Download Types of Hypersensitivity Reactions

IMMUNOLOGY
7105306
HYPERSENSITIVITY (UPDATED)
Part-11
References:
Immunology , David Male et al 8th ed 2013
Basic Immunology , Abul K. Abbas and Andrew H. Lichtman, 3ed, 2011
Instructor: Dr Alaeddin Abuzant, PhD Microbiology and Immunology
Email: [email protected]
The immune system is required for defending the host against infections ( and tumor
cells)
However, excessive ( uncontrolled ) or aberrant immune responses are capable of
causing tissue injury and disease. Such immune responses are called hypersensitivity
reactions.
In general, hypersensitivity reactions may occur in two situations:
1- Uncontrolled excessive responses to foreign antigens that may result in tissue injury.
2- An aberrant immune responses that may be directed against self (autologous)
antigens, as a result of the failure of self-tolerance that result in autoimmune diseases.
What are the mechanisms of different types of hypersensitivity reactions?
What are the major clinical and pathologic features of diseases caused by these
reactions
what principles underlie treatment of such diseases?
Types of Hypersensitivity Reactions
On the basis of the principal immunologic mechanism that mediates hypersensitivity
reactions, these reactions can be classified:
1- Immediate hypersensitivity, or type I hypersensitivity:
It is a type of pathologic reaction that is mediated by the release of mediators from
mast cells.
It is mostly triggered by the production of excessive amount of IgE antibody directed
against environmental antigens ( foreign antigens/allergen ) and the binding of IgE to
mast cells in various tissues.
2- Type II hypersensitivity:
It is mediated by antibodies directed against self cellular or tissue antigens that either
cause
A- Damage these cells or tissues
B- Impair their functions.
3- Type III hypersensitivity: it is mediated by antigen-antibody complex (immune
complexes) that may deposit in blood vessels in various tissues, causing inflammation
and tissue injury.
Note: type II and III are mediated by antibodies other than IgE
4- Type IV hypersensitivity:
It is mediated by T lymphocytes that attack self antigens in tissues to cause tissue
injury
1- Immediate Hypersensitivity Reactions ( Type I hypersensitivity)
Immediate hypersensitivity is a rapid immunologic reaction that is mediated certain
mediators released from activated mast cells
Immediate hypersensitivity reactions are also called allergy, or atopy
Individuals with a strong propensity to develop these reactions are said to be “atopic.”
…..allergic individuals
Such reactions may affect various tissues and may be of varying severity in different
individuals.
The reactions caused by mast cell mediators can be classified as
1- Immediate phase reactions : some of the mast cells cause mediators ( such as
histamine) cause a rapid increase vascular permeability and smooth muscle
contractions that may occur within minutes of reintroduction of antigen into a
previously sensitized atopic individual (hence the name immediate hypersensitivity)
2- late phase reaction inflammatory reaction: is mediated by other mast cell
mediators which are cytokines ( Chemokines) that recruit Neutophils and Eosinophils
over several hours resulting in inflammation that is mainly responsible for the tissue
injury
Common types of immediate hypersensitivity reactions include:
Hay fever
Food allergies
Bronchial asthma
Anaphylaxis
Allergies ( type I hypersensitivity) are the most frequent disorders of the immune
system, estimated to affect about 20% of the population.
The sequence of events in the development of immediate
hypersensitivity reactions consists of:
I- Sensitization: Occurs in atopic person upon exposure (first exposure) to an
environmental antigen ( foreign antigens). Such antigen are called allergens
In response to an allergen, atopic people tend to produce large amount of IgE
antibodies that bind to IgE to Fc receptors of mast cells. This process is called
sensitization
2- Activation of mast cells and the release of mast cell mediators: Upon re-exposure
to the same allergen, this allergen causes cross-linking of the bound IgE antibodies on
mast cells. This cross-linking of the bound IgE antibodies on mast cells causes
aggregation of the IgE to Fc receptors) triggers the release of mast cell mediators
The immune response triggered in atopic individuals upon
exposure to a particular allergen results in the activation of
TH2 cells and the production of IgE antibody
 Normal individuals do not mount strong TH2 responses to most foreign antigens.
