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TOLERANCE& AUTOIMMUNITY
Topic Overview
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Concept and significance of tolerance
Factors which determine induction of tolerance
Mechanism of tolerance induction
Concept of autoimmunity and disease
Features of major autoimmune diseases
Examples of autoimmune diseases.
Theories on aetiology of autoimmune diseases
Definition
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Autoimmunity is a state in which the body’s
immune system fails to distinguish between
self and non self by formation of auto
antibodies against one’s own tissues
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A condition that occurs when the immune
system mistakenly attacks and destroys
healthy body tissue
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Loss of immunologic tolerance to one’s own
tissue
autoimmunity
Immunological tolerance
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Is a type of specific unresponsiveness to an
antigen induced by the exposure of specific
lymphocytes to that antigen, but respond to
other antigens normally
It is a normal phenomenon present from fetal life
of an individual to recognize self tissues and
antigens
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This protects ability of individual’ immune system
to mount a response towards their own antigens,
regarded as self.
By so doing the individual avoids attacking and
destroying oneself
Aspect of immune tolerance
Natural or "self" tolerance.
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This is the failure to attack the body's own proteins
and other antigens.
This protect the body from developing
autoimmune diseases.
Induced tolerance.
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This involves tolerance to external antigens.
It is created by manipulating the immune system.
This provide protection from allergic reactions
acquired from food (e.g. peanuts), insect stings, or
grass pollen (hay fever).
Tolerance Mechanisms
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The mechanisms the immune system uses to
ensure the absence of self-reactivity
(autoimmunity) include:
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Central Tolerance - this occurs during lymphocyte
development.
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Peripheral Tolerance - occurs after lymphocytes
leave the primary lymphoid organs.
Central Tolerance
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Operates in the thymus and bone marrow.
Clonal deletion of T and B lymphocytes that
recognize self antigens which occurs before they
develop into fully immunocompetent cells in
order to prevent autoimmunity.
This process is most active in fetal life
It may also continue throughout life as immature
lymphocytes are generated.
Central Tolerance
Peripheral Tolerance
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This is deletion of those self-reactive T&B cells
that escape central tolerance achieved by 3
mechanisms
-Clonal deletion
-Clonal anergy
-Peripheral suppression by T cells
Peripheral Tolerance
Tolerance
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When an antigen induces tolerance, it is
termed tolerogen.
Tolerance is specific and like immunological
memory, it can exist in T-cells, B cells or both
Like immunological memory, T cell tolerance
is longer lasting than B cell tolerance.
Tolerance to tissues and cells
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Tolerance to tissue and cell antigens can be induced by
injection of hemopoietic (stem) cells in neonatal or
severely immunocompromised (by lethal irradiation or
drug treatment) animals.
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Also, grafting of allogeneic bone marrow or thymus in
early life results in tolerance to the donor type cells and
tissues.
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Such animals are known as chimeras. These findings
are of significant practical application in bone marrow
grafting.
Tolerance to soluble antigens
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A state of tolerance to a variety of Tdependent and T-independent antigens has
been achieved in various experimental
models.
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Based on these observations it is clear that a
number of factors determine whether an
antigen will stimulate an immune response
or tolerance
Tolerance
Tolerance cont……..
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Induction of tolerance in T cells is easier and
requires relatively smaller amounts of tolerogen
than tolerance in B cells.
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Maintenance of immunological tolerance requires
persistence of antigen.
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Tolerance can be broken naturally (as in
autoimmune diseases) or artificially (as shown in
experimental animals, by x-irradiation, certain drug
treatments and by exposure to cross reactive
antigens).
Ignorance
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It is a passive form of immunological
tolerance
It can be shown that there are T cells and B
cells specific for auto-antigens present in
circulation.
These cells are quite capable of making a
response but are unaware of the presence of
their auto-antigen.
Ignorance cont….
This arises for 2 reasons
The antigen may appear in a very low
concentration.
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Since all lymphocytes have a threshold for
receptor occupancy which is required to trigger
a response then very low concentrations of
antigen will not be sensed.
Ignorance……
2.Some antigens are sequestered from the
immune system in locations which are not
freely exposed to surveillance, e.g. eye, CNS
and testis.
 Pathologically mediated disruption of these
privileged sites may expose the sequestered
antigens leading to an autoimmune response.
Mechanism of tolerance induction
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Clonal deletion:
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Functionally immature cells of a clone
encountering antigen undergo a
programmed cell death, as auto-reactive Tcells are eliminated in the thymus following
interaction with self antigen during their
differentiation
Mechanism of tolerance induction
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Lymphocytes & many cells express Fas(CD95)
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The ligand for Fas(Fas L) is expressed on activated
T lymphocytes
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The engagement of Fas by Fas L,coexpresed on
activated T cells, dampens the immune response by
inducing apoptosis of the activated T lymphocytes
Mechanism of tolerance induction
2.
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Clonal anergy:
Auto-reactive T cells, when exposed to antigenic
peptides which do not possess co-stimulatory
molecules, become anergic to the antigen
In addition, B cells when exposed to large
amounts of soluble antigen down regulate their
surface IgM and become anergic.
