HYPERSENSITIVITY
The adaptive immune response is a critical component of host defense against infection
and is essential for normal health.
The term hypersensivity is used to define a set of responses (result of exaggerated
normal responses ) categorized as types I–IV by Gell and Coombs.
In one circumstance - harmful immunologically mediated hypersensitivity type I
reactions known generally as allergic reactions occur in response to inherently harmless
‘environmental’ antigens such as pollen, food, and drugs.
Type I. IgE-mediated reactions (commonly called allergic reactions or allergy) are
stimulated by the binding of IgE, via its Fc region, to high-affinity IgE-specific Fc
receptors designated FcεRI.
FcεRI are expressed on mast cells, basophils, and eosinophils.
Binding of antigen to preformed antigen-specific IgE bound to high-affinity FcεRI
initiates type I hypersensitivity reactions.
When the IgE molecules encounter antigens, a cascade of events leads to
degranulation and release of inflammatory mediators and cytokines from mast
cells and basophils.
This ultimately results in the clinical manifestations of type I hypersensitivity, which
include rhinitis, asthma, and, in severe cases, anaphylaxis (from the
Greek ana, which means “away from,” and phylaxis, which means “protection”).
Type I hypersensitivity reactions are rapid, occurring within minutes after challenge
(reexposure to antigen). Consequently, allergic reactions are also called
immediate hypersensitivity.
GENERAL CHARACTERISITICS OF TYPE I HYPERSENSTIVITY
Sequence of events involved in the development of allergic reactions can be divided into
several phases:
(1) the sensitization phase, during which IgE antibody is produced in response to an
antigenic stimulus and binds to specific receptors on mast cells and basophils
(2) the activation phase, during which re-exposure to antigen (challenge) triggers
the mast cells and basophils to respond by release of the contents of their granules
(3) the effector phase, during which a complex response occurs as a result of the
effects of the many inflammatory mediators released by the mast cells and basophils.
A predisposition to become IgE-sensitized to environmental allergens is called atopy
To produce an, allergic reaction against a given antigen:
 an atopic individual must first be exposed to the antigen under conditions that
result in the production of IgE antibodies.
 Allergic symptoms occur when an individual who has been sensitized in this fashion
has subsequent exposure to the antigen.
 Exposure can lead to different clusters of symptoms, characterized by the tissues
that are most prominently affected.
Common forms of allergic response:
----airborne allergens,: causing symptoms that affect predominantly the nasal passages
(allergic rhinitis), the eyes (allergic conjunctivitis), or the lower airways and lungs
(asthma).
------Ingested allergens can lead to food allergy, sometimes affecting only the
gastrointestinal tract (for example, eosinophilic esophagitis),
------Allergic reactions also involve locations distant from the site of antigen entry then
the reactions are considered to be systemic reactions due to spread of the antigen
throughout the body via the blood circulation.
Systemic reactions can be limited to a single distant organ, causing:
1.
2.
3.
4.
hives (also called urticaria) when they target the skin,
wheezing (or bronchospasms) when they involve the lungs,
life-threatening lowering of the blood pressure when they target the vascular system.
Serious systemic reactions are designated by the term anaphylaxis.
It is not known why sensitization with a particular allergen in one individual leads
to local reactions at the time of allergen challenge, whereas sensitization with same can
cause serious anaphylatic shock in oihers
-- Hives also called urticaria is a common skin rash triggered by many things, including
certain foods, medication and stress.
---Symptoms include itchy, raised, red or skin-coloured welts on the skin's surface.
Mast-cell activation has
different effects on different tissues.
SEQUENCE OF EVENTS IN ALLERGGIC RESPONSE
SENSITIZATION PHASE
All normal individuals can make IgE antibody specific for a variety of antigens
While most of the population does not develop clinically significant allergic reactions to
the majority of potential allergens, some individuals manifest allergic responses to
multiple common antigens.
TH2 Cell Dependency of IgE Antibody Production
>The immune response leading to IgE production in response to antigen is driven by two
main groups of signals:
(1) signals that favor the differentiation of naive CD4+T cells to a TH2 phenotype
(2) TH2 cytokines like IL-4 stimulate B cells to class-switch to the production of IgE.
> IL-4 levels are significantly higher in the allergic population.
>I gE levels are approximately tenfold higher in allergic individuals.
>Low levels of IgE antibody in non-allergic individuals are maintained by suppressor
effects mediated by IFN-γ produced by TH1 cells
in normal individuals, a balance is maintained between TH2-derived cytokines, which
upregulate IgE responses, and TH1-derived cytokines, which downregulate IgE
responses.
 Once adequate exposure to the allergen occurs by repeated mucosal contact,
ingestion, or parenteral injection and failure of a control mechanism
--- leading to overproduction of IL-4 by TH2 cells
-----ultimately, increased IgE production by B cells occurs.
