express CD40 ligand, which binds to CD40 on activated B cells and, in combination with secreted IL-4 and IL-13, it
drives isotype switching to IgE and IgG4
o
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Mast cells, eosinophils, and basophils often act in concert –mast cell degranulation initiates the inflammatory response, which then
recruits eosinophils and basophils. Eosinophil degranulation released major basic protein, which causes the degranulation of mast
cells and basophils.
Very few antigens that enter the human body are allergens that stimulate an IgE response
o The allergens that provoke type I hypersensitivity responses are invariably proteins or chemicals, like some rug, that chemically
modify human proteins
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Most allergens are inhaled or ingested and cross a mucosal surface to activate mucosal mast cells ; others penetrate the
body through wounds in the skin and activate connective mast cells
o Most allergens are small, soluble proteins that are present in dried-up particles of material derived from plants and animals
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The light dry particles become airborne and are inhaled. The particles then become caught in the mucus bathing the
epithelia of the airway and lungs where they rehydrate and release antigenic proteins.
o The major allergen responsible for more than 20% of the allergies in the human population in North America is a cysteine protease
derived from the house dust mite, D. pteronyssimus
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The cysteine protease is related to the protease papain, which comes from the papaya fruit and is used in cooking as a
meat tenderizer; Chymopapain, a protease related to papain, is used in medicine to degrade intervertebral disks in
patients with sciatica
Predisposition to allergic disease has a genetic basis
o Atopy – the genetically determined tendency of some people to produce IgE-mediated hypersensitivity reactions against innocuous
substances
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As a group, atopic people have higher levels of soluble IgE and circulating eosinophils than non-atopic people
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The IL-4 gene is part of a cluster of genes on chromosome 5 that contains IL-3, IL-5, IL-9, IL-12, IL-13, and GM-CSF genes
that are all directly involved in isotype switching, eosinophil survival, and mast-cell proliferation
o Allergic disease is caused by a slight, but significant, perturbation of the balance between the T H1 and TH2 response, which can be
caused by many combinations of gene polymorphisms in combination with environmental factors
IgE mediated allergic reactions consist of an immediate response followed by a late-phase response
o Wheal and flare – reaction observed when small amounts of allergen are injected into the dermis of an individual who is allergic to
the antigen. The reaction consists of a raised area of skin containing fluid (the wheal) with a spreading, red itchy reaction around it
(the flare)
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The wheal and flare is called an immediate reaction – the direct consequence of IgE-mediated degranulation of mast cells
in the skin.
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Released histamine and other mediators cause increased permeability of local blood vessels, whereupon fluid
leaves the blood and produces local swelling and increased blood flow into the surrounding area
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Some 6 to 8 hours after the immediate reaction subsides, a second reaction (late-phase reaction) occurs at the site of
injection – this consists of a more widespread swelling and is due to the leukotrienes, chemokines and cytokines
synthesized by mast cells after IgE mediated activation
o Although skin tests are a good way of determining whether a patient has developed an allergen-specific IgE response, they cannot
assess, for example, whether the response to a particular antigen is the cause of a patient’s asthma.
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To ascertain this, allergists make a direct measurement of a person’s breathing capacity in the absence and presence of
inhaled allergen. On inhalation of an allergen to which a patient is sensitized, mucosal mast cells in the respiratory tract
degranulate releasing mediators that cause the immediate constriction of bronchial smooth muscle
o In allergies to inhaled antigens, the late-phase reaction is more damaging – it induces the recruitment of leukocytes, particularly
eosinophils and TH2 lymphocytes, into the site and, if antigen persists, the late-phase response can easily develop into a chronic
inflammatory response in which allergen-specific TH2 cells promote eosinophilia and IgE production
The effects of IgE-mediated allergic reactions vary with the site of mast cell activation
o Only those mast cells at the site of exposre degranulate and, once released, the preformed mediators are short lived. The more
sustained effects of the late-phase response are also restricted to the site of allergen exposure, because the leukotrienes and other
induced mediators are also short-lived
o The tissues most commonly exposed to allergens are the mucosa of the respiratory and gastrointestinal tracts, the blood and
connective tissues
o For parasite infections:
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Interactions between antigen, IgE, and mast cells trigger violent muscular contractions that can expel worms from the GI
tract and increase fluid flow to wash them out ; in the lungs this is a way to expel organisms attached to the respiratory
epithelium, such as lung fluke
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In allergy, this defense if mistakenly ranged against non-threatening particle s and proteins that are often smaller
than any microorganism; the violence and power of the response means that the clinical manifestations of an
