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DEFINITION AND PREVALENCE

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 20–150 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.

PATHOGENESIS AND ETIOLOGY

The proposed pathogenic mechanisms of SLE are illustrated in Fig. 349-1. The abnormal immune responses underlying SLE may be summarized as leading to production of increased quantities and immunogenic forms of nucleic acids, their accompanying proteins, and other self-antigens. The process may begin with autoimmunity-inducing activation of innate immunity, partly through binding of DNA/RNA/proteins by toll-like receptors in those cells. The changes include dendritic cells producing interferon α (IFNα), activated macrophages producing inflammatory cytokines/chemokines such as interleukin (IL12), tumor necrosis factor α (TNFα), and the B cell maturation/survival factor BLys/BAFF, neutrophils releasing DNA/protein-containing nets, and natural killer (NK) cells unable to kill autoreactive T and B cells or to produce the transforming growth factor β (TGFβ) needed for development of regulatory T cells. Upregulation of genes induced by IFNs is a genetic “signature” in peripheral blood cells of 50–80% of SLE patients. The innate immune system interacts with the B and T cells of adaptive immunity, which further drive autoimmune responses. T lymphocytes have altered metabolism (abnormal mitochondrial electron transport, membrane potential, and oxidative stress), increased glucose utilization, increased pyruvate production, activation of mTOR, and increased autophagy. T and B cells are more easily activated and driven into apoptosis than are normal cells, probably due to autoantibodies binding them plus abnormal signaling after engagement of surface molecules resulting in abnormally low production of IL2, which is required for T cell survival. B cells present antigen and secrete IL6 and IL10, further promoting autoreactive B cell survival (which is also favored by estrogen). Lupus phagocytic cells have reduced capacity to clear immune complexes, apoptotic cells, and their DNA/RNA/Ro/La and phospholipid containing surface blebs. The result is persistence of large quantities of autoantigens and resultant large quantities of autoantibodies with increased numbers of activated B cells and plasmablasts/plasma cells, and autoreactive T cells with shifts away from regulatory populations toward increased numbers and functions of Th1, T17, and Tfh cells, all of which promote production of autoantibodies and tissue damage. This damage begins with deposition of autoantibodies and/or immune complexes, followed by destruction mediated by complement activation and release of cytokines/chemokines. Non-immune tissue-fixed cells are then activated to produce more inflammation and damage, such as basal cells of the dermis, synovial fibroblasts, renal mesangial cells, podocytes and tubular epithelium, and endothelial cells throughout the body. Meanwhile, the initial immune attack is ...

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