PATHOGENESIS.

Many manifestations are mediated by antibodies. The classic example is that of diffuse proliferative glomerulonephritis. Immune complexes, which consist of nuclear antigens (especially DNA) and high-affinity complement-fixing IgG (especially IgG1 and IgG3) and ANAs (especially antibodies to DNA), form in the circulation and are deposited in the glomerular basement membrane (GBM) or form in situ; histone may facilitate immune complex deposition. The complement system is then activated and chemotactic factors are generated. These factors induce the attraction and infiltration of leukocytes, which then phagocytose immune complexes and cause the release of mediators (such as activators of the clotting system), which further perpetuate the glomerular inflammation. With continuing immune complex deposition, chronic inflammation may ensue, ultimately leading to fibrinoid necrosis and scarring (crescents) and loss of renal function. In lupus membranous glomerulonephritis, similar mechanisms occur, although immune complex-containing, poorly complement-fixing IgG2 and IgG4 form primarily in situ on the GBM; there is no cellular infiltrate. The mechanism for the GBM protein leakage, which results in the nephrotic syndrome, is not clear. In lupus mesangial glomerulonephritis, mesangial cells (macrophage-like

cells) have phagocytosed immune complexes, thus preventing them from being deposited on the GBM. Immune complexes have been detected (by immunofluorescence and/or electron microscopy) at the dermal-epidermal junction in both skin lesions and normal skin, in the choroid plexus, in the pericardium, and in the pleural cavity. The pathogenic potential of immune complexes depends on the antibody (its specificity, affinity, charge, ability to activate complement or other mediators of inflammation), the nature of the antigen (size, charge), the ability of the immune complex to be solubilized by complement or bound to and cleared by red blood cells (RBCs) (both systems may be defective in SLE), the clearance ability of the mononuclear phagocytosis system, and other factors.

Patients with SLE also make antibodies to cell-surface antigens. RBCs, white blood cells (WBCs), and platelets coated with such

antibodies are cleared from the circulation either through (Fc) receptors on macrophages of the reticuloendothelial system, by complement-mediated cytotoxicity, or by antibody-dependent cellular cytotoxicity--resulting in (hemolytic) anemia, leukopenia, and thrombocytopenia. Antibodies to endothelial cells have been implicated in vasculitis, antibodies to neuronal cells have been associated with neuropsychiatric lupus, and antibodies to renal glomerular and tubular antigens have been implicated in lupus nephritis. Of recent particular interest are antibodies to the phospholipid-beta₂-glycoprotein I complex. These antibodies appear to interfere with the normal anticoagulant effect of beta₂-glycoprotein I and are thus implicated in the arterial and venous thromboses (causing strokes and thrombophlebitis) and placental infarcts (causing miscarriages) complicating SLE.

Skin lesions are thought to be multifactorial in origin. UV light (1) damages DNA (the patient makes antibodies to DNA, immune complexes form, complement is activated, and a local inflammatory response ensues); (2) increases binding of anti-Ro, anti-La, and anti-RNP to UV-activated keratinocytes; (3) alters cellular membrane phospholipid metabolism; (4) increases IL-1 release from cutaneous keratinocytes and Langerhans' cells; and (5) affects suppressor T cells.