allergic reaction can vary markedly with the amount of IgE that a sensitized person has made, the amount of
allergen triggering the reaction, and the route by which it entered the body
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Systemic anaphylaxis is caused by allergens in the blood
o Systemic anaphylaxis – rapid-onset and potentially fatal IgE-mediated allergic reaction, in which antigen in the bloodstream triggers
the activation of mast cells throughout the body, causing circulatory collapse and suffocation due to tracheal swelling
o Anaphylactic shock – IgE mediated allergic reaction to a systemically administered antigen (i.e. insect venom entering the
bloodstream via a sting) that causes collapse of the circulation and suffocation due to tracheal swelling
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Fluid leaving the blood causes the blood pressure to drop; damage is sustained by many organ systems, and their function
is impaired
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Anaphylactic reactions can be fatal, but treatment with an injection of epinephrine usually brings them under control
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Epinephrine stimulates the reformation of tight junctions between endothelial cells, reducing their permeability and
preventing fluid loss from the blood, diminishing tissue swelling and raising BP
Rhinitis and asthma are caused by inhaled allergens
o Allergic rhinitis – a mild allergy to inhaled antigens, manifested as violent bursts of sneezing and a runny nose; caused by allergens
that diffuse across the mucous membrane of the nasal passages and activate the mucosal mast cells beneath the nasal epithelium
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The reaction can extend to the ear and throat, and the accumulation of fluid in the blocked sinuses and Eustachian tubes is
conducive to bacterial infections
o Allergic conjunctivitis – produces itchiness, tears and inflammation
o Allergic asthma – allergic reactions cause chronic difficulties breathing; triggered by allergens activating submucosal mast cells in the
lower airways of the respiratory tract. Within seconds of degranulation, there is an increase in the fluid and mucus being secreted
into the respiratory tract and bronchial constriction due to contraction of the smooth muscle surrounding the airway
o Chronic asthma – the airway can become almost totally occluded by plugs of mucus; the airway of chronic asthmatics are hyperreactive to chemical irritants commonly present in air and the disease can be exacerbated by immune responses to bacterial/viral
infections of the respiratory tract, especially when they are dominated by TH2 cells –for this reason, chronic asthma is classified as a
Type IV hypersensitivity reaction caused by T cells
Urticaria, angioedema, and eczema are allergic reactions of the skin
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Urticaria (hives) – raised itchy swellings ; caused by allergens activating mast cells in the skin to release histamine
Angioedema – activation of mast cells in deeper subcutaneous tissue leads to a similar, but more diffuse swelling
Eczema – a prolonged allergic response in the skin characterized by an inflammatory response that causes a chronic and itching rash
with associated skin eruptions and fluid discharge
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Severity is not readily correlated with exposure to particular antigens or levels of allergen-specific IgE ; thus, the etiology of
eczema remains poorly understood
Food allergies cause systemic effects as well as gut reactions
o IgE is made against only an extremely small proportion of the proteins ingested ; foods that commonly cause allergies include grains,
nuts, fruits, legumes, fish, shellfish, eggs, and milk
o Once sensitized, any subsequent intake causes a marked and immediate reaction:
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The food allergen passes across the epithelial wall of the gut and binds IgE on the mucosal mast cells associated with the
GI tract; the mast cells degranulate, releasing their mediators, principally histamine. Local blood vessels become
permeable and fluid leaves the blood and passes across the gut epithelium and into the lumen of the gut; contraction of
smooth muscle in the stomach induces cramps and vomiting, and the same reaction in the intestines produce diarrhea
o Food allergens also causes reactions in other tissues, notably the skin
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Mast cells in the connective tissue in the seeper layers of the skin tend to be activated by blood-borne allergens, and their
degranulation produces urticarial and angioedema
People with parasite infections and high levels of IgE rarely develop allergic disease
o Several facts may contribute to the resistance:
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Nonspecific IgE competes with parasite-specific IgE or any allergen specific IgE, for binding to mast cells, basophils and
activated eosinophils
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T cell responses are generaly suppressed in chronic parasitic infections, probably as a result of the participation of
regulatory T cells and the inhibitory effects of IL-10, TGF-β, and nitric oxide
Allergic reactions are prevented and treated by three complementary approaches
o Prevention – modify a patient’s behavior and environment so that contact with allergen is avoided
o Pharmacological – use drugs that reduce the impact of any contact with antigen; such drugs block the effector pathways of the
allergic response and limit the inflammation after IgE-induced activation of mast cells, eosinophils and basophils
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One potential set of targets for drugs are the signaling pathways that cells of the immune system use to enhance the IgE
response – inhibitors of IL-4, IL-5, or IL-13 could block such pathways
o Immunological – prevent the production of allergen-specific IgE
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Desensitization – patients are given a series of allergen injections in which the dose is initially very small and is gradually