 In atopic individuals (so far unknown reasons), cellular adaptive immune
responses, to certain foreign antigens, tend to skewed toward the development of a
dominant TH2 cells. Recall that cytokines produced by TH2 cells causes the production
of IgE antibodies by ( class switching)
Foreign antigen that trigger allergic reactions are know as (allergens)
Example of common allergens: proteins in pollen, certain foods, insect venoms, or
animal dander, certain drugs such as penicillin.
Any atopic individual may be allergic to one or more of these antigens
IgE antibody class switching:
Two of the cytokines secreted by TH2 cells, interleukin (IL)-4 and IL-13, stimulate B
lymphocytes ( that have receptors for the same allergen that trigger the development
of TH2 cells)
These cytokines that cause IgE antibody class switching in these B cells
Therefore, in atopic persons, immune responses to certain antigens ( allergens)
produce large amounts of IgE antibody (this does not happen in most people that
usually do not mount a strong TH2 response upon exposure to the same antigens)
It is believed that the propensity toward TH2 development, and consequently IgE
production that may result in immediate hypersensitivity reactions has a
strong genetic basis, with many different genes playing contributory roles.
ACTIVATION OF MAST CELLS AND SECRETION OF MEDIATORS
In an atopic individual, an immune response triggered by an allergen causes the
production of large amount of IgE antibodies that bind to high-affinity Fc receptor
on mast cells that is specific for the ε heavy chain of IgE antibodies (known as FcεRI
)(Fc epsilon RI) (Fig. 11-3).
This process of coating mast cells with a large amount IgE is called “sensitization,”
This is because coating of mast cells with a large number of IgE antibody molecules
specific for a particular allergen makes the mast cells very sensitive to activation by
subsequent ( next time) exposure to the same allergen.
Note: Suppose we have an antigen called X
In normal individuals, exposure to X antigen may elicit (induce) small amount of anti-X
IgE antibodies ( recall that in response to most antigens , normal individuals do not
develop an immune response that is largely skewed toward TH2)
In contrast, in atopic people , the immune response to X antigen is largely skewed toward
TH2 …..TH2 cytokines…IgE class switching…production of large amount of anti X IgE
antibody
So, in an X antigen atopic person (allergic to X antigen), mast cells become coated with a
large number of anti- X IgE antibody molecules ( the presence of a large number of one
type of IgE directed against X antigen makes mast cells very sensitive to activation upon reexposure to the same allergen). Upon re-exposure to X antigen, X antigen bind to several
IgE antibodies ( cross- link several IgE antibodies ) found on the surface of mast cells (
assuming that X antigen is a muti-valent antigen). This causes aggregation of several FcεRI
that is necessary to trigger an activation signal that is strong enough for activation of mast
cells. Activation of mast cells results in the release of mast cell mediators
that are enough to cause immediate hypersensitivity reactions upon re-exposure to x
antigen…that causes large number of eggergations of the Fc receptor on mast
cells…enough to trigger a string signal needed for mast cells activation
In contrast, in normal individuals, mast cells may have a small number of anti X IgE
antibody bound to it…..
Normally ..these mast cells in normal individuals may also be coated with different
types of IgE antibodies. However, each type of these IgE antibodies is also found in small
number on the surface of mast cells.
Upon re-exposure to X antigen, the X antigen may bind to anti-X IgE antibodies on the
surface of mast cells. Since there is only a small number of anti-X IgE on the surface of
mast cells, X antigen will not be able to cross link these antibodies..and thus no
aggregation FcεRI happens …..accordingly, there will be no strong activation signal would
be generated that will be enough to activate mast cells
( since IgE antibody on mast cell are found in small number, these antibodies will be
distributed on the surface of mast cell so that they will not be close enough to each
other in such a way that the X antigen ( upon re-exposure) will not be able to cross-link
bound IgE antibodies on the surface of mast cells since they locate far a way from each
other)
.
