ch. 16. tolerance and autoimmunity tolerance sometimes is broken
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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 - PowerPoint PPT PresentationTRANSCRIPT
Ch. 16
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 mediatedSystemic vs. organ-specificFemales > males (p.416) Tendency sometimes runs in familiesIf one, may have > 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 AgSoluble form of Ag Persistence of Ag in hostIntravenous or oral administration of AgAbsence of adjuvantsLow levels of costimulators
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Central tolerance
Deletion of lymphocytes that react with self Ag’s in the primary lymphid organs (thymus = T cells, bone marrow = B cells)
Peripheral tolerance
Deletion or rendering anergic any lymphocytes that react with self Ag’s in the secondary lymphoid organs
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p. 402
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p. 403
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Organ-specifictarget is a molecule unique to that organ
Hashimoto’s thyroiditis
Th1 cells and autoantibodies specific for thyroid Ag’s infiltration of thyroid
by L, M, and PC’s hypothyroidism
Chronic inflammation and enlargement
Others: AIHA, Goodpasture’s syndrome
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normal
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Hashimoto’s thyroiditis
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Goodpasture’s 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 involvedCTLs, autoantibodies
subsequent DTH response kills pancreatic
beta cells that make insulin
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IDDM
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Antibodies to receptors
Grave’s disease
Autoantibody mimics TSH, leads to constantthyroid stimulation
Myasthenia gravis
Autoantibody blocks ACh receptor, eventually destroys it
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p. 410
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Systemic diseases- damage is widespread
Systemic lupus erythematosis
autoantibodies to DNA, RNA, histones, leukocytes, RBC’s, platelets, clotting factorsanti-nuclear antibodies (ANA) are diagnostic
Type II, III and inflammatory damage; elevated C3a and C5a, vasculitis
10:1 female to male ratio; 20-40 yr-old women
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Multiple sclerosisT cell mediatedMyelin sheath of nerves targetedCNS attacked by inflammatory lesionsStarts in 20-40 yr. old people
Rheumatoid arthritis Chronic inflammation of the joints Starts in 40-60 yr. old women Many produce rheumatoid factors (RF’s),
IgM autoAb’s that react with Fc of IgG IgM-IgG complexes deposited in joints Type III inflammatory reaction
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How does autoimmunity occur?
Transferred by T cells (CD4+ cells specifically)
TH1 cells transfer diseaseTH2 cells protect against it
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In Ab-caused autoimmune diseases,
Autoantibody can be transferred from patientto recipient, then symptoms appear in recipient
Graves’ disease can be transferred from humanto rat
Also autoAb’s can go from mother to fetus - child is born with Graves’ diseasetreated by plasmapheresis
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Why does autoimmunity occur? Many possibilities:
1. Release of “sequestered antigens”- seen, so L not deleted in T cell development
MBPheart muscle proteinsnuclear antigenssperm
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 Ag’s to self- Ag’s
3% of anti-viral mAb’s react with normal tissue Ag’s
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 IIantigen (and act as APCs) – IDDM, Hahimoto’s
Additional signals, such as IFN-gamma IL-1 and TNF
4. 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
ImmunosuppressionCorticosteroids, azathioprine, cyclophosamide
Removal of thymus (MG)
Plasmapheresis Short-term relief(MG, Grave’s disease, RA, SLE)
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Treatment of autoimmune disease (cont’d)
Reduce inflammation TNF-alpha blockers (RA, Crohn’s dis., psoriasis)
e.g., Enbrel, Remicade, Humira IL-1 receptor antagonist (RA) Ab’s against IL6R and IL-15R Statins, shown to lower CRP (RA, MS)
Rituxin = monoclonal Ab = anti-CD20Eliminates 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 successfulin mice than humans