In myasthenia gravis, autoantibodies against the α chain of the nicotinic acetylcholine receptor present at neuromuscular junctions in skeletal muscle cells can block stimulation of muscle contraction. The antibodies are believed to drive internalization and degradation of the receptor (Fig. 15.22).
Fig. 15.22 Autoantibodies inhibit receptor function in myasthenia gravis. In normal circumstances, acetylcholine released from stimulated motor neurons at the neuromuscular junction binds to acetylcholine receptors on skeletal muscle cells, triggering muscle contraction (upper panel). Myasthenia gravis is caused by autoantibodies against the α subunit of the receptor for acetylcholine. These autoantibodies bind to the receptor without activating it and also cause receptor internalization and degradation (lower panel). As the number of receptors on the muscle is decreased, the muscle becomes less responsive to acetylcholine.
Fig. 15.23 Autoimmune diseases caused by autoantibodies against cell-surface receptors. These antibodies produce different effects depending on whether they are agonists (which stimulate the receptor) or antagonists (which inhibit it). Note that different autoantibodies against the insulin receptor can either stimulate or inhibit signaling.
Patients with myasthenia gravis develop potentially fatal progressive weakness as a result of their disease. Diseases caused by autoantibodies that act as agonists or antagonists on cell-surface receptors are listed in Fig. 15.23.
15-16 Autoantibodies against extracellular antigens cause inflammatory injury.
Antibody responses to extracellular matrix molecules are infrequent, but can be very damaging. In Goodpasture’s syndrome, antibodies are formed against the α3 chain of basement membrane collagen (type IV collagen). These antibodies bind to the basement membranes of renal glomeruli (Fig. 15.24) and, in some cases, to the basement membranes of pulmonary alveoli, causing a rapidly fatal disease if untreated. The autoantibodies bound to basement membrane ligate Fcγreceptors on innate effector cells, such as monocytes and neutrophils, leading to their activation. These cells, in turn, release chemokines that attract a further influx of monocytes and neutrophils into glomeruli, causing severe tissue injury. The autoantibodies also cause a local activation of complement, which amplifies tissue injury.
Immune complexes are produced when there is an antibody response to a soluble antigen. Normally, such complexes cause little tissue damage because they are cleared efficiently by red blood cells that bear complement receptors and by phagocytes of the mononuclear phagocytic system that have both complement and Fc receptors. This clearance system can, however, fail in circumstances where the production of immune complexes exceeds the capacity
Fig. 15.24 Autoantibodies reacting with glomerular basement membrane cause the inflammatory glomerular disease known as Goodpasture’s syndrome.