Small number of
Anti X IgE
antibodies
High number of
Anti X IgE
antibodies
Upon Re-Exposure to X antigen
In normal individual
In atopic individual
No cross-linking of anti X IgE on
the surface of mast cell
Cross-linking of anti X IgE on the
surface of sensitized mast cell
No aggregation FcεRI happens, thus
no activation signal
Mast cell mediators
are NOT released
Aggregation FcεRI happens that lead
to the induction of the activation
signal
X antigen do NOT cross link anti X
IgE on the surface of mast cell
because they are far from each
other on the surface of mast cell
(low number)
Mast cell mediators
are released
X antigen cross link anti X IgE on the surface
of sensitized mast cell
(anti X IgE are close to each other so that
they can be easily cross-inked)(found in
high number)
No aggregation of
Fc receptor
Aggregation of Fc
receptor
No Activation signal
Activation signal is
triggered
No mast cell mediators
are released
Mast cell mediators are
released
The sequence of events in immediate
hypersensitivity.
Immediate hypersensitivity diseases are initiated by
the introduction of an allergen, which stimulates TH2
reactions and immunoglobulin E (IgE) production.
IgE binds to Fc receptors (FcεRI) on mast cells, and
subsequent exposure to the allergen activates the
mast cells to secrete the mediators that are
responsible for the pathologic reactions of immediate
hypersensitivity.
Mast cells are present in all connective tissues, and which of the body’s mast cells
are activated by cross-linking of allergen-specific IgE often depends on the
route of entry of the allergen.
Example:
Inhaled allergens activate mast cells in the sub mucosal tissues of the bronchus,
Ingested allergens activate mast cells in the wall of the intestine.
The high-affinity Fcε receptor, called FcεRI, consists of three chains, one of which binds
the Fc portion of the ε heavy chain very strongly, the other two chains of the receptor
are signaling proteins.
The same FcεRI also is present on basophils, the circulating counterpart of mast cells, but
the role of basophils in immediate hypersensitivity is not as well established as the role
of mast cells.
The activation signal lead to three types of responses in the mast cell:
1. Rapid release of granule contents (degranulation/exocytosis)
2. Synthesis and secretion of lipid mediators (products of arachidonic acid
metabolism)
3. Synthesis and secretion of cytokines
The most important mediators produced by mast cells are:
1. Vasoactive amines (histamine) and proteases that are released fronm the granules of
mast cells,
2. Products of arachidonic acid metabolism
3. Cytokines
.
Mast cell mediators have different actions
1- Mast cell mediators released from mast cell degranulation, these include
A- Histamine: it causes:
Dilation of small blood vessels,
Increases vascular permeability
Stimulates transient contraction of smooth muscles.
B- Proteases: that may cause damage to local tissues.
2- Arachidonic acid metabolites . These include:
A- prostaglandins, which cause vascular dilation
B- leukotrienes, which stimulate prolonged smooth muscle contraction
3- Cytokines and chemokines:these induce local inflammation (the late phase
reaction).
Thus, mast cell mediators are responsible for
1- Acute vascular and Smooth muscle reactions
2- inflammation
These two effects of mast cell mediators are the hallmarks of immediate
hypersensitivity.
Cytokines produced by mast cells stimulate the recruitment of leukocytes, which
mediate the late phase inflammatory reaction
The principal leukocytes involved in this reaction are:
1. Eosinophils
2. Neutrophils
3. TH2 cells
Mast cell-derived tumor necrosis factor (TNF) and IL-4 promote Neutrophil and
Eosinophil rich inflammation. The inflammation is mediated by proteases released
from these cells that cause tissue damage
Eosinophils are prominent components of many allergic reactions and are an
important cause of tissue injury in these reactions. These cells are activated by the
cytokine IL-5, which is produced by TH2 cells and mast cells.
The TH2 cytokine, IL-13 acts on airway epithelial cells to stimulate the secretion of
mucus
Note: Chemokines produced by mast cells and by epithelial cells in the tissues also
contribute to Neutrophil and Eosinophil to the site of the allergic reaction
Biochemical events in mast cell activation. Cross-linking of immunoglobulin E (IgE)
on a mast cell by an allergen stimulates phosphorylation of immunoreceptor
tyrosine–based activation motifs (ITAMs) in the signaling chains of the IgE Fc
receptor (FcεRI), which then initiates multiple signaling pathways. These signaling
pathways stimulate the release of mast cell granule contents (amines, proteases),
the synthesis of arachidonic acid metabolites (prostaglandins, leukotrienes), and the
synthesis of various cytokines. These mast cell mediators stimulate the various
reactions of immediate hypersensitivity. TNF, tumor necrosis factor
CLINICAL SYNDROMES OF TYPE I HYPERSENSITIVITY
Immediate hypersensitivity reactions have diverse clinical and pathologic features, all
of which are attributable to mediators produced by mast cells
in different amounts and in different tissues (Fig. 11-5).
