Immunology Chapter 20

1. ImmunologyChapter 20 • Richard L. Myers, Ph.D. • Department of Biology • Southwest Missouri State • Temple Hall 227 • Springfield, MO 65804 • 417-836-5307 • rlm967f@wpgate.smsu.edu • Homepage: http://science.smsu.edu/~myers

2. Autoimmunity • Autoimmunity results when the immune system responds to self-components • tolerance usually protects an individual • protection is through clonal anergy or clonal suppression • A breakdown in tolerance can lead to self-reactive clones of T or B cells • can cause serious damage to cells and organs

3. Organ-specific disease • Humoral or cell-mediated damage can be directed to target organs • Cellular damage • antibodies or lymphocytes bind to cell-membrane antigens • cause cellular lysis/inflammatory response • function of the organ is gradually lost

4. Hashimoto’s thyroiditis • Autoantibodies are produced • also sensitized TTDH cells • Characterized by infiltration of lymphocytes, macrophages and plasma cells into the thyroid • the inflammatory response causes a goiter • an enlargement of the thyroid gland • Autoantibodies react with thyroid proteins, interfering with iodine uptake

5. Autoimmune anemias • Includes 1) pernicious anemia, 2) autoimmune hemolytic anemia and 3) drug-induced hemolytic anemia • Pernicious anemia caused by antibodies to an intestinal protein, intrinsic factor • prevents uptake of vitamin B12 • Autoimmune hemolytic anemia caused by autoantibodies to RBC antigens • results in complement-mediated lysis or antibody-mediated opsonization

7. Goodpasture’s syndrome • Autoantibodies specific for basement membrane antigens produced • bind to membranes of kidney glomeruli and alveoli of the lungs • complement activation leads to cell damage and inflammatory response • Damage is progressive kidney damage • and pulmonary hemorrhage

8. Insulin-dependent diabetes • Insulin-dependent diabetes mellitus (IDDM) • caused by autoimmune attack on the pancreas • large numbers of TDTH cells and macrophages • directed to insulin-producing cells (beta cells) • Result is decreased production of insulin • therefore increased levels of blood glucose • Beta cell destruction mediated by cytokines • also lytic enzymes from activated macrophages • autoantibodies may also contribute

10. Normal islets (left) and diabetic (right). Note selective loss of beta cells (brown) and infiltlration by lymphocytes

11. Diseases caused by autoantibodies • Antibodies bind to hormone receptors • stimulate inappropriate activity • Graves’ disease is a good example • thyroid-stimulating hormone (TSH) binds to a receptor on thyroid cells • activates adenylate cyclase to stimulate thyroid hormones • In Graves’ an autoantibody is produced to the receptor for TSH

16. Diseases caused by blocking-autoantibodies • Autoantibodies bind to hormone receptors • act as antagonists • inhibit receptor function • Myasthenia gravis is the prototype disease • autoantibodies are produced to the acetylcholine receptors • on motor end-plates of muscles • inhibits muscle activation

19. Systemic autoimmune diseases • Represent a generalized defect in immunity • hyperactive T and B cells • cause tissue damage • from autoantibodies and cell-mediated also • immune complexes important

20. Systemic lupus erythematosus • SLE is the best example of a systemic autoimmune disease • Usually occurs in young women • characterized by fever, weakness, joint pain, erythematous lesion, pleurisy and kidney dysfunction • Patients produce autoanibodies to a variety of tissue antigens like DNA, histones, etc. • diagnosis made by identifying ANA

21. Animal models for autoimmunity • We understand more about autoimmunity because of animal models • autoimmunity develops spontaneously • can also be induced experimentally • Examples of spontaneous autoimmunity • systemic lupus erythematosus • nonobese diabetic (NOD) mouse

22. Experimentally induced autoimmunity • Several experimental animal models are very similar to certain autoimmune diseases • Experimental autoimmune encephalomyelitis • an excellent model for understanding autoimmunity • produced by immunizing animals with MBP • in Freund’s adjuvant • animals develop cellular infiltration of myelin sheaths resulting in demyelination and paralysis • model for multiple sclerosis

25. Role of CD4 in autoimmunity • CD4 is the primary mediator of autoimmunity • However, to become autoimmune • must possess MHC and T-cell receptors capable of binding self-antigens

26. Evidence for association of MHC • There is association between expression of a particular MHC allele and suceptibility to autoimmunity • Can be shown by using antibodies to HLA alleles • some allelles occur at higher frequency amoung autoimmune individuals • association expressed as relative risk • values above 1 indicate association

28. Mechanism for induction • Autoimmunity usually develops from a number of different events • Sequestered antigens • myelin basic protein is a good example • normally sequestered from the immune system • by the blood brain barrier • trauma or an infection releases antigens • i.e., sperm after vasectomy, lens protein after eye damage and heart antigens after infarction

29. Molecular mimicry • Some bacteria and viruses possess antigens identical to the host • fairly common • i.e., cross-reacting antibodies causing rheumatic fever • another example are the heat-shock proteins • produced by cells following temperature • these proteins found in a variety of pathogens • therefore, when you make a response to a pathogen’s heat-shock proteins, it will cross-react through molecular mimicry

30. Inappropriate expression of class II MHC • in insulin-dependent diabetes mellitus (IDDM) healthy beta cells do not express class II MHC • same for thyroid acinar cells • an inappropriate expression sensitizes T cells to peptides derived from the beta cells or thyroid cells

31. Treatment of autoimmune disease • Treatments are aimed at reducing symptoms • They provide nonspecific suppression of the immune response • does not differentiate between good and bad • Use immunosuppressive drugs • i.e., corticosteroids, azathioprine and cyclophamide • patients at greater risk for infections or cancer

32. Assignment • Read Chapter 21, Immunodeficiency Diseases • Review question 3 (pg 521)