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Systemic lupus erythematosus (SLE) is an autoimmune disease in which organs and cells undergo damage initially mediated by tissue-binding autoantibodies and immune complexes. In most patients, autoantibodies are present for a few years before the first clinical symptom appears; clinical manifestations are heterogeneous. Ninety percent of patients at diagnosis are women of childbearing years; people of all genders, ages, and ethnic groups are susceptible. Prevalence of SLE in the United States is 10 to 400 per 100,000 depending on race and gender; highest prevalence is in black women and lowest is in white men.


The proposed pathogenic mechanisms of SLE are illustrated in Fig. 319-1. Interactions between susceptibility genes and environmental factors result in abnormal immune responses, which vary among different patients. Those responses may include (1) activation of innate immunity (dendritic cells, monocyte/macrophages) by CpG DNA, DNA in immune complexes, viral RNA, and RNA in RNA/protein self-antigens; (2) lowered activation thresholds and abnormal activation pathways in adaptive immunity cells (T and B lymphocytes); (3) ineffective regulatory CD4+ and CD8+ T cells; and (4) reduced clearance of immune complexes and of apoptotic cells. Self-antigens (nucleosomal DNA/protein; RNA/protein in Sm, Ro, and La; phospholipids) are available for recognition by the immune system in surface blebs of apoptotic cells; thus antigens, autoantibodies, and immune complexes persist for prolonged periods of time, allowing inflammation and disease to develop. Immune cell activation is accompanied by increased secretion of proinflammatory type 1 and 2 interferons (IFNs), tumor necrosis factor α (TNF-α), interleukin (IL)-17 and B cell–maturation/survival cytokines B lymphocyte stimulator (BLyS/BAFF), and IL-10. Upregulation of genes induced by interferons is a genetic “signature” in peripheral blood cells of SLE in approximately 50% of patients. Decreased production of other cytokines also contributes to SLE: Lupus T and natural killer (NK) cells fail to produce enough IL-2 and transforming growth factor β (TGF-β) to induce and sustain regulatory CD4+ and CD8+ T cells. The result of these abnormalities is sustained production of autoantibodies (referred to in Fig. 319-1 and described in Table 319-1) and immune complexes; pathogenic subsets bind target tissues, with activation of complement, leading to release of cytokines, chemokines, vasoactive peptides, oxidants, and destructive enzymes. This is accompanied by influx into target tissues of T cells, monocyte/macrophages, and dendritic cells, as well as activation of resident macrophages and dendritic cells. In the setting of chronic inflammation, accumulation of growth factors and products of chronic oxidation contribute to irreversible tissue damage, including fibrosis/sclerosis, in glomeruli, arteries, brain, lungs, and other tissues.

Figure 319-1
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Pathogenesis of SLE. Genes confirmed in more than one genome-wide association analysis in Northern European whites as increasing susceptibility to SLE or lupus nephritis are listed (reviewed in Moser KL et al, Recent insights into the genetic basis of SLE. Genes Immun 2009:10:373). Gene-environment interactions result in abnormal immune responses that generate pathogenic autoantibodies and immune complexes that deposit ...

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