Examples of Type I Hypersensitivity Reactions:
Hey fever ( A mild Type I hypersensitivity reaction):
It is characterized by allergic rhinitis and sinusitis, which are reactions to inhaled
allergens, such as the ragweed protein of pollen.
Increased production of mucus in the nasal mucosa seen in Hey fever is mediated by
histamine released from mast cells and by IL-13 produced by TH2 cells.
Late phase reactions seen in Type I hypersensitivity reactions
may lead to more prolonged inflammation.
Food allergies: ingested allergens trigger mast cell degranulation found in intestinal
tissue . The released histamine causes increased peristalsis that may result in diarrhea
Bronchial asthma:
Is a form of respiratory allergy in which inhaled allergens (often undefined) stimulate
bronchial mast cells of the lungs to release mediators , which include leukotrienes
 Leukotrienes cause repeated bouts of bronchial constriction and excessive secretion
of mucus that may lead to airway obstruction.
Chronic asthma is characterized by:
1- the presence of a large numbers of eosinophils in the bronchial mucosa
2- the bronchial smooth muscle becomes hyper-reactive to various stimuli
NOTE:
Some cases of asthma are NOT associated with IgE production, although all are
caused by mast cell activation.
In some affected persons, asthma may be triggered by cold or exercise that cause
mast cell activation by unknown mechanism.
Anaphylaxis (Anaphylactic Shock)
It is the most severe form of immediate type I hypersensitivity reaction that is
caused by widespread mast cell degranulation (systemic…in all body tissue) in
response to a systemic antigen ( an allergen that reaches the blood stream)
Anaphylaxis is defined as a systemic Type I hypersensitivity reaction that is
characterized by edema in most body tissues, including the larynx ( causes airway
obstruction) and is associated by a sudden fall in blood pressure.
Accordingly, anaphylaxis is a life-threatening reaction because of the sudden fall in
blood pressure and airway obstruction
THERAPY OF TYPE I HYPERSENSITIVITY REACTIONS:
The therapy for immediate hypersensitivity reactions (Type I) is aimed at
1- Inhibiting mast cell de-granulation
2- Antagonizing ( stop) the effects of mast cell mediators
3- Reducing inflammation
You need to know and memorize the ENTIRE table
Please, pay attention to the information framed in RED
II- Desensitization
Desensitization involves repeated administration of small doses of an allergen,
that may stop the allergic response to this allergen ( so that the patient stop being
allergic to this allergen and will not have an allergic response to it in the future)
This treatment may work by changing the T cell response away from TH2
dominance or by inducing tolerance (anergy) in allergen specific T cells.
Evolution and Type I Hypersensitivities:
What is known about IgE antibodies and mast cells is :
IgE antibody and eosinophils are important mechanisms of defense
against helminthic infections
Mast cells play a role in innate immunity against some bacteria.
Anyhow, it is still important to address the following question:
Why evolution has preserved (IgE antibody/mast cell) -mediated allergic immune
response whose major effects are pathologic.??????
There is no good answer to this puzzle!!!!!!!!????????
Moreover, it is NOT understood why common environmental antigens (allergens) induce
immune reactions (that involves TH2 cells….IgE antibodies …. and mast cells) that are
capable of causing considerable damage ( maybe because of genetic factors)
.
TYPE II Hypersensitivity
These are caused by antibodies (other than IgE antibodies).
1- Auto-antibodies and
2- Cross-reacting antibodies:
Definitions:
1- Auto-antibodies (self-reacting) antibodies directed against self antigens. Such
antibodies are generated because of the of that are generated because of the failure
of self-tolerance
2- Cross-reacting antibodies are kind of auto-antibodies that are generated in certain
microbial infections. In these cases the antibodies induced against a particular
microbial antigen is also able to recognize and bind to a self antigen that is very
similar to the microbial antigen to which the antibody was directed against….hence
the name cross-reacting reacting antibodies …..(In this case, microbial infection causes
failure of self tolerance)
An example of microbial Infection that causes the production of cross-reacting
antibodies that are produced against microbial antigens.
