Immunology Chapter 20 Richard L. Myers, Ph.D. Department of Biology Southwest Missouri State Temple Hall 227 Telephone: 417-836-5307 Email: rlm967f@mail.smsu.edu Homepage: http://creative.smsu.edu/biology/myersr/index.html TopClass: http://creative.smsu.edu

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

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

Hashimoto’s thyroiditis Autoantibodies are produced also sensitized TDTH 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

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

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

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

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

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

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

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

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

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

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

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

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

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

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 fever 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

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

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

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