Mechanism of tolerance induction
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These cells also up-regulate the Fas
molecules on their surface.
An interaction of these B cells with Fasligand-bearing cells results in their death via
apoptosis.
Mechanism of tolerance induction
Receptor editing:
 B cells which encounter large amounts of
soluble antigen, as they do in the body, and
bind to this antigen with very low affinity
become activated to re-express their RAG-1
and RAG-2 genes.
 These genes cause them to undergo DNA
recombination and change their antigen
specificity.
Mechanism of tolerance induction
Anti-idiotype antibody:
 Anti-idiotype antibodies produced experimentally
 Have been demonstrated to inhibit immune response to
specific antigens.
 They are produced during the process of tolerization.
 May respond to the unique receptors of other
lymphocytes and serve to shut off antigen specific
responses.
 Therefore, they prevent the receptor from combining
with antigen.
Mechanism of tolerance induction
Termination of tolerance
 Experimentally induced tolerance can be
terminated by prolonged absence of
exposure to the tolerogen, by treatments
which severely damage the immune
system (x-irradiation) or by immunization
with cross reactive antigens.
 These observations are of significance in
the conceptualization of autoimmune
diseases.
Mechanism of tolerance induction
Suppressor cells:
 Both low and high doses of antigen may
induce suppressor T cells (Regulatory T
cells) which can specifically suppress
immune responses of both B and T cells,
either directly or by production of cytokines,
most importantly, TGF-b and IL-10.
Regulatory T cells
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CD4+ T lymphocytes that express high levels
of IL-2r a chain (CD25) but not other markers
of activation.
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Regulatory T cells may be generated by self
antigen recognition in the thymus or in the
periphery.
AUTOIMMUNE DISEASES
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Defination:
Autoimmune diseases are disorders in which
the body's immune system reacts against
some (or all) of its own tissue and produces
antibodies to attack itself
Causes of Autoimmunity
Epidemiology
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About 3% of US population is affected by
autoimmune disorders
Women are most frequently affected e.g.
85% of SLE, Scleroderma and thyroiditis are
women.
Higher Mortality and morbidity is reported
among the young and middle aged.
Twin studies have been widely used in
studies of familial tendencies of AID’s
Pathogenesis
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The exact etiology of autoimmune disease is
not known
However the pathogenesis of autoimmunity
appears to involve immunologic, genetic and
microbial factors interacting through several
mechanisms
Mechanisms leading to failure of peripheral
tolerance contributes to the pathogenesis of
autoimmune diseases.
Immunological
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This involves failure of immunological
mechanism of tolerance e.g.
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Polyclonal activation of B-cells
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Escape of auto reactive clones
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Failure of Apoptosis of auto reactive T cells
Genetic factors
Evidenced by:
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increased expression of class II HLA antigens
on tissues involved in autoimmunity
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Increased familial incidence of some of the
autoimmune disorders
Microbial factors
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Infections with organisms, particularly viruses
eg ( EBV infection), Bacterial (streptococci,
Klebsiella and mycoplasma has been
implicated in the pathogenesis of auto
immune diseases
Autoimmunity Classification
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b)
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Autoimmunity can affect ANY organ/organ
system in the human body
Classified into 2 groups depending on the
type of auto antibody formation.
Organ specific diseases
Non organ specific (systemic) diseases
Both – can get overlap
Organ specific
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Organ specific means the auto-immunity is
directed against a component of one particular
type of organ.
Examples of organ specific auto.
diseases
Lungs of a patient
with Goodpasture’s
Hashimoto’s disease
(thyroiditis
Vitiligo
Hashimoto's Thyroiditis
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Hashimoto's Thyroiditis is a type of autoimmune
thyroid disease in which the immune system
attacks and destroys the thyroid gland.
The thyroid helps set the rate of metabolism the rate at which the body uses energy.
Hashimoto’s prevents the gland from producing
enough thyroid hormones for the body to work
correctly.
It is the most common form of Hypothyroidism
(underactive thyroid).
Hashimoto’s Thyroiditis cont…
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Organ specific disease affecting the thyroid
gland.
Most often seen in women 30 to 40 years old,
may be genetic predisposition.
Causes diffuse hyperplasia in the gland
resulting in development of a goiter.
Thyroid autoantibodies are formed.
Symptoms
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The most common symptoms includes:
Goiter (enlarged thyroid gland which may cause a
bulge in the neck)
 Other endocrine disorders such as diabetes, an
underactive adrenal gland, underactive parathyroid
glands, and other autoimmune disorders
 Fatigue
 Muscle weakness
 Weight gain
However, each individual may experience symptoms
differently:
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Thyroid hormones are produced by the thyroid
gland. This gland is located in the lower part of
the neck, below the Adam's apple.
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The gland wraps around the windpipe
(trachea) and has a shape that is similar to a
butterfly - formed by two wings (lobes) and
attached by a middle part (isthmus).