.
Type II Hypersensitivity Diseases Caused by Self-Reacting
Auto-antibodies
Type II hypersensitivity is a type of an autoimmune disease that is caused by autoantibodies (self-reacting) that are directed against self antigens found on extracellular
matrix components or cell surface molecules.
A- Autoantibodies bind to self-antigens on extracellular matrix:
In this case, the Fc regions of the auto-antibodies bind to Fc receptors on Macrophages and
Neutrophils causing their activation. Upon activation, these cells, start to release lysosomal
enzymes and Reactive Oxygen intermediates , resulting in inflammation and damage the
adjacent tissues. In addition, the Fc regions of certain autoantibodies resulting in
complement activation causing damage to adjacent tissue. The generated complement
fragments function as chemokines to recruit more leukocyte.
Tissue inflammation mediated by autoantibodies bind to selfantigens on extracellular matrix
B- Auto-antibodies bind to self cell surface antigens (molecules )( Example: on the
surface of erythrocytes and platelets):
In this case, these cells become opsonized by the Fc region of the bound antibodies
and by complement fragments such as C3b. Opsonized cells may be ingested and
destroyed by host phagocytes. In addition, activation of complement on the surface of
these cells may result in their destruction
C- Auto-antibodies bind to certain self antigens (molecules) that function as cell
surface receptors such as hormone receptors or neurotransmitter receptors
In this case, these self-reacting auto-antibodies may interfere with normal cellular
functions ((without causing tissue injury)).
In this case, the target of the auto-antibodies are cell surface receptors..such as
hormone receptors or neurotransmitter receptors) …see examples on next slide
1- Graves’ disease is an autoimmune disease that is caused by self-reacting
autoantibodies directed against hormone receptor (TSH receptor).
Binding of self-reacting auto-antibodies to the hormone receptor may directly activate
receptors ( mimicking their physiologic effect of hormone binding to this receptor)
A form of hyperthyroidism called Graves’ disease: In this case, self reacting autoantibodies antibodies against the receptor for thyroid-stimulating hormone (TSH)
stimulate thyroid cells to produce large amounts of T2 and T4 hormone ………
2- Myasthenia gravis is an antoimuune disease that is caused by self-reacting auto
antibodies directed against neurotransmitter receptor ( Acetylcholine receptor) :
Myasthenia gravis is a autoimmune disease that is mediated by self-reacting
autoantibodies directed against the acetylcholine receptor on muscles. This will inhibit
neuromuscular transmission, causing paralysis.
Self-reacting auto-antibodies interfering with normal cellular functions, such as
hormone or a neurotransmitter receptor
You need to know and memorize this table
DO NOT MEMORISE THIS TABLE
Type II Hypersensitivity Diseases Caused Cross-Reacting
Antibodies:
Remember that cross-reacting antibodies are kind of auto-antibodies that are generated
during certain microbial infections. In these cases the antibodies induced against a
particular microbial antigen is also able to recognize and bind to a self antigen that is very
similar to the microbial antigen to which the antibody was directed against….hence the
name cross-reacting antibodies …..
During infection with certain microbes, the infecting microbe may cause failure of self
tolerance to trigger the generation of cross-reacting antibodies that recognize both
microbial and host self antigens at the same time
The indicate that the infecting microbial pathogen has an antigen that is very similar to host
antigen….in this case the induction of an immune response to the microbial antigen could
be behind the failure of self tolerance to that antigen
Examples of clinical situations caused by microbial induced cross-reaction antibodies (Type
II hypersensitivity caused by cross-reacting antibodies ):
1- Gummas seen during the late stages of case of Syphilis (Caused by the bacterial pathogen
Treponama pallidum)
2- Arthritis as well as Cardiac and Neuronal complications that are seen during the late
stages of Lyme disease, (caused by the bacterial pathogen Borrelia burgdorferi)
3- Rheumatic fever: cross-reacting antibodies that could be generated in response to certain
strains of the bacterial pathogen Streptococcus pyogenes that bind to heart valves heart
and results in inflammation of heart valves ( one of the clinical situations described as poststreptococcal complications)
Type III Hypersensitivity
Type III Hypersensitivities are autoimmune diseases that are mediated by immune
complexes generated by:
1- Self-reacting auto-antibodies directed against soluble self antigens
2- Cross-reacting antibodies directed against soluble self antigens
These immune complexes tend to deposit in blood vessels specially:
1- At turbulence sites where blood vessels make branches or
2- In blood capillaries with high pressure (such as these found in Glomeruli of the kidneys
and synovium of joints).
