Porth's Essentials of Pathophysiology, 4e

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Disorders of the Immune Response

C h a p t e r 1 6

Type III, Immune Complex–Mediated Disorders Immune complex allergic disorders are mediated by the formation of insoluble antigen–antibody complexes, complement fixation, and localized inflammation 2,3 (Fig. 16-3). Immune complexes formed in the circula- tion produce damage when they come in contact with the vessel lining or are deposited in tissues, such as the renal glomerulus, skin venules, lung tissue, and joint synovium. Once deposited, the immune complexes elicit an inflammatory response by activating complement, thereby leading to chemotactic recruitment of neutro- phils and other inflammatory cells. Activation of these inflammatory cells by immune complexes and comple- ment, accompanied by the release of potent inflamma- tory mediators, is directly responsible for the injury. Type III reactions are responsible for the vasculitis seen in certain autoimmune diseases such as systemic lupus erythematosus (SLE) or the kidney damage seen with acute glomerulonephritis. As with type I hypersensitivity reactions, type III immune complex disorders may pres- ent with systemic manifestations or as a local reaction. Systemic Immune Complex Disorders Serum sickness is a type III systemic immune complex disorder that is triggered by the deposition of insolu- ble antigen–antibody (IgM, IgG, and occasionally IgA)

Complement- and Antibody-Mediated Cell Destruction The deletion of antibody-targeted cells can occur by way of the complement system or by antibody-dependent cell- mediated cytotoxicity (ADCC), which does not require complement. 2,3 Complement-mediated cell destruction can occur because the cells are coated with molecules (opsonized; see Fig. 16-2A) that make them attractive to phagocytes or because of the formation of mem- brane attack proteins that disrupt the integrity of the cell membrane and cause cell lysis (see Chapter 15, Understanding the Complement System). With ADCC destruction, cells that are coated with low levels of IgG antibody are killed by a variety of effector cells that bind to their target by their receptors for IgG, and cell lysis occurs without phagocytosis. Examples of antibody-mediated cell destruction include mismatched blood transfusion reactions, hemo- lytic disease of the newborn due to ABO or Rh incom- patibility (see Chapter 13), and certain drug reactions. In the latter, the binding of certain drugs or drug metab- olites to the surface of red or white blood cells elicits an antibody response that lyses the drug-coated cell. Lytic drug reactions can produce transient anemia, leukope- nia, or thrombocytopenia, which often are corrected by the removal of the offending drug. Complement- and Antibody-Mediated Inflammation When antibodies are deposited in extracellular tissue components, such as basement membranes and matrix, injury results from inflammation rather than phago- cytosis or cell lysis (see Fig. 16-2B). 2,3 In this case, the deposited antibodies activate complement, generating chemotactic by-products that recruit and activate neu- trophils and monocytes. The activated leukocytes release injurious substances, such as enzymes and reactive oxy- gen intermediates, that cause inflammation and tissue damage. Antibody-mediated inflammation is responsible for the tissue injury seen in some forms of glomerulone- phritis, vascular rejection of organ grafts, and other dis- eases. In Goodpasture syndrome, for example, antibody binds to a major structural component of pulmonary and glomerular basement membranes, causing pulmonary hemorrhage and glomerulonephritis 3 (see Chapter 25). Antibody-Mediated Cellular Dysfunction In some type II reactions, antibody binding to specific target cell receptors does not lead to cell death, but to a change in cell function (see Figs. 16-2C, D). In Graves disease, for example, autoantibodies directed against thyroid-stimulating hormone (TSH) receptors on thy- roid cells stimulates thyroxine production, leading to hyperthyroidism 2,3 (see Chapter 32). In myasthenia gravis, autoantibodies to acetylcholine receptors on the neuromuscular endplates either block the action of ace- tylcholine or mediate internalization or destruction of receptors, leading to decreased neuromuscular function (see Chapter 36).

Vessel endothelium

Antibody

Antigens

1

Formation of antigen–antibody complexes

2

Deposition of immune complexes

3

Attraction of inflammatory cells

Complement activation

Fibrinoid necrosis

Tissue-damaging mediators

FIGURE 16-3. Type III, immune complex reactions involving complement-activating IgG or IgM immunoglobulins with (1) formation of blood-borne immune complexes that are (2) deposited in tissues. Complement activation at the site of immune complex deposition (3) leads to attraction of leukocytes that are responsible for vessel and tissue injury.