------This IgE rapidly attaches to the Fc receptors on circulating mast cells and
basophils and the individual is sensitized.
--One of the most important features that mast cells and basophils share is receptors
(FcεRI) on their cell membranes that bind with high affinity to the Fc portion of IgE.
---Once bound, the IgE molecules persist at the cell surface for weeks. The cell
will remain sensitized as long as enough IgE- antibody remains attached.
-- the IgE molecules will trigger the activation of the cell when it comes into contact with
antigen.
---The mast cell is not specific for any particular antigen; the IgE bound to it is.
Passive Sensitization can be achieved by transfer of serum that contains IgE antibody to a
specific antigen. A procedure known as the Prausnitz-Kustner (P-K) test, is performed as a
test for the antibodies responsible for anaphylactic reactions.
Serum from an allergic individual is injected into the skin of a nonallergic person. After 1–2
days, during which the locally injected antibody diffused toward neighboring mast cells
and became bound to them, the site of injection was said to be sensitized, and would
respond with an urticarial reaction (hives) when injected with the antigen to which the
donor was allergic.
Such a reaction in passively sensitized animals is called passive cutaneous anaphylaxis
(PCA).
ACTIVATION PHASE
The activation phase of allergic reactions begins when the mast cell is triggered to
release its granules and their inflammatory mediators.
At least two of the FcεRIs must be bridged together in a stable configuration for the
activation phase to occur.
This linkage is accomplished by a multivalent antigen that can bind a different
molecule of IgE to each of several epitopes, thus cross-linking them
Experimental crosslinking of FcεRI receptors: to
activate mast cells
Anti-IgE cross-linking, Lectin cross-linking,
Chemical cross-linking, Anti Fc εRI cross-linking
Natural mechanisms other than IgE Fc receptor
cross-linking:
Anaphylatoxins C3a and C5a (Mast cells express
receptors for complement anaphylatoxins C3a and
C5a (i.e., C3aR and C5aR))
Physical factors such as heat, cold, or pressure:
cold-induced urticaria, dermatographic uticaria in
which the skin becomes raised and inflamed when
stroked, scratched, or slapped.
The triggering of a mast cell by the bridging of its receptors initiates a rapid and
complex series of events culminating in the degranulation of the mast cell and the
release of potent inflammatory mediators.
Allergic reactions are often referred to as immediate hypersensitivity
Physiologic consequences of IgE-mediated mast-cell degranulation depend on
the dose of antigen and route of entry.
---Mast cells that degranulate:
--In the gastrointestinal tract cause increased fluid secretion and peristalsis,
which, in turn, can result in diarrhea and vomiting
--in the lung -decrease in airway diameters and increased mucus secretion
leading to congestion and blockage of the airways (coughing, wheezing,
phlegm), swelling and mucus secretion in nasal passages
--degranuulation of mast cells present along the blood vessels causes increased
blood flow and vascular permeability > increased fluid in tissues or edema.
increased cells and protein in tissues, increased effector response in tissues>
Hypotension potentially leading to anaphylactic shock
EFFECTOR PHASE Mast-cell degranulation begins within seconds of antigen binding,
releasing an array of preformed and newly generated inflammatory mediators
1. preformed mediators such as short-lived vasoactive amine histamine, serine
esterases, and proteases such as chymase and tryptase stored in their intracellular
granules
2. synthesized de novo. chemokines, cytokines, and lipid mediators—prostaglandins,
leukotrienes, thromboxanes (collectively called eicosanoids), and platelet-activating
factor (PAF).
Granule contents include the short-lived vasoactive amine histamine, serine esterases,
and proteases such as chymase and tryptase.
Preformed Mediators
Histamine.
>Histamine is formed in the cell by decarboxylation of the amino acid histidine; it is
stored in the cell by binding via electrostatic interaction to an acid matrix protein
called heparin.
>When released, histamine binds rapidly to a variety of cells via two major types of
receptor, H1 and H2, which have different tissue distribution and mediate different
effects.
------When histamine binds to H1 receptors in smooth muscles, it causes constriction; -------when it binds to H1 receptors on endothelial cells, it causes separation at their
junctions, resulting in vascular permeability.
-------H2 receptors are involved in mucus secretion, increased vascular permeability,
and the release of acid from stomach mucosa.
All these effects are responsible for some of the major signs of systemic anaphylaxis:
difficulty in breathing (asthma) or asphyxiation result from the constriction of smooth
muscle around the bronchi in the lung,
and the drop in blood pressure is a consequence of the extravasation of fluid into
tissue spaces as the permeability of blood vessels increases.
H1 receptors are blocked by antihistamines, such as Benadryl®, which compete
directly for H1 receptor sites with histamine; when these drugs are given soon
enough, they can counteract its effects.
Blockage of H2 receptors requires other drugs, such as cimetidine.
