Ch. 16. Tolerance and Autoimmunity

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Ch. 16. Tolerance and Autoimmunity Tolerance
sometimes is broken - self reactive cells do
form, but are usually inactivated or
suppressed Failure of tolerance leads to
autoimmunity Damage can be antibody-mediated
and/or T-cell mediated Systemic vs.
organ-specific Females gt males (p.416)
Tendency sometimes runs in families If one,
may have gt one autoimmune disease
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Establishment and maintenance of
tolerance Tolerance is a state of
unresponsiveness to an antigen (Ag) it is
specific To establish tolerance, it helps to
have High doses of Ag Soluble form of Ag
Persistence of Ag in host Intravenous or oral
administration of Ag Absence of adjuvants Low
levels of costimulators
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Central tolerance Deletion of lymphocytes that
react with self Ags in the primary lymphid
organs (thymus T cells, bone marrow B
cells) Peripheral tolerance Deletion or
rendering anergic any lymphocytes that react
with self Ags in the secondary lymphoid organs

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p. 402
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p. 403
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Organ-specific target is a molecule unique to
that organ Hashimotos thyroiditis Th1 cells
and autoantibodies specific for thyroid Ags
? infiltration of thyroid by L, M, and PCs ?
hypothyroidism Chronic inflammation and
enlargement Others AIHA, Goodpastures syndrome
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normal
p. 408
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Hashimotos thyroiditis
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Goodpastures syndrome Antibodies to membrane
antigens in kidney and alveoli in
lungs Complement activation, cell
damage, inflammation IDDM (insulin-dependent
diabetes mellitus) both T and B cells
involved CTLs, autoantibodies subsequent DTH
response kills pancreatic beta cells that make
insulin
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p. 408
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IDDM
p. 409
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Antibodies to receptors Graves disease
Autoantibody mimics TSH, leads to
constant thyroid stimulation Myasthenia
gravis Autoantibody blocks ACh receptor,
eventually destroys it
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p. 410
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p. 410
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Systemic diseases- damage is widespread Systemic
lupus erythematosis autoantibodies to DNA, RNA,
histones, leukocytes, RBCs, platelets,
clotting factors anti-nuclear antibodies (ANA)
are diagnostic Type II, III and inflammatory
damage elevated C3a and C5a, vasculitis 101
female to male ratio 20-40 yr-old women
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Multiple sclerosis T cell mediated Myelin
sheath of nerves targeted CNS attacked by
inflammatory lesions Starts in 20-40 yr. old
people Rheumatoid arthritis Chronic
inflammation of the joints Starts in 40-60 yr.
old women Many produce rheumatoid factors
(RFs), IgM autoAbs that react with Fc of IgG
IgM-IgG complexes deposited in joints ?
Type III inflammatory reaction
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p. 412
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How does autoimmunity occur? Transferred by T
cells (CD4 cells specifically) TH1 cells
transfer disease TH2 cells protect against it
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p. 413
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In Ab-caused autoimmune diseases, Autoantibody
can be transferred from patient to recipient,
then symptoms appear in recipient Graves
disease can be transferred from human to
rat Also autoAbs can go from mother to fetus -
child is born with Graves disease treated by
plasmapheresis
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p. 415
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Why does autoimmunity occur? Many
possibilities 1. Release of sequestered
antigens- seen, so L not deleted in T cell
development MBP heart muscle proteins nuclear
antigens sperm In animals, can avoid
autoimmune disease by injection of sequestered
antigen into thymus ? tolerance
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2. Molecular mimicry Several viruses and
bacteria have ID or similar Ags to self-
Ags 3 of anti-viral mAbs react with
normal tissue Ags Post-rabies encephalitis
when virus grown in rabbit TC
Post-streptococcal rheumatic heart disease
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p. 418
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• 3. Inappropriate expression of class II MHC
• Wrong cells induced to express MHC Class II
• antigen (and act as APCs) IDDM, Hahimotos
• Additional signals,
• such as IFN-gamma ?IL-1 and TNF
• Polyclonal B cell activation by CMV, EBV,
• and some G-negative bacteria
• - T-cell-independent
• - Large amounts of IgM produced

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Treatment of autoimmune disease Reduce
symptoms Immunosuppression Corticosteroids,
azathioprine, cyclophosamide Removal of
thymus (MG) Plasmapheresis Short-term
relief (MG, Graves disease, RA, SLE)
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Treatment of autoimmune disease (contd) Reduce
inflammation TNF-alpha blockers (RA, Crohns
dis., psoriasis) e.g., Enbrel, Remicade, Humira
IL-1 receptor antagonist (RA) Abs against
IL6R and IL-15R Statins, shown to lower CRP
(RA, MS) Rituxin monoclonal Ab
anti-CD20 Eliminates B cells in non-Hodgkins
lymphoma (maybe also RA, and other
Ab-mediated autoimmune diseases)
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Possible experimental approaches
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T cell vaccines (against activated Ag-specific
T cells) Interfere with antigen presentation
(anti-MHC) Monoclonal antibodies against a
variety of target antigens Oral induction of
tolerance (MS) So far, efforts have been more
successful in mice than humans