Transcript 241.Autoimmunity

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In innate Immunity,
 Relies upon a set of genetically encoded receptors
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In adaptive Immunity
 A system evolved to discriminate between self and
non-self signals. This is developed during fetal life
 This system is not so efficient, so there must be a
system that identifies self-reactive cells (lymphocytes
that attack our own body) and kill them,
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If the body fails to inactivate self-reactive cells,
this will lead to autoimmunity.
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Tolerence: is when the immune system doesn’t
respond to a particular antigen.
 In normal cases, the immune system is tolerant to
self antigns.
 Cells which are not self-tolerant are self-reactive
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To ensure self-tolerance, the self-reactive Band T- lymphocytes should be deleted or
inactivated.
 This deletion or inactivation may be in early
development (central tolerance)
 Or may be applied to the lymphocytes in the
periphery (peripheral tolerance).
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Occurs during early
differentiation of B cells in
bone marrow and T cells in
the thymus (in primary
lymphoid organs)
The cell (T or B) that binds
to self antigens is deleted by
apoptosis.
The elimination of selfreactive
In the thymus, the
elimination of self-reactive T
cells involves contact with
APC presenting selfpeptides.
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Some of the T and B
cells are still selfreactive and they are
either inactivated
(by clonal anergy) or
deleted (by
apoptosis) in
peripheral tissues.
(Absence of Costimulation)
Inactive T-cell 
deletion or clonal anergy
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Anergy: a state of
nonresponsiveness
in lymphocytes after
there receptors bind
to antigens or APC.
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In normal cases, for an APC (antigen presenting cell) to
present an antigen to the T cell, it should express also
another signal (B7 molecule) on its surface, that binds to
CD-28 receptor on the surface of the T-cell.
This is called co-stimulation.
So, the T-cell is activated by 2 signals
1)
2)
The MHC molecule (with the antigen)
Co-stimulation signal
- Unless the T-cell gets both these signals, it will not induce
an immune response
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If the co-stimulatory signal is absent, the T-cell
undergoes anergy.
 The self-reactive cells bind to antigens on the
MHC-I and MHC-II cells (body cells) without costimulation. (not good )
 For that, they undergo anergy, and are
inactivated forever.
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If a B-cell is selfreactive, and recognizes
a self-antigen without
the additional necessary
T-cell signals, the B-cell
becomes anergic
The CD4 T-cells
encouters the anergic Bcell and sends a “death
message”, that is Fas
(on B-cell) binds to FasL (on T-cell) to induce
apoptosis. This makes
sure that anergic B-cells
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(A)
(B)
(C)
Autoimmune diseases related to hypersensitivity reactions (II, III
and IV)
Organ specific autoimmune diseases
Proposed mechanisms of Autoimmune diseases
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Autoimmune diseases (AI): diseases
involving an immunological response to
normal tissue.
 Concept:
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 a mutation happens to some receptors on
leukocytes.
 These receptors are specific for a foreign
antigen but when they get mutated, they
form a new class of receptors that are
specific to self antigens
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Autoimmun
e diseases
can be
either
systemic or
organspecific.
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Most of the autoimmune diseases
attributed to autoantibodies (selfreacting antibodies)
 Other autoimmune diseases have an
autoreactive (self-reactive) T cell
component.
 Disease processes and tissue damage
are due to Type II, Type III and Type IV
hypersensitivity reactions.
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Antibody attacks and deposit at a fixed
antigen from the body, e.g. in
extracellular matrix
 This attracts and activates complement
system, which atracts neutrophils and
cause inflammation and tissue injury
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Antigenanitbody
complex
Complement
system
inflammation
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A soluble antigen swimming in the
circulation is caught by a complex of
anitbodies that form insoluble antigenantibody complexes that circulate in
blood, and then they deposit in tissues,
activating complement system and
causing inflammation.
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Mediated through cells (no antibodies
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Direct cellular damage
stimulating or blocking
autoantibodies
• Graves’ disease
• Myasthenia gravis
• Hashimoto thyroiditis:
Autoabs & T DTH
• Autoimmune
Anaemia: Pernicious
A, A hemolytic A,
Drug—induced A.
• Goodpasture’s
syndrome
• Insulin dep. DM
(IDDM)
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Organ-specific AI disease
Autoantibodies bind to the
receptor of thyroid
stimulating hormones
(TSH), causing
overstimulation of the
receptor and so
overstimulation of the
thyroid gland.
 These autoantibodies are
called long-acting thyroid
stimulating hormones
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Organ-specific AI disease
Caused by autoantibodies that block to
nicotonic receptors at neuromuscular junction,
and so prevents Ach from combining to the
receptor. No action potential and no muscle
contraction is produced.
 The patient’s muscles will be flaccid and weak
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Note that unlike grave’s disease, where the
antibodies mimic the action and activate the
receptor, here in myasthenia gravis, the
autoantiobies block the action of the
receptor
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Motor end-plates
of muscles
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1) Systemic Lupus Erythromatosis
(SLE)
- An autoimmune disease affecting
connective tissue all over the
body.