Antihistamines are ineffective in controlling constriction of smooth muscles
That has late second onset which is slower but is more persistent than that produced
by histamine. This observation led to the discovery of the slow-reacting substance of
anaphylaxis (SRS-A), now known to be a group of molecules called leukotrienes.
Serotonin. Serotonin is present in the mast cells of humans with effects are similar to
those of histamine- causing constriction of smooth muscle and increases vascular
permeability.
Chemotactic Factors. A variety of chemotactic factors are released following
degranulation of mast cells.
----Lowmolecular- weight peptides called eosinophilic chemotactic factors (ECFs) are
also released upon degranulation.
Heparin. Heparin is an acidic proteoglycan that constitutes the matrix of the granule, and
to which basic mediators, such as histamine and serotonin, are bound.
Mast cells also synthesize de novo and release chemokines,
cytokines, and lipid mediators—prostaglandins, leukotrienes, thromboxanes
(collectively called eicosanoids), and platelet-activating factor.
----Platelet-activating factor (PAF) and leukotrienes are late-phase mediators that also
participate in the chemotaxis of inflammatory cells to the site
--- Important inflammatory cell attracted to the site is the neutrophil.
Chemotaxis of these polymorphonuclear granulocytes occurs in response to IL-8 released
by activated mast cells. They are are important in the late phase of IgE-mediated
hypersensitivity. Other cells attracted to the site in response to mast cell-derived
chemotactic factors include basophils, macrophages, platelets, and lymphocytes
These secreted products contribute to both acute and chronic inflammation.
The lipid mediators, in particular, can act both rapidly and persistently to cause smooth
muscle contraction, increased vascular permeability, and the secretion of mucus, as well
as induce the influx and activation of leukocytes, which contribute to allergic
inflammation.
Late-Phase Reaction
Many of the substances released during mast-cell activation and degranulation are
responsible for the initiation of a profound inflammatory response, which consists of
infiltration and accumulation of eosinophils, neutrophils, basophils, lymphocytes, and
macrophages.
The most important of these elements, which constitute a large percentage of the cells
activated during an inflammatory response, are eosinophils and neutrophils.
This response, referred to as the late-phase reaction, often occurs within 48 hours and
may persist for several days.
1. mast cell, degranulated releases eosinophilic chemotactic factor (ECF-A), > recruits
eosinophils to the reaction area.
2. Increased vascular permeability caused by histamine and other mediators> provides
passage of eosinophils and other leukocytes from the circulation to the tissue
3. Various cytokines, including GM-CSF, IL-3, IL-4, IL-5, and IL-13, play important roles in
eosinophil growth and differentiation, and in the cell adhesion of certain cell types.
4. Together these inflammatory mediators generate a second, milder wave of smooth
muscle contraction than the immediate response, along with sustained edema.
In allergic asthma, the late-phase reaction also promotes the development of one of the
cardinal features of this form of asthma: airway hyperreactivity to nonspecific
bronchoconstrictor stimuli like histamine.
Late-phase reaction of type I IgE-mediated hypersensitivity showing some of the
mediators involved.
Eosinophils bind IgE through their low-affinity IgE Fc receptor (FcεRII), They also
express Fc receptors to the Fc portion of IgG.
Thus, both IgE- and IgG-bound antigen will bind to their respective Fc receptors, causing
eosinophil activation, degranulation and release releasing leukotrienes that cause
muscle contraction.
They also release PAF and major basic protein (MBP). eosinophilic cationic protein
(ECP) which damage tissues like the respiratory tract.
Recruited neutrophils phagocytose the antigen–antibody immune complexes,
degranulation release their powerful lysosomal enzymes that damage tissue;
leukotrienes and PAF.
T and B lymphocytes and macrophages also enter the area, further sensitizing or
immunizing the host against the antigen.
These reactions occur in response to antigen like pollen, animal dander, or the
common dust mite, and result in tissue damage in actopic individuals.
Allergic rhinitis (commonly known as hay fever) is the most common atopic disorder
worldwide. It is caused by airborne allergens that react with IgE-sensitized mast cells in
the nasal passages and conjunctiva.
The route of administration of allergen determines the type of IgE-mediated
allergic reaction that results.
Food Allergies:
intake of certain foods (e.g., peanuts, rice, eggs, etc.). cross-linking of allergen-specific IgE
on mast cells of the upper and lower gastrointestinal tract.
If the allergen is absorbed into the bloodstream as a consequence of increased
permeability of mucous membranes, allowing food allergens to be transported
to mast cells present in skin. This causes wheal and flare reactions (atopic urticaria),
commonly known as hives.
Atopic Dermatitis
A form of allergic reaction most frequently seen in young children, allergic dermatitis is
caused by the development of inflammatory skin lesions induced by mast cell cytokines
released following degranulation. The skin eruptions that develop are erythematous
(symmetrical, red, raised skin areas) and pus (white cell)-filled.
