Autoimmunity

1. Autoimmunity • Loss of self tolerance leading to immune response to self tissues • May be organ-specific, localized or systemic • Genetic background plays a role in extent & severity of diseases. • Virtually all autoimmune responses are T-dep. • Formation of new or altered epitopes • Sharing epitopes between tissues & agents (molecular mimicry) • Exposure of hidden antigens • Viral infections • Loss of control of lymphocyte responses

2. Assumption of NO autoimmunity- T cell unresponsiveness because of : • Clonal deletion • T-suppression • Clonal anergy • Inadequate anto-antigen presentation

3. Criteria for autoimmune disease • Direct proof • Transferring autoantibodies or self-reactive lymphocytes to healthy individuals & reproduce the disease (for ethical reason, use scid mice) • Indirect proof • Identify target antigen & reproduce the disease in the experimental animals • Genetically predisposed animal models • Isolation of self-reactive antibodies or T cells from the target organs • Circumstantial evidence • Familial tendency • Lymphocyte infiltration or MHC association • Clinical improvement with immune suppressive drugs

5. Causes of Autoimmune Disease • Genetic susceptibility - MHC association • Environmental susceptibility • Sequestered antigens • Molecular mimicry • Polyclonal activation

6. From immunoprivileged site

7. Figure 17.1Possible mechanisms of induction of autoimmunity. • Molecular mimicry, a B cell specific for a self antigen fails to be activated in the absence of T cell help, however, it can be activated by a microbial antigen that contains a crossreactive epitope that is shared by the self antigen and a carrier epitope that is distinct. A T cell specific for this non-self carrier can provide help for activation of the autoreactive B cell. • In polyclonal B cell activation; all mouse B cells, including some that are autoreactive, may be activated nonsepcifically by a polyclonal activator that binds to a receptor.

10. Fig. 12.7. Autoantibodies specific for cell-surface receptors can be either receptor agonists for antagonists. The antibody to the acetylcholine receptor in myasthenia gravis acts as an antagonist that blocks binding of Ach to the receptor and prevents transmission of the nerve impulse across the neuromuscular junction. The antibody to the TSH receptor in Graves disease acts as a receptor agonist and induces chronic stimulation of the thyroid to release thyroid hormones.

11. “Butterfly” rash over the cheeks of a young girl with systemic lupus erythematosus (SLE) ``Lumpy-bumpy'' staining pattern of fluorescent antibody specific for human Ig: immune aggregate deposits in glomerular basement membrane. [Courtesy of Dr. Angelo Ucci, Tufts University School of Medicine.]

12. Islet of Langerhans in pacreas from a normal mouse (a) and from a mouse with a disease resembling insulin-dependent diabetes mellitus (b)

13. Normal thyroid gland Gland in Hashimoto’s thyroiditis

14. Rheumatoid arthirtis

15. Treatment of autoimmune diseases • Current therapies • Immunosuppressive drugs • Removal of target tissues • Experimental therapeutic approaches • T cell vaccination • Peptide blockade of MHC molecules • Anticytokine therapy (against TNF-a or IL-1b) • Monoclonal antibody therapy (CD3, B7, CD28 …) • Tolerance induction by oral antigens