Autoimmunity

Tolerance sometimes is brokenself reactive cells do form, but are usually

inactivated or suppressed

Damage can be antibody- or T-cell mediated

Some disease are systemic, others organ-specific

Organ-specifictarget is a molecule unique to that organ

Hashimoto’s thyroiditisT cell and antibody mediatedinflammation leads to goiter

antibodies to thyroid protein interfere withiodine uptake

Graves’ disease (TSH receptor)MS- myelin

Goodpasture’s syndrome

Antibodies to membrane antigens in kidney andalveoli

Complement activation, cell damage, inflammation

IDDM (insulin-dependent diabetes mellitus)both T and B cells involvedCTLs, autoantibodies

subsequent DTH response kills beta cells

Antibodies to receptors

Graves- disease

Autoantibody mimics TSH, leads to constantthyroid stimulation

Myasthenia gravis

Autoantibody blocks Ach receptor, eventuallydestroys it

Multiple sclerosis- T cell mediated

Rheumatoid arthritis: IgM autoantibodies thatreact with IgG Fc

Systemic diseases- damage is widespread

Systemic lupus erythematosis

autoantibodies to everythinganti-nuclear antibodies are diagnostic

Type II, III and inflammatory damage

p. 466

How does autoimmunity occur?

Transferred by T cells (CD4+ cells specifically)

TH1 cells transfer disease

TH2 cells protect against it

Role for mast cells? (Lee et al., Science, 9/6/02)Inflammatory arthritisComplementFc receptorsCytokines (esp. TNF-)

Mast cells produce lots of cytokinesActivated by immune complexes?

“Adoptive transfer” p. 467

Autoantibody can be transferred from patientto recipient

Graves’ disease can be transferred from humanto rat

Also from mother to fetuschild is born with Graves’diseasetreated by plasmapheresis

Why does autoimmunity occur?

“sequestered antigens”- normally not seen, sonot deleted, in T cell development

MBPheart muscle proteinsnuclear antigenssperm

Avoid by injection of antigen into thymus?

p. 469

Hormonal status of patient

Many autoimmune diseases are more frequentin one sex than the other

(Ankylosing spondylitis in men; MS, SLE, Graves’disease, RA in women)

Onset during reproductive years

(RA- remission during pregnancy?)

p. 510

“Wrong” cells induced to express MHC Class IIantigen (and act as APCs)maybe additional signals, such as IL-1and TNF

Polyclonal B cell activationT cell independentLarge amounts of IgM produced

Treatment of autoimmune disease

Immunosuppression

Removal of thymus

Plasmapheresis

Experimental approaches p. 475

T cell vaccines (Ag-specific T cells)

Interfere with antigen presentation

Monoclonal antibodiesvariety of target antigens

Oral induction of tolerance

So far, efforts have been more successfulin mice than humans