Asthma is a common form of localized anaphylaxis. a common chronic disorder of
the airways that involves a complex interaction of airflow obstruction, bronchial
hyperresponsiveness, and an underlying inflammation.
three basic pathophysiologic events within the airways: (1) reversible obstruction; (2)
augmented bronchial responsiveness to a variety of physical and chemical stimuli
(airwayhyperreactivity); and (3) inflammation.
Allergens- including airborne pollens, dust, viral antigens, and various chemicals, can
induce allergic asthma.
Asthma may also be induced by phenomena ranging from exercise to exposure
to cold temperatures independent of allergen exposure, a phenomenon known as intrinsic
asthma.
Corticosteroids (CSTs) remain the gold standard for asthma management. while it improves asthma symptoms, it does
not alter the natural course of asthma or offer clear long-lasting improvement of respiratory performance.
Allergen introduced into the bloodstream can cause anaphylaxis.
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 (see Fig. 14.12, first and last panels).
Acute urticaria is a response to foreign allergens that are delivered to the skin via the
systemic blood circulation. Activation of mast cells in the skin by allergen causes
them to release histamine, which in turn causes itchy, red swellings all over the
body—a disseminated version of the wheal-and-flare reaction.
Although acute urticaria is commonly caused by an IgE-mediated reaction against an
allergen, the causes of chronic urticaria, in which the urticarial rash persists or recurs
over long periods, remain incompletely defined. Some cases of chronic urticaria are
caused by autoantibodies
In anaphylactic shock, a widespread increase in vascular permeability and
smooth muscle contraction results from a massive release of histamine
and other mast cell- and basophil-derived mediators such as leukotrienes.
The consequences are a catastrophic reduction of blood pressure, culminating
in hypotensive shock, (a condition in which low blood pressure leads to inadequate
supply of blood to vital organs, often leading to death), and constriction of
the airways, culminating in respiratory failure.
The most common causes of anaphylaxis are allergic reactions to wasp and bee stings,
ingested or injected medications, or allergic responses to foods in sensitized individuals.
For example, anaphylaxis in individuals allergic to peanuts is relatively common.
Severe anaphylactic shock can be rapidly fatal if untreated, but can usually be
controlled by the immediate injection of epinephrine, which via stimulation of βadrenergic receptors causes relaxation of airway smooth muscles, and via stimulation
of α-adrenergic receptors reverses the life-threatening cardiovascular effects.
Systemic allergic reactions can occur following repeated treatment with many classes of
drugs. A relatively common inducer of IgE-mediated allergic reaction is penicillin and
other drugs that share aspects of its structure and immunological reactivity. In people
who have developed IgE antibodies against penicillin, injection of the drug can cause
anaphylaxis and even death.
Overview of induction and effector
mechanisms in type I hypersensitivity.
HYPERSENSITIVITY: TYPES II AND III
 Hypersensitivity reactions characterized as type II and type III reactions are mediated
by antibodies belonging to the IgG, IgM, and, in some cases, IgA or IgE isotypes.
> Distinction between these two forms of hypersensitivity:
------type and location of antigen involved
-----and the way in which antigen is brought together with antibody.
>Type II hypersensitivity reactions are the result of the binding of antibody directly to an
antigen on the surface of a cell.
>Type III reactions are the result of deposition of antigen–antibody immune complexes.
>The target antigens involved in type II and type III hypersensitivity reactions are often
self-antigens
TYPE II HYPERSENSITIVITY
Three different antibody-mediated mechanisms are involved i.e. the targeted cell is
either damaged or destroyed through a variety of mechanisms:
(a) complement-mediated reactions
(b) antibody-dependent cell-mediated cytotoxicity
(c) antibody-mediated cellular dysfunction.
Many of these reactions are manifestations of antibody-mediated autoimmunity.
The antibodies involved in these hypersensitivity reactions are either directed against
normal self-antigens (e.g., cross-reactive antibodies elicited following an infection) or
modified self-antigens (e.g., drug-induced autoantibodies elicited following the binding
of drugs to certain cell membranes).
Complement-Mediated Reactions
Antibodies react with cell membrane self-antigens and this is followed by complement
fixation > activates the complement cascade > leads to lysis of the cell Membrane Attack
Complex.
Alternatively, binding of antibody to the cell surface and subsequent activation of
complement to yield C3b effectively opsonize the target cell.
---Opsonization culminates in the phagocytosis and destruction of the cell by
macrophages and neutrophils expressing surface Fc receptors or receptors that bind C3b.
Blood cells are most commonly affected by this mechanism.
IgG Fc receptor knockout mice fail to mount type II (and type III) hypersensitivity
reactions, a finding that underscores the pivotal role played by IgG Fc receptors in
initiating these reaction cascades.