Goiter
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This enlargement is due to the inflammatory
cells which destroy thyroid cells, resulting in
long term scarring. When the cells are
damaged they cease thyroid hormone
production, resulting in hypothyroidism
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A goiter only needs to be treated if it is
causing symptoms.
Laboratory diagnosis
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Hashimoto's thyroiditis is simply diagnosed
by two blood tests.
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Routine thyroid function tests to confirm that
a patient has an underactive thyroid gland.
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Anti-microsomal and anti-thyroglobulin
antibodies are immune cells which the body
produces to attack specific portions of the
thyroid cells which pinpoint Hashimoto's
thyroiditis as the cause of the
hypothyroidism.
Lab. Diagnosis cont..
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The anti-microsomal antibody test is much
more sensitive than the anti-thyroglobulin,
therefore some doctors use only the former
blood test.
These thyroid auto-antibodies blood tests are
high in about 95% of patients with
Hashimoto's thyroiditis, but are not
diagnostic.
Treatment
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Thyroid hormone replacement.
Spontaneous remissions have occurred.
The enlarged thyroid can be treated with
radioactive iodine to shrink the gland or
with surgical removal of part or all of the
gland (thyroidectomy).
Small doses of iodine (Lugol's or potassium
iodine solution) may help when the goiter is
due to iodine deficiency.
Non organ specific (systemic)
autoimmune diseases
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Systemic autoimmunity is directed against an
antigen that is present at many different sites
and can involve several organs
Examples of systemic autoimmune
Systemic Lupus Erythematosus
(SLE)
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Chronic, systemic inflammatory disease caused
by immune complex formation.
The word "systemic" means the disease can
affect many parts of the body.
Pathophysiology associated with clinical
features secondary to immune complexes
depositing in tissues resulting in inflammation.
Parts of the body affected include: the joints,
skin, kidneys, heart, lungs, blood vessels, and
brain.
SLE cont…
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Peak age of onset is 20 to 40 years of age.
Found more frequently in women.
Has both genetic and environmental factors.
SLE clinical signs
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Extremely diverse and nonspecific.
Joint involvement most frequent sign:
polyarthralgia and arthritis occur in 90% of
patients.
Skin manifestations next most common.
Erythematosus rash may appear.
Most classic is butterfly rash.
SLE clinical signs cont…
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Renal involvement very common.
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Caused by deposition of immune complexes in
kidney tissue.
Leads to renal failure, most common cause of
death.
Other systemic effects:
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Cardiac
Central nervous system.
Hematologic abnormalities.
SLE Laboratory diagnosis
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Screening test for anti-nuclear antibodies
(ANA)
Antibodies directed against nuclear material of
cells.
Flourescent anti-nuclear antibody (FANA) most
widely used, extremely sensitive, low
diagnostic specificity.
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Animal or human cells fixed to slide.
Add patient serum and incubate.
Wash to remove un-reacted antibody.
Add anti-human globulin labeled with
fluorescent tag or enzyme.
Antinuclear Antibody Test
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Antinuclear antibodies (ANA) are
autoantibodies against various cell nucleus
antigens and are found in patients with
autoimmune diseases such as SLE.
Some of ANA are considered to be useful for
diagnosis of autoimmune diseases.
Treatment
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Aspirin and anti-inflammatories for fever
and arthritis.
Skin manifestations-anti-malarials or
topical steroids.
Systemic corticosteroids for acute
fulminant lupus, lupus nephritis or central
nervous system complications.
Five year survival rate is 80 to 90%.
Rheumatoid Arthritis
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Chronic inflammatory disease primarily
affecting joints, but can affect heart, lung and
blood vessels.
Women three more times as likely as men to
have it.
Typically strikes at ages between 20 and 40,
but can occur at any age.
Involves joint pain, inflammation, and
stiffness.
Clinical Signs
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Morning stiffness lasting 1 hour.
Swelling of soft tissue around 3 or more joints.
Swelling of hand/wrist joints.
Symmetric arthritis.Subcutaneous nodules
Positive test for rheumatoid factor.
Xray evidence of joint erosion.
Immunologic Findings
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Rheumatoid Factor (RF) is an IgM antibody
directed against the Fc portion of the IgG
molecule, it is an anti-antibody.
Not specific for RA, found in other diseases.
Immune complexes form and activate
complement and the inflammatory response.
Enzymatic destruction of cartilage is followed
by abnormal growth of synovial cells
Rheumatoid Arthritis
Diagnosis
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Diagnosis is based on:
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Clinical findings.
Radiographic findings
Laboratory testing.
Laboratory tests involve testing patients serum
with red blood cells or latex particles coated with
IgG, agglutination is a positive result.
Nephelometry and ELISA techniques are
available to quantitate the RF.
Erythrocyte Sedimentation Rate (ESR) used to
monitor inflammation.
C-Reactive protein (CRP) is utilized to monitor
inflammation
• Treatment
Treatments of RA include:
NSAIDs, glucocorticoids,
DMARDs, and biological agents. of
the pathophysiology of RA