increased; successful treatments are associated with production of allergen-specific antibodies of the IgG4 isotype and
increased levels of IL-10
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IgG4 is functionally monovalent and forms complexes with antigen that do not recruit effector cells
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A more recent approach is to vaccinate patients with allergen-derived peptides that are presented by HLA class II
molecules to CD4 TH2 cells ; the aim is to induce anergy of allergen-specific T cells in vivo by decreasing the expression of
the CD3:T cells receptor complex at the TH2 cell surface
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HLA class II polymorphisms complicate this approach
TYPE II, III, AND IV HYPERSENSITIVITIES
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IgG antibodies and specific T cells can cause both acute and chronic adverse hypersensitivity reactions
Type II hypersensitivity reactions are caused by antibodies specific for altered components of human cells
o Occasional side-effects seen after the administration of certain drugs are hemolytic anemia caused by the destruction of RBCs,
and thrombocytopenia caused by the destruction of platelets –both associated with penicillin, quinidine and methyldopa
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In each case, chemically reactive drug molecules bind to surface components of RBCs or platelets and create new
epitopes to which the immune system is not tolerant
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Penicillin-modified red cells acquire a coating of C3b as a side-effect of complement activation by the bacterial
infection for which the drug has been given. The cells are then phagocytosed by macrophages, which process the
penicillin-modified proteins and present peptide antigens to specific CD4 T cells. These T cells are then activated to
become TH2 cells, which stimulate antigen-specific B cells to produce antibodies against the penicillin-modified
epitope
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Binding of antibodies to the drug-conjugated cell activated complement by the classical pathway, resulting in either
cell lysis by the terminal complement components or receptor-mediated phagocytosis by macrophages in the spleen
To avoid type II hypersensitivity reactions in blood transfusions, donors and recipients are matched for ABO antigens
o The major immunogenetic barrier to transfusion with RBCs arises from structural polymorphisms in the carbohydrates on
glycolipids of the erythrocyte surface – basis for ABO system of blood group antigens
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To prevent hemolysis and other transfusion reactions, patients needing transfusions are given only blood of
compatible ABO type – Four blood types: O, A, B and AB
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Blood group antigens A and B have structural similarities to some cell surface carbs of common bacteria;
people without these structures do not tolerate them and produce antibodies against them
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Besides thwarting the purpose of a blood transfusion, hemolytic reactions can cause fever, chills, shock,
renal failure and even death
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Cross-match test – used in blood typing and histocompatibility testing to determine whether donor and recipient
have antibodies against each other’s’ cells that might interfere with successful transfusion or transplantation
Type III hypersensitivity reactions are caused by immune complexes formed from IgG and soluble antigens
o Smaller immune complexes are less efficient at fixing complement and tend to circulate in the blood and become deposited in
the blood vessel walls. When the complexes accumulate, they become capable of fixing complement and initiating tissuedamaging inflammatory reactions through their interactions with the Fc receptors and complement receptors on circulating
leukocytes and mast cells TYPE III HYPERSENSITIVITY
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Platelets accumulate around the site of immune-complex deposition, and the clots they form cause the blood vessels
to burst, producing hemorrhage in the skin
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Arthus reaction – immune reaction in the skin caused by injection of antigen into the dermis; the antigen reacts with
specific IgG antibodies, activating complement and phagocytic cells to induce and inflammatory response
Systemic disease caused by immune complexes can follow the administration of large quantities of soluble antigens
o Serum sickness – the collection of symptoms that follow the injection of large amounts of a foreign molecule (such as serum
protein) into a person. It is caused by the immune complexes formed between the injected protein and the antibodies that are
made against it; characterized by fever, arthralgias and nephritis – symptoms depend on which tissues are affected
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A disease similar to serum sickness can be seen in certain infections in which the immune system fails to clear the
pathogen and both the infection and the immune response persist (i.e. subacute bacterial endocarditis or chronic
viral hepatitis)
Inhaled antigens can cause type III hypersensitivity
o Continued exposure to inhaled antigens leads to formation of immune complexes and their deposition in the walls of the alveoli
of the lungs which then stimulate an inflammatory response
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Resulting accumulation of fluid, antigen and cells impedes the lungs’ normal function of gas exchange, and the
patients experiences difficulty breathing
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Farmer’s lung – a hypersensitivity disease caused by the interaction of IgG with large particles of inhaled
allergen in the alveolar wall of the lung.