Antibody-Dependent Cell-Mediated Cytotoxicity
Antibody-dependent cell-mediated cytotoxicity (ADCC) utilizes Fc receptors expressed
on many cell types (e.g., natural killer [NK] cells, macrophages, neutrophils,
eosinophils) as a means of bringing these cells into contact with antibody-coated target
cells.
Lysis of these target cells requires contact but does not involve phagocytosis or
complement fixation.
ADCC-mediated lysis of target cells is analogous to that of cytotoxic T cells and
involves the release of cytoplasmic granules (modified lysosomes) containing perforin
and granzymes.
Once released from the lytic granules, perforins insert into the target cell membrane
and polymerize to form pores. In contrast, granzymes, which consist of at lease three
serine proteases, enter the cytoplasm of the target cell and activate events
leading to apoptosis.
ADCC reactions are typically triggered by IgG binding to IgG-specific Fc receptors (FcγIII,
also known as CD16) on the effector cells.
IgE antibodies can also be involved in ADCC. In this situation, the low-affinity IgE Fc
receptor (FcεRII) expressed on certain cells, including eosinophils binds to the Fc portion
of IgE antibodies bound to target antigens (e.g., parasites)
Antibody-Mediated Cellular Dysfunction
In some type II hypersensitivity reactions, antibodies bind to cell-surface receptors
that are critical for the functional integrity of the cell.
---When autoantibodies bind to such receptors they impair or dysregulate cell
function without causing cell injury or inflammation.
EXAMPLES OF TYPE II HYPERSENSITIVITY REACTIONS
Transfusion Reactions:
>Transfusion of ABO-incompatible blood results in complement-mediated cytotoxic
reactions
> Example, individuals with type O blood have in their circulation IgM anti-A and anti-B
antibodies (isohemagglutinins), which react with the A and B blood-group substances,
respectively.
>a single IgM molecule is sufficient to activate many complement moleculeswhich will
destroy transfused A or B type blood cells in recipient of O type blood group.
Drug-Induced Reactions:
>In some people, certain drugs act as haptens and combine with cells or with other
circulating blood constituents and induce antibody formation.
>When antibody combines with cells coated with the drug, cytotoxic damage results.
Example, some drugs can bind to platelets causing them to become immunogenic.
Antibody responses that are generated cause lysis of the platelets and resulting
thrombocytopenia (low blood platelet count).
Hypersensitivity to drugs may also induce IgE-mediated immediate type I hypersensitivity
reactions
Rhesus Incompatibility Reactions: Rhesus (Rh) incompatibility reaction seen in infants
born of mothers with Rh-incompatible blood groups.
Rh− mothers can become sensitized to Rh antigens during their first pregnancy with a
child whose RBCs are Rh+.
This occurs as a result of the release of some of the baby’s RBCs intothe mother’s
circulation perinatally and particularly during birth.
If the mother is thereby sufficiently immunized toproduce anti-Rh antibody of the IgG
isotype, subsequent Rh+ fetuses will be at risk, since, IgG antibody is capable of crossing
the placenta.
Thus, in second or subsequent pregnancies, when the anti-Rh IgG antibodies have
crossed the placenta, they bind to the Rh antigen on the RBCs of the fetus.
Because the density of Rh antigen on the surface of RBCs is low, these antibodies
usually fail to agglutinate or lyse the cells directly.
However, the antibody-coated cells are readily destroyed by the opsonic effect of the Fc
portions of the IgG, which interact with the receptors for Fc on the phagocytic cells of the
reticuloendothelial system.
The result is progressive destruction of the fetal or newborn RBCs, with the pathologic
consequences that come from decreased transport of oxygen and from increased
bilirubin from the products of the breakdown of hemoglobin, a condition known as
erythroblastosisfetalis (hemolytic disease of the newborn). Prevention
of this Rh incompatibility reaction can be achieved
with the administration of anti-Rh antibodies (passive
Reactions Involving Cell Membrane Receptors:
> An example of antibody-mediated cellular dysfunction due to reactivity with a cell
receptor is seen in the autoimmune disease myasthenia gravis.
--Antagonistic autoantibodies reactive with acetylcholine receptors in the motor end
platesof skeletal muscles impair neuromuscular transmission, causing muscle weakness
 Graves’ disease, the autoantibodies serve as agonists, causing stimulation of the
target cells. These antibodies are directed against thyroid-stimulating hormone
receptor on thyroid epithelial cells and stimulate the cells, resulting
inhyperthyroidism.
Reactions Involving Other Cell Membrane Determinants:
>As a consequence of certain infectious diseases, or for other, still unknown reasons,
some individuals produce autoantibodies reactive against their own blood cells.
--When RBCs are the target, binding of anti-RBC autoantibody shortens their life span
or destroys them immediately. This may lead to progressive anemia if the
production of new RBCs cannot keep pace with destruction.
