Arthritis Research

Systemic Lupus Erythematosus Attacks Many Tissues

One of the best examples of a systemic autoimmune disease is systemic lupus erythematosus (SLE), which typically appears in women between 20 and 40 years of age; the ratio of female to male patients is 10:1. SLE is characterized by fever, weakness, arthritis, skin rashes, pleurisy, and kidney dysfunction (Figure 20-6). Lupus is more frequent in African-American and Hispanic women than in Caucasians, although it is not known why this is so. Affected individuals may produce auto-antibodies to a vast array of tissue antigens, such as DNA, his-tones, RBCs, platelets, leukocytes, and clotting factors; interaction of these auto-antibodies with their specific antigens produces various symptoms. Auto-antibody specific for RBCs and platelets, for example, can lead to complement-mediated lysis, resulting in hemolytic anemia and thrombocytopenia, respectively. When immune complexes of auto-antibodies with various nuclear antigens are deposited along the walls of

BLOCKING AUTO-ANTIBODIES (Myasthenia gravis)

Acetylcholine

Acetylcholine

Auto-antibody to AChR

v Muscle cell

Muscle activation

Muscle activation inhibited

FIGURE 20-5

In myasthenia gravis, binding of auto-antibodies to the acetylcholine receptor (right) blocks the normal binding of acetylcholine (burgandy dots) and subsequent muscle activation (left). In addition, the anti-AChR auto-antibody activates complement, which damages the muscle end-plate; the number of acetylcholine receptors declines as the disease progresses. AChR = acetylcholine receptor.

FIGURE 20-6

Characteristic "butterfly" rash over the cheeks of a young girl with systemic lupus erythematosus. [From L. Steinman, 1993, Sci. Am. 269(3):80.]

FIGURE 20-6

Characteristic "butterfly" rash over the cheeks of a young girl with systemic lupus erythematosus. [From L. Steinman, 1993, Sci. Am. 269(3):80.]

small blood vessels, a type III hypersensitive reaction develops. The complexes activate the complement system and generate membrane-attack complexes and complement split products that damage the wall of the blood vessel, resulting in vasculitis and glomerulonephritis.

Excessive complement activation in patients with severe SLE produces elevated serum levels of the complement split products C3a and C5a, which may be three to four times higher than normal. C5a induces increased expression of the type 3 complement receptor (CR3) on neutrophils, facilitating neutrophil aggregation and attachment to the vascular endothelium. As neutrophils attach to small blood vessels, the number of circulating neutrophils declines (neutropenia) and various occlusions of the small blood vessels develop (vasculi-tis). These occlusions can lead to widespread tissue damage.

Laboratory diagnosis of SLE focuses on the characteristic antinuclear antibodies, which are directed against double-stranded or single-stranded DNA, nucleoprotein, histones, and nucleolar RNA. Indirect immunofluorescent staining with serum from SLE patients produces various characteristic nucleus-staining patterns.

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