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Complement- and Fc Receptor-Mediated Inflammation

When antibodies deposit in extracellular tissues, such as basement membranes and matrix, the resultant injury is because of inflammation and not because of phagocytosis or lysis of cells.

The deposited antibodies activate complement, generating byproducts, such as C5a (and to a lesser extent C4a and C3a), that recruit neutrophils and monocytes. The same cells also bind to

the deposited antibodies via their Fc receptors. The leukocytes are activated, they release injurious substances, such as enzymes and reactive oxygen intermediates, and the result is damage

to the tissues ( Fig. 6-14B ). It was once thought that complement was the major mediator of antibody-induced inflammation, but knockout mice lacking Fc receptors also show striking

reduction in these reactions. It is now believed that inflammation in antibody-mediated (and immune complex-mediated) diseases is because of both complement and Fc receptordependent

reactions.[29]

Antibody-mediated inflammation is the mechanism responsible for tissue injury in some forms of glomerulonephritis, vascular rejection in organ grafts, and other diseases ( Table 6-4 ).

As we shall discuss in more detail below, the same reaction is involved in immune complex-mediated diseases.

Antibody-Mediated Cellular Dysfunction

In some cases, antibodies directed against cell-surface receptors impair or dysregulate function without causing cell injury or inflammation. For example, in myasthenia gravis, antibodies

reactive with acetylcholine receptors in the motor end-plates of skeletal muscles impair neuromuscular transmission and therefore cause muscle weakness ( Fig. 6-14C ). In pemphigus

vulgaris, antibodies against desmosomes disrupt intercellular junctions in epidermis, leading to the formation of skin vesicles. The converse (i.e., antibody-mediated stimulation of cell

function) is noted in Graves disease. In this disorder, antibodies against the thyroid-stimulating hormone receptor on thyroid epithelial cells stimulate the cells, resulting in hyperthyroidism.

Immune Complex-Mediated (Type III) Hypersensitivity

Antigen-antibody complexes produce tissue damage mainly by eliciting inflammation at the sites of deposition. The toxic

Figure 6-14Schematic illustration of the three major mechanisms of antibody-mediated injury. A, Opsonization of cells by antibodies and complement components and ingestion by

phagocytes. B, Inflammation induced by antibody binding to Fc receptors of leukocytes and by complement breakdown products. C, Antireceptor antibodies disturb the normal function of

receptors. In these examples, antibodies against the thyroid stimulating hormone (TSH) receptor activate thyroid cells in Graves disease, and acetylcholine (ACh) receptor antibodies

impair neuromuscular transmission in myasthenia gravis.

 

TABLE 6-4-- Examples of Antibody-Mediated Diseases (Type II Hypersensitivity)


Date: 2016-04-22; view: 780


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