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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Ch. 16

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

Ch. 16 p. 408

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

Ch. 16 p. 408

Ch. 16 p. 409

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

Ch. 16p. 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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Ch. 16

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

Ch. 16 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

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