>immune thrombocytopenia purpura (ITP) :antibodies directed to platelets result in
platelet destruction
>
 Autoantibodies directed against granulocytes can induce agranulocytosis
predisposing individuals to various infections.
 Antibodies may form against other tissue components such as a type of basement
membrane collagen particularly prevalent in the lung and kidneys, causing
Goodpasture’s syndrome
> desmosomes between keratinocytes in the skin resulting in pemphigus vulgaris.
Type III Hypersensitivity
Under normal conditions, circulating immune complexes composed of antibodies
bound to foreign antigens :
1. Phagocytic cells - Phagocytosis is facilitated by the binding of the Fc regions of the
antibodies present in such complexes to IgG Fc receptors expressed on these cells.
2. RBCs that have C3b receptors - bind immune complexes that have fixed complement
and transport them to the liver, where the complexes are removed by phagocytic
Kupffer cells.
3. Histidine-rich glycoprotein (HRG): abundantly synthesized by the liver and released
into the blood stream. HRG does not require pre-activation unlike complements.
HRG is readily available to engage in the removal of immune complexes via an FcγRdependent mechanism.
HRG has the ability to clear apoptotic cells by binding naked DNA.
Through its interactions with naked DNA and immune complexes, HRG may mask
epitopes recognized byautoantibody-producing B cells (e.g., rheumatoid factors
and anti-double stranded DNA antibodies)
When physiologic mechanisms for clearing immune complexes are overwhelmed with
large quantities of such complexes, then immune complexes of a certain size can
inappropriately deposit in the tissues and trigger a variety of systemic pathogenic
events known as type III hypersensitivity reactions.
> These reactions can be:
--- systemic (also called systemic immune complex disease)
---- localized (also known as localized immune complex disease)
> Associated with immune complex deposition in the kidneys, skin, joints,
choroid plexus, and ciliary artery of the eye.
> Generation of immune complexes can be stimulated by exogenous antigens
such as bacteria and viruses or, as in the case of the Arthus reaction, by intradermal or
intrapulmonary exposure to large amounts of foreign protein.
 Alternatively, endogenous antigens, such as DNA, can serve as a target for
autoantibodies as seen in systemic lupus erythematosus. Patients with SLE often
have both systemic (multiorgan) and localized manifestations of immune complex
disease. Like glomerular disease.caused by deposition of IC in kidneys.
 Mechanism of injury to tissues :
----IgG is the immunoglobulin isotype usually involved in type III hypersensitivity
reactions, but IgM can also be involved. As with type II hypersensitivity reactions
---IgG Fc receptors (CD16) expressed on leukocytes play a pivotal role in initiating type
III reaction cascades.
---The antibody–antigen complexes may fix complement and/or activate effector cells
(the main cell type being the neutrophil) that cause tissue damage.
---C3a and C5a generated by complement activation induce mast cells and basophils to
release arachidonic acid metabolites and chemokines that attract additional basophils,
eosinophils, macrophages, and neutrophils into the area.
---The polymorphonuclear cells release their lysosomal enzymes at the surface of the
affected tissues.
---Macrophages are stimulated to release tumor necrosis factor-α (TNF-α) and
interleukin-1 (IL-1)
Systemic Immune Complex Disease
Pathogenesis of systemic immune complex disease canbe divided into three phases.
1. antigen– antibody immune complexes form in the circulation.
2. This is followed by deposition of immune complexes in various issues that initiates the
3. third phase in which inflammatory reactions in various tissues occur
Several factors help to determine whether immune complex formation will lead to
tissue deposition and disease.
---The size of the complexes appears to be important.
> Very large complexes formed under conditions of antibody excess are rapidly removed
from the circulation by phagocytic cells and therefore are harmless.
 Small or intermediate complexes circulate for longer periods of time and bind less
avidly to IgG Fc receptors expressed on phagocytic cells. T
Therefore, small-to-intermediate sized immune complexes tend to be more pathogenic
as compared with large complexes.
---Integrity of the mononuclear phagocytic system.
An intrinsic dysfunction of this system increases the probability of persistence of
immune complexes in the circulation.
The favored sites of immune complex deposition are the kidneys, joints, skin, heart,
and small blood vessels.
Serum sickness:
Infection by both the Corynebacterium and the Clostridium organisms lead to pathological
consequences due to the secretion of exotoxins that are extremely damaging to host cells.
In pre-antibiotics era, the strategy that evolved to treat these diseases was to neutralize
the toxins rapidly by administering passive immunization by injecting large amounts of a
serum containing preformed antitoxin antibody from immunized horses.
administration of large quantities of heterologous serum from another species causes the
recipient to synthesize antibodies to the foreign immunoglobulin, leading to the formation
of antigen–antibody complexes that result in the clinical symptoms associated with serum
sickness. The classic clinical manifestations consist of chills, fever, rash, arthritis, and
sometimes glomerulonephritis (inflammation of the glomeruli of the kidneys).