Immune complexes deposited (precipitate) in blood vessels induce inflammation by
attracting and activating leukocytes as well as activating complements by the Fc region of
antibodies in immune complexes. Activation of phagocytes and complement resulting in
the destruction to adjacent cell and tissue such as endothelial cells of blood vessels . In
addition, the complement by-products that recruit leukocytes and induce inflammation.
Accordingly, Immune complex diseases tend to be systemic complications and often
manifested as vasculitis, arthritis, and nephritis.
Examples of a type III hypersensitivity disease:
1- Glomerulonephritis: which is one the clinical conditions of post-streptococcal
complications. This clinical situation is induced by the formation of immune complexes by
cross-reacting antibodies seen in response to infections caused by certain strains of
Streptococcus pyogenes. Glomerulonephritis may lead to renal failure ( Type III
hypersensitivity caused by cross-reacting antibodies)
2- Serum sickness: is induced by systemic administration of a protein antigen, which
induces an antibody response and leads to the formation of circulating immune
complexes.
Example: human serum sickness can occur after a person receives injections of serum
from other individuals or animals, which sometimes is used for the treatment of
snakebite or exposure to rabies virus.
3- The Arthus reaction : an an autoimuune reaction that is mediated by immune
comlexes in experimental animals
Initially, an experimental animal is injected by a foreign protein that induces an
immune response that generates antibodies . After certain period of time, the
same animal that was previously immunized is injected again by the same foreign
protein. This results in the formation of immune complexes in blood vessels at the
site of the second injection resulting in a local cutaneous vasculitis
Some More examples of human diseases that are caused by the
deposition of immune complexes
THERAPY OF TYPE II and TYPE III
HYPERSESNISTIVITIES
Therapy for these diseases aims to reduce inflammation and its injurious
consequences with drugs such as
1- Corticosteroids
2- Plasmapheresis is used to reduce levels of circulating
antibodies or immune complexes.
3- Treatment of patients with an antibody specific for CD20, a surface
protein of mature B cells, results in depletion of the B cells (it is useful for treating
antibody and immune complex–mediated diseases)
Novel approaches for inhibiting the production of auto-antibodies
1- Antagonists that block CD40L and thus inhibit helper T cell–dependent B
cell activation.
2- Attempts to induce of tolerance in cases auto-antigens are known.
These newer therapies are at the stage of preclinical testing and early clinical
trials.
(Delayed Type Hypersensitivity Reactions)
Type IV Hypersensitivity Reactions
Delayed Type Hypersensitivity Reactions are caused by
1- Autoimmunity due to activation of self-reacting T cells ( failure of self tolerance) and
2- By responses to environmental antigens.
Note: T cell-mediated autoimmune diseases tend to be limited to a particular organs or
tissue and are not usually systemic.
1- Autoimmunity Caused By Self Reacting T cells :
These autoimmune reactions mediated by self reacting T cells are usually directed
against particular cellular antigens with restricted tissue distribution. ( most likely
because of the failure of self tolerance)
2- By responses to environmental antigens.
A- Contact sensitivity to chemicals is a T cell-mediated reaction.
B- Tissue injury also may accompany T cell responses to microbes.
1- In tuberculosis, a T cell–mediated immune response is raised against Mycobacterium
tuberculosis. However, the response becomes chronic because the infection is difficult to
eradicate the bacterium ( Mycobacterium tuberculosis)
The resultant granulomatous inflammation causes injury to normal tissues at the site of
infection.
