The binding of IgG and IgM antibodies to cells in tissues causes inflammatory injury by a variety of mechanisms. One of these is the fixation of complement. Although nucleated cells are relatively resistant to lysis by complement, the assembly of sublytic amounts of the membrane-attack complex on their surface provides a powerful activating stimulus. Depending on the cell type, this interaction can cause cytokine release, a respiratory burst, or the mobilization of membrane phospholipids to generate arachidonic acid—the precursor of prostaglandins and leukotrienes, lipid mediators of inflammation.
Most cells in tissues are fixed in place, and innate and adaptive immune cells are attracted to them by chemoattractant molecules. One such molecule is the complement fragment C5a, which is released as a result of complement activation triggered by autoantibody binding. Other chemoattractants, such as leukotriene B4, can be released by the autoantibody-targeted cells. Inflammatory leukocytes are further activated by binding to autoantibody Fc regions and fixed complement C3 fragments on cells. Tissue injury can result from the products of the activated leukocytes and by antibody-dependent cellular cytotoxicity mediated by NK cells (see Section 10-23).
A probable example of this type of autoimmunity is Hashimoto’s thyroiditis, in which autoantibodies against tissue-specific antigens are found at extremely high levels for prolonged periods. Direct T-cell-mediated cytotoxicity, which we discuss later, is probably also important in this disease.
Fig. 15.20 Antibodies specific for cell-surface antigens can destroy cells. In autoimmune hemolytic anemias, red blood cells (erythrocytes) coated with IgG autoantibodies against a cell‑surface antigen (upper panel) are rapidly cleared from the circulation by uptake by Fc receptor‑bearing macrophages located primarily in the spleen (lower left panel). Erythrocytes coated with IgM autoantibodies fix C3 and are cleared by CR1‑bearing macrophages. The binding of certain rare autoantibodies that fix complement extremely efficiently causes the formation of the membrane‑attack complex on the red cells, leading to intravascular hemolysis (lower right panel).
Fig. 15.21 Feedback regulation of thyroid hormone production is disrupted in Graves’ disease. Graves’ disease is caused by autoantibodies specific for the receptor for thyroid‑stimulating hormone (TSH). Normally, thyroid hormones are produced in response to TSH and limit their own production by inhibiting the production of TSH by the pituitary (left panels). In Graves’ disease, the autoantibodies are agonists for the TSH receptor and therefore stimulate the production of thyroid hormones (right panels). The thyroid hormones inhibit TSH production in the normal way but do not affect production of the autoantibody; the excessive thyroid hormone production induced in this way causes hyperthyroidism.
15-15 Autoantibodies against receptors cause disease by stimulating or blocking receptor function.
Autoimmune disease can occur when autoantibody binds a cell-surface receptor. Antibody binding to a receptor can either stimulate the receptor or block stimulation by the natural ligand. In Graves’ disease, autoantibodies against the thyroid-stimulating hormone (TSH) receptor on thyroid cells stimulate excessive production of thyroid hormone. The production of thyroid hormone is normally controlled by feedback regulation; high levels of thyroid hormone inhibit the release of TSH by the pituitary. In Graves’ disease, feedback inhibition fails because the autoantibody continues to stimulate the TSH receptor in the absence of TSH, and the patient produces chronically elevated levels of thyroid hormone (‘hyperthyroidism’; Fig. 15.21).