Infection-Associated Immune Complex Disease.
Example: Rheumatic feve: disease is associated with infections (e.g., throat) caused by
group A streptococci, and it involves inflammation and damage to heart, joints, and
kidneys.
A variety of antigens in the cell walls and membranes of streptococci have been shown to
be cross-reactive with antigenspresent in human heart muscle, cartilage, and glomerular
basement membrane.
Antibody to the streptococcal antigens binds to these components of normal
tissue and induces inflammatory reactions
Rheumatoid arthritis:
rheumatoid factor-an IgM autoantibody that binds to the Fc portion of normal IgG.
These immune complexes participate in causing inflammation and damage of joints.
In a number of infectious diseases (malaria, leprosy, dengue) there may be times
during the course of the infection when large amounts of antigen and antibody exist
simultaneously and cause the formation of immune aggregates that are deposited in
a variety of locations. Thus, the complex of symptoms in any of these diseases may
include a component attributable to a type III hypersensitivity reaction.
Complement deficiency
Complexes that contain C3b bind to erythrocytes bearing CR1. The erythrocytes
deliver the complexes to mononuclear phagocytes within the liver and spleen for
removal by phagocytosis.
The components of the classical complement pathway reduce the number of antigen
epitopes that antibodies can bind to by intercalating into the lattice of the
complex, resulting in smaller, soluble complexes.
It is these small, soluble complexes that bind most readily to the erythrocytes.
In patients with complement deficiencies affecting C1, C2, and C4, the
complexes remain large and bind poorly to the erythrocytes.
These non-erythrocyte-bound complexes are taken up rapidly by the liver and then
released to be deposited in tissues such as skin, kidney and muscle, where they can
set up inflammatory reactions.
A local hypersensitivity reaction called an Arthus reaction :
Result of local inflammatory responses generated occur following reactivity of antigen
with already formed, antigen-specific IgG antibody.
When such preformed antibodies come in contact with antigen at the appropriate
concentrations (antibody excess), in or near vessel walls (venules), insoluble
immune complexes form and accumulate. The end result is rupture of the vessel wall and
hemorrhage, accompanied by necrosis of local tissue.
HYPERSENSITIVITY: TYPE IV
 type IV hypersensitivity is T-cell mediated.
 type IV responses involve the activation, proliferation, and mobilization of antigenspecific T cells. Thus, type IV hypersensitivity is delayed as compared with antibodymediated hypersensitivity reactions, and it is often referred to as delayed-type
hypersensitivity (DTH).
 DTH reactions can also result in damage to host cells and tissues.
DTH reactions are cell-mediated immune responses.- basically TH1 and CD8 cytotoxic T
cells
Depending on the antigen involved, they mediate beneficial (resistance to viruses,
bacteria, fungi, and tumors) or harmful (allergic dermatitis, autoimmunity) aspects of
immune function.
Other antigens capable of eliciting DTHreactions:
---Alloantigens those expressed by foreign cells in transplantation (allografts)
---one of many chemicals (serving as haptens) capable of penetrating skin and coupling to
body proteins that serve as carriers
GENERAL CHARACTERISTICS AND PATHOPHYSIOLOGY OF DTH
Clinical features of type IV hypersensitivity reactions vary:
---depending on the sensitizing antigen and the route of antigen exposure.
These variants include contact hypersensitivity, tuberculin-type hypersensitivity, and
granulomatous hypersensitivity
Common pathophysiologic mechanisms account for each of these variants:
The major events leading to these reactions involve the following three steps:
(1) activation of antigen-specific inflammatory TH1 and TH17 cells in a previously
sensitized individual
(2) elaboration of pro-inflammatory cytokines by the antigen-specific TH1 cells
(3) recruitment and activation of antigen-nonspecific inflammatory leukocytes.
These events typically occur over a period of several days (48–72 hours).
MECHANISM INVOLVED IN DTH REACTION
Previous exposure to the antigen is required to generate DTH reactions.
Such exposure (the sensitization stage) activates and expands the number of
antigen-specific TH1 and TH17 cells that, when subsequently challenged with the
same antigen, respond by producing cytokines that promote DTH reactions (the
elicitation stage).
During the elicitation phase, activated TH1 and TH17 cells mediate the activation and
recruitment of innate immune cells (antigen-nonspecific inflammatory cells) to the
area of the reaction, including the activation and recruitment of macrophages and NK
cells, and neutrophils.
The sensitization stage typically occurs over a 1–2 week period
The elicitation stage requires approximately 18–48 hours from time of antigenic
challenge to recruit and activate these cells, a period that culminates in the
histological and clinical features of DTH.
