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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. Ninety percent of patients are women of child-bearing years; people of all genders, ages, and ethnic groups are susceptible. Prevalence of SLE in the United States is 20 to 150 per 100,000 women depending on race and gender; highest prevalence is in African-American and Afro-Caribbean women, and lowest prevalence is in white men.


The proposed pathogenic mechanisms of SLE are illustrated in Fig. 378-1. Interactions between susceptibility genes and environmental factors result in abnormal immune responses, which vary between different patients. Those responses may include (1) activation of innate immunity (dendritic cells, monocyte/macrophages) by CpG DNA, DNA in immune complexes, viral DNA or RNA, and RNA in RNA/protein self-antigens; (2) lowered activation thresholds and abnormal activation pathways in adaptive immunity cells (mature T and B lymphocytes); (3) ineffective regulatory CD4+ and CD8+ T cells, B cells, and myeloid-derived suppressor cells; and (4) reduced clearance of immune complexes and apoptotic cells. Self-antigens (nucleosomal DNA/protein; RNA/protein in Sm, Ro, and La; phospholipids) are recognized by the immune system in surface blebs of apoptotic cells; thus autoantigens, 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 IFNs is a genetic “signature” in peripheral blood cells of 50–60% of SLE 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 beta (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. 378-1 and described in Table 378-1) and immune complexes; pathogenic subsets bind target tissues, with activation of complement, leading to release of cytokines, chemokines, vasoactive peptides, oxidants, and proteolytic enzymes. This results in activation of multiple tissue cells (endothelial cells, tissue-fixed macrophages, mesangial cells, podocytes, renal tubular epithelial cells) and influx into target tissues of T and B cells, monocyte/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, lungs, and other tissues.

FIGURE 378-1

Pathogenesis of systemic lupus erythematosus (SLE). Genes confirmed in more than one genome-wide association analysis in northern European whites (several confirmed in Asians as well) as increasing susceptibility to SLE or lupus nephritis are listed (reviewed in SG Guerra et al: Arthritis Res Ther 14:211, 2012). Gene-environment interactions ...

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