Fig. 5.23 Modelforthepathogenesisofsystemiclupuserythematosus.Inthishypotheticalmodel,susceptibilitygenesinterferewiththemaintenanceofself-tolerance,andexternaltriggersleadtopersistenceofnuclearantigens.Theresultisanantibodyresponseagainstselfnuclearantigens,whichisamplifiedbytheactionofnucleicacidsondendriticcells(DCs)andBcells,andtheproductionoftypeIinterferons.TLRs, Toll-likereceptors.
produce interferons and other cytokines, which further enhance the immune response and cause more apoptosis. The net result is a cycle of antigen release and immune activation resulting in the production of high-affinity autoantibodies.
Different autoantibodies are the cause of most of the lesions of SLE.
• Most of the systemic lesions are caused by immune complexes (type III hypersensitivity). DNA-anti-DNA complexes can be detected in the glomeruli and small blood vessels. Low levels of serum complement (secondary to consumption of complement proteins) and granular deposits of complement and immunoglobulins in the glomeruli further support the immune complex nature of the disease. T cell infiltrates are also frequently seen in the kidneys, but the role of these cells in tissue damage is not established.
Autoantibodies of different specificities contribute to the pathology and clinical manifestations of SLE (type II hypersensitivity). Autoantibodies specific for red blood cells, white blood cells, and platelets opsonize these cells and promote their phagocytosis, resulting in cytopenias. There is no evidence that ANAs, which are involved in immune complex formation, can penetrate intact cells. If cell nuclei are exposed, however, the ANAs can bind to them. In tissues, nuclei of damaged cells react with ANAs, lose their chromatin pattern, and become homogeneous, producing so-called “LE bodies” or hematoxylin bodies. Related to this phenomenon are LE cells, which are readily seen when blood is agitated in vitro. An LE cell is a phagocyte (neutrophil or macrophage) that has engulfed the denatured nucleus of an injured cell. The demonstration of LE cells in vitro was used in the past as a test for SLE. With new techniques for detection of ANAs, however, this test is now only of historic interest. Sometimes, LE cells are found in pericardial or pleural effusions in patients.
Anti-phospholipid antibody syndrome. Patients with antiphospholipid antibodies may develop venous and arterial thromboses, which may be associated with recurrent spontaneous miscarriages and focal cerebral or ocular ischemia. This constellation of clinical features, in association with lupus, is referred to as the secondary antiphospholipid antibody syndrome. The mechanisms of thrombosis are not defined, and antibodies against clotting factors, platelets, and endothelial cells have all been proposed as being responsible for thrombosis (Chapter 4). Some patients develop these autoantibodies and the clinical syndrome without associated SLE. They are said to have the primary anti-phospholipid antibody syndrome (Chapter 4).
The neuropsychiatric manifestations of SLE have been attributed to antibodies that cross the blood-brain barrier and react with neurons or receptors for various neurotransmitters. However, this is not established in all cases, and mechanisms involving other immune factors, such as cytokines, also may underlie the cognitive dysfunction and other CNS abnormalities that are associated with SLE.
MORPHOLOGYThemorphologicchangesinSLEareextremelyvariable.Thefrequencyofindividualorganinvolvementisshownin
Table5.12 .Themostcharacteristiclesionsresultfromimmunecomplexdepositioninbloodvessels,kidneys,connectivetissue,andskin.