The clinical manifestations of DTH can last for several weeks or, in some cases, can
be chronic (e.g., DTH occurring in certain autoimmune diseases).
The antigen-challenged TH1 cells produce several cytokines during the elicitation stage,
most notably chemokines and IFN-γ, which cause chemotaxis and activation
of macrophages .
Another cytokine produced by these cells is IL-12.
IL-12 suppresses the TH2 subpopulation and promotes the expansion of the TH1
subpopulation thereby driving the response to produce moreTH1-synthesized cytokines
that activate macrophages. Thus, IL-12 plays an important role in DTH.
DTH reactions also involve CD8+ T cells, which are first activated and expanded during the
sensitization stage of the response.
These cells can damage tissues by cell-mediated cytotoxicity .
Activation of CD8+ T cells occurs as a consequence of the ability of many lipid-soluble
chemicals capable of inducing DTH reactions.
EXAMPLES OF DTH
1. Contact Sensitivity:
Contact sensitivity (sometimes called contact dermatitis) is a form of DTH in which the
target organ is the skin.
The inflammatory response is produced as the result of contact with sensitizing
substances on the surface of the skin. Thus, it is primarily an epidermal reaction
characterized by eczema at the site of contact with the allergen that typically peaks
48–72 hours after contact.
The prototype for this form of DTH is poison ivy dermatitis caused by CD8 T-cell
response to urushiol oil (a mixture of pentadecacatechols) in the plant.
These chemicals are lipid-soluble and so can cross the cell membrane and attach to
intracellular proteins. Within the cell, these chemicals react with cytosolic proteins to
generate modified peptides that are translocated to the endoplasmic reticulum and
then delivered to the cell surface in the contextof MHC class I molecules.
Cells presenting such modified self-proteins are subsequently damaged or killed by
CD8+ T cells.
2. Tuberculin-Type Hypersensitivity
Tuberculin-type reactions are cutaneous inflammatory reactions characterized by an
area of firm red swelling of the skin that is maximal at 48–72 hours after challenge.
The term tuberculin-type derives from the prototype DTH reaction in which a
lipoprotein antigen isolated from Mycobacterium tuberculosis called tuberculin was
used to test for evidence of exposure to the causative agent of tuberculosis.
Today, TB tests are performed by intradermally injecting a more purified lipoprotein
extract isolated from M. tuberculosis called purified protein derivative (PPD).
The PPD test (also called the Mantoux test) is extremely useful for public health
surveillance of TB.
If an individual has been previously sensitized to antigens expressed by M. tuberculosis
as a consequence of infection with this organism, the characteristic tuberculin type
lesion will appear at the site of injection within 48–72 hours.
Evidence of erythema (redness) and induration (raised thickening) appear, reaching
maximal levels 72 hours after the challenge. These reactions, even when severe, rarely
lead to necrotic damage and resolve slowly.
3. Allograft Rejection
if an individual receives grafts of cells, tissues, or organs taken from an allogeneic
donor (a genetically different individual of the same species), it will usually become
vascularized and initially be accepted.
However, if the genetic differences are within the major histocompatibility complex
(MHC), T-cellmediated rejection of the graft ensues, whose duration and intensity is
related to the degree of incompatibility between donor and recipient.
After vascularization, there is an initial invasion of the graft by a mixed population of
antigen-specific T cells and antigen-nonspecific monocytes through the blood vessel
walls. This inflammatory reaction soon leads to destruction of the vessels; this
deprivation of nutrients is quickly followed by necrosis and breakdown of the
grafted tissue.
4. Examples of autoimmune diseases in which DTH reactions are involved include
rheumatoid arthritis, type I diabetes, and multiple sclerosis
Historically, hypersensitivity reactions due to immunological responses were
classified by Gell and Coombs into four broad types, of which type
I hypersensitivity reactions represented immediate-type allergic reactions mediated by
IgE antibodies, with mast-cell activation the major final effector mechanism.
Type II and III hypersensitivity responses were defined as those that were
driven by antigen-specific IgG antibodies, the final effector mechanism being
complement (type II) or FcR-bearing cellular effectors (type III).
Finally, type IV hypersensitivity responses were depicted as being driven by cellular
effectors, including lymphocytes and a variety of myeloid cell types.
The sequence of events involved in the development of allergic reactions can be
divided into several phases:
(1) The sensitization phase, during which IgE antibody is produced in response to an
antigenic stimulus and binds to specificreceptors on mast cells and basophils
(2) the activation phase, during which reexposure (challenge) to antigen triggers
the mast cells and basophils to respond by release of the contents of their granules
(3) the effector phase, during which a complex response occurs as a result of the
effects of the many inflammatory mediators released by the mast cells and basophils.
As noted above, the clinical manifestations of these effector mechanisms include
rhinitis, asthma, and anaphylaxis.