- Variety of symptoms (according to
american college of rheumatology,
if a patient has 4 of these 11
symptoms, he has SLE:
- Molar rash, discoid rash,
photophobia, serositis,
hematologial disorders, renal
disorder, neurological disorder,
oral ulcer,
- For more information, go to wikipedia
(SLE).
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Autoreactive T cells attack the
myelin sheath of nerve fibers,
causing slower nerve signals
that hardly reaches its target.
Affects CNS mainly, but can
affect peripheral nerves, and
that’s why it is a systemic AI
disease
Individuals with
the DR2&DR3
variant of MHC
genes are most
susceptible to
the disease.
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DR, DP and DQ are genes involved with
MHC-II
DA, DB and DC are genes involved with
MHC-I
Individuals with the DR2&DR3 variant of
MHC genes are most susceptible to
multiple sclerosis
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Affects peripheral joints.
 May cause destruction of
both cartilage and bone.
 Affects mainly individuals
carrying the DR4 gene
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There are three proposed mechanisms
that may explain how autoimmune
diseases occur:
1) Sequestered (hidden) antigens
2) Molecular mimicry
3) Inappropriate expression of class II MHC
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Early in life, immature T-cells are exposed
to self-antigens in primary lymphoid organs
to induce self-tolerance.
 Some antigens, called sequestered
antigens, do not appear in the thymus
during this process, and so the T-cells do
not recognize them.
 If the T-lymphocyte encouters these
antigens, they will attack them considering
them as foreign antigens.
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Examples:
 Myelin basic protien (MBP) in Multiple
Sclerosis
 Sperm-associated antigens in some
individuals following vasectomy
 Lens and corneal proteins of the eye
following infection or trauma
 Heart muscle antigens following myocardial
infarction
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Occurs when a virus or a bacterium
posses antigenic determinants that are
very similar or identical to normal host
cell components
 Molecular mimicry may be the initiating
step in a variety of autoimmune
diseases.
 E.g. Rheumatoid fever occurs after
streptococcal infection
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Some normal body proteins (highly specific
proteins) are formed later in life, after the
development of T-cells in primary lymphoid
organs, and so are not presented to T-cells
during their development. And so no clonal
deletion or self-tolerance is developed
against them.
 In normal cases, the T-cell doesn’t attack
them because they do not express MHC-II,
and because they are not circulating in the
blood (they are fixed).
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If abnormally they express MHC-II (in
addition to their MHC-I and the highly
specific proteins), the T-cells will attack
them.
 This is caused by over-production of IFN-γ (due
to a viral infection or so), which will increase the
expression of MHC-II in different cells.
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If the tissue containing the highly specific
proteins gets injured and circulates in the
blood, it will be considered as foreign
antigen  attacked by T-cell.
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Type I Diabetes: Pancreatic β cells express abnormally
high levels of MHC I and MHC II
MHC II – APC only! This may hypersensitize TH cells to
β cell peptides.
Normal Pancreas
Pancreas with Insulitis
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Some viruses and bacteria can induce nonspecific
polyclonal B cell activation, including:
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Certain gram negative bacteria
Herpes simplex virus.
Cytomegalovirus
Epstein Barr Virus
Human immunodeficiency virus (HIV)
They induce the proliferation of numerous clones
of B cells to secrete IgM even without needing CD4
T cell help.
 Polyclonal activation leads to the activation of selfreactive B cells and autoantibody production.
 Patients with mononucleosis (caused by EBV) and
AIDS (HIV) have a variety of autoantibodies.
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•Autoimmunity can be caused by immunological,
genetic, viral, drug-induced, and hormonal factors.
•There are 4 immunological mechanisms of
autoimmunity.
•All mechanisms cause abnormal B or T cell
activation.
•Most instances of autoimmune diseases occur
with multiple mechanisms, which makes treatment
difficult.
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Read & Understand page 470-471
Why are women more susceptible than
men to autoimmunity?
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Problem 1
A 60-year-old woman, presents with atrial fibrillation (abnormal
hearth rhythm). The patient says that for the last several months
she was experienced intermittent palpitation, has lost
approximately ten pounds, and has mild heat intolerance and
frequent bowel movements. Physical examination revealed an
anxious female with slight exophthalmos (protrusion of the
eyeball) and hand resting tremor (involuntary shaking). The
patient also mentioned that her mother also had similar symptoms
many years ago and died because there was no treatment.
Q: What immunologic processes might be involved in her
problems?
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Problem 2
1.What is the association between infection, autoimmunity
and hypersensitivity ?
2.Mention 2 infections which may lead to development
of autoimmunity and the underlying hypersensitivity
causing the pathological tissue damage ?
3.Mention 2 autoimmune diseases in which tissue damage
is caused by more than one hypersensitivity reaction ?
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