2- In hepatitis virus infection, the virus itself may not be highly cytopathic, but the
cytotoxic T lymphocyte (CTL) response to infected hepatocytes may cause liver injury
3- Superantigens cause massive-nonspecific polyclonal T cell activation by certain
microbial toxins produced by some bacteria and viruses .
These toxins are called super antigens that bind to invariant parts of T cell receptors
on many different clones of T cells, regardless of antigen specificity of the TCR
This causes massive non-specific activation of these T cells that can lead to production
of large amounts of inflammatory cytokines, that may lead to life-threatening clinical
condition know that is called septic shock (or similar to Bacterial toxic shock)
.
.
Mechanisms of Tissue Injury In Type IV Hypersensitivity Reactions
T cell-mediated tissue injury seen in a delayed-type hypersensitivity reaction is
mediated by CD4+ T cells or CD8+ CTLs ( or BOTH) (Fig. 11-11).
The mechanisms of tissue injury are the same as the mechanisms used by T cells to eliminate
cell-associated microbes.
1- The Role of CD4+ T cells:
CD4+ T cells may react against cell or tissue antigens and secrete cytokines that induce local
inflammation and activate macrophages. Different diseases may be associated with
activation of TH1 and TH17 cells.
TH1 cells are the source of IFN-γ, the principal macrophage activating cytokine
TH17 cells are thought to be responsible for recruitment of leukocytes, including
Neutrophils.
Tissue damage mediated by self reacting CD4+ T cells seen in autoimmune diseases is
caused due to excessive activation the Macrophages and Neutrophils ( this may lead to
release of lysosomal enzymes and free radicals from activated cells, which cause tissue
injury)
2- The Role of CD8+ T cells
CD8+ T specific for antigens on host cells may directly kill these cells.
NOTE: In many T cell-mediated autoimmune diseases, both CD4+ T cells and CD8+ T
cells specific for self antigens are present, and both contribute to tissue injury.
Mechanisms of T cell–mediated tissue injury. T cells may cause tissue injury and disease by
two mechanisms: (1) delayed type hypersensitivity reactions (A), which may be triggered by
CD4+ and CD8+ T cells and in which tissue injury is caused by activated macrophages and
inflammatory cells, and (2) direct killing of target cells (B), which is mediated by CD8+ CTLs.
Note: APC, antigen-presenting cell; CTLs, cytotoxic T lymphocytes.
T cell Mediated Autoimmune Diseases are Typically Chronic and
Progressive.
This is because of the following reasons:
1- Continuous T cell-macrophage interactions tend to amplify the autoimmune
reaction. (self reacting T cells )
2- In T cell mediated autoimmune diseases, persistent tissue injury result in the
release of hidden self protein antigens OR alteration of self proteins. ( release of
self proteins that are not usually exposed to T cells)
This may result in exacerbating the autoimmune disease ( as well as tissue injury) due
to activation of T cells that are specific for the above mentioned proteins
This phenomenon of exacerbation of T cell mediated autoimmune diseases is called
“epitope spreading” to indicate that the initial immune response against one or a few
self antigen epitopes may expand to include responses against many more self ntigens.
Chronic inflammatory diseases that are initiated by self reacting T cells immune
reactions are called T Cell mediated -mediated inflammatory diseases.
The therapy for T cell–mediated hypersensitivity disorders is designed to
reduce inflammation.
This could be achieved by:
1- Using corticosteroids
2- Antagonists against cytokines (such as TNF). Antagonists of TNF have proved to be
beneficial in patients with rheumatoid arthritis and inflammatory bowel disease.
3- Inhibition of T cell responses with immunosuppressive drugs such as cyclosporine.
Many newer agents are being developed to inhibit T cell autoimmune responses
such as .
1- These include agents that block co-stimulators such as B7
2- Antagonists against cytokines receptors such as IL-2 receptor
3- Induction of tolerance in self reacting T cells (so far, no successful clinical trials
have been reported yet)
Note: In the previous table, please, pay attention to the genetic association. Some of these
genes (mutation in these genes) were discussed in the chapter of TOLEANCE. Mutations in
the genes (PTPN22 and NOD-2) may be the reason behind the failure of self tolerance