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Continued deposition of immune complexes in the alveolar membranes eventually leads to irreversible lung
damage
Type IV hypersensitivity reactions are mediated by antigen-specific effector T cells
o Aka delayed-type hypersensitivity reactions (DTH) – they typically occur 1 to 3 days after contact with antigen
o Best studied example – tuberculin test used to determine whether a person has been infected with M. tuberculosis
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A small amount of protein antigen is injected intradermally; people who have immunity develop an inflammatory
reaction around the site of injection 24 to 72 hours later.
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The response if mediated by TH1 cells that recognize peptides from the M. tuberculosis protein that are presented by
HLA class II molecules. After activation, the TH1 cells initiate further inflammatory reactions that recruit fluid, proteins
and other leukocytes to the area
o Type IV hypersensitivity responses can be developed to a variety of antigens – for instance, dermatitis caused by contact with
poison ivy (Toxicodendron radicans) and poison oak (T. diversilobium) is due to a reaction of this type and involves both CD4
and CD8 T cells
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Reaction is caused by petadecacatechol, a small highly receptive lipid-like molecule that is present in the leaves and
roots of the plant and is easily transferred to human skin
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On contact, pentadecacatechol penetrates the outer layers of the skin and form covalent bonds with
extracellular proteins and skin cell-surface proteins; it also crosses the plasma membranes of cells and
chemically modifies intracellular proteins
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On first contact, a person might only experience a minor or undetectable reaction – during this response, Langerhans
cells or dendritic cells carry pentadecacatechol-modified proteins to the draining lymph node, where the T cell
response is initiated; once immunological memory is created, subsequent contact can yield red, raised, weeping skin
lesions that are due to heavy infiltration of the contact sites with blood cells, combined with the localized destruction
of skin cells and the extracellular matrix that holds the skin together
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This type of reaction is called contact sensitivity – can also develop to coins, jewelry, and other metallic objects
containing nickel
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Celiac disease is caused by hypersensitivity to common food proteins
o Celiac disease is an inflammatory autoimmune disease of the gut mucosa; caused by an immune response to gluten proteins of
wheat flour, or the related proteins of barley and rye, all of which are major components of western diets
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CD4 T cells respond to gluten-derived peptides and activate tissue macrophages, which secrete cytokines and induce
inflammation of the small intestine; persistent intake of gluten leads to chronic inflammation that eventually causes
atrophy of the intestinal villi, malabsorption of nutrients, and diarrhea
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There is a strong association with allotypes of MHC class II locus HLA-DQ - a majority of patients with celiac disease
have the HLA-DQ2 allotype and most of the rest have HLA-DQ8
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In the intestinal lesions of celiacs there are TH1 cells that respond to gluten-derived peptides presented by
either DQ2 or DQ8; these T cells are not detectable in the gut tissue of people who do not have celiac
disease, nor are they found in the gut tissue of patients who have embraced a gluten-free diet
Severe hypersensitivity reactions to certain drugs are strongly correlated with HLA class I allotypes
o In a small minority os people a prescribed drug can cause a life-threatening disease called Stevens-Johnson Syndrome
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During the first two week, this syndrome resembles an infection, then a rash with blisters develops and the epidermis
begins to peel away from the dermis. Severe blisters also develop at the mucous membranes – typically, less than
10% of skin is affected
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In more severe cases, called toxic epidermal necrolysis (TEN), more than 30% of the skin is affected
o Carbamazepine is a major cause of SJS and TEN
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All patients receiving the drug who developed SJS has the HLA-B*1502 allele – which suggests the disease is caused by
cytotoxic T cells responding to peptides presented by HLA-B*1502 and have been chemically modified by
carbamazepine
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The B*1502 allele is restricted to south-east Asian populations, explaining their higher incidence of carbamazepineinduced SJS
o Allopurinol can also produce SJS and TEN in populations worldwide – there is a similar associated with HLA-B*5801 in people of
south-east Asian descent
o Abacavir, a nucleoside analog used to treat HIV-1 infection, induces hypersensitivity in 5 to 8% of patients, which is strongly
associated with HLA-B*5701 allele found in predominantly in caucasians