Ref Robbins 9/e p219, 8/e p214 ,7/e p228 Spectrum of Autoantibodies in SLE Antibodies have been identified against a host of nuclear and cytoplasmic components of the cell that are specific to neither organs nor species. Another group of antibodies is directed against surface antigens of blood cells, while yet another is reactive with proteins in complex with phospho- lipids (antiphospholipid antibodies) (Chapter 3). * Antinuclear antibodies. ANAs are directed against several nuclear antigens and can be grouped into four catego- ries: (1) antibodies to DNA, (2) antibodies to histones, (3) antibodies to nonhistone proteins bound to RNA, and (4) antibodies to nucleolar antigens. Table 4-10 lists several autoantibodies, including ANAs, and their asso- ciation with SLE as well as with other autoimmune dis- eases, to be discussed later. The most widely used method of detecting ANAs is the indirect immunofluo- rescence assay (IFA), which screens for autoantibodies that bind to a variety of nuclear antigens, including DNA, RNA, and proteins. Four staining patterns are seen with IFA: homogeneous or diffuse, rim or periph- eral, speckled, and nucleolar. While each pattern can be suggestive of the presence of specific autoantibodies, the strength of these associations is limited and should not be relied on. ANA testing by IFA is extremely sensitive, as more than 95% of patients with SLE will test positive, but the test's specificity is quite limited, because patients with other autoimmune diseases, chronic infections, and cancer will test positive as well. Fuhermore, ANAs are seen in approximately 5% to 15% of healthy people, and the incidence increases with age. Recently, the IFA has been replaced in many clinical laboratories by multiplex flow cytometry immunoassays that can simultaneously test for multiple specific autoantibodies, but these assays may lack the sensitivity of the IFA. Antibodies to double- stranded DNA (dsDNA) and the so-called Smith (Sm) antigen can be detected by ELISA or multiplex flow methods and are specific for SLE. * Other autoantibodies. Antibodies against blood cells, including red cells, platelets, and lymphocytes, are found in many patients. Antiphospholipid antibodies are present in 40% to 50% of patients with lupus and react with a wide variety of proteins in complex with phospholipids. Some bind to cardiolipin antigen, used in serologic tests for syphilis, so patients with lupus may have a false-positive test result for syphilis. Antiphos- pholipid antibodies contribute to coagulation abnormal- ities, which are described below. Mechanisms of Tissue Injury Regardless of the exact sequence by which autoantibodies are formed, they are likely to be the mediators of tissue injury, probably through multiple mechanisms. * Most organ damage in SLE is caused by immune complex deposition. Skin and kidney biopsies from patients with SLE typically demonstrate diffuse and heavy granular deposits of complement and immunoglobulin. Autoan- tibodies complexed with DNA can be detected as well. These deposits of immune complexes had been thought to cause tissue damage by activating the classical com- plement pathway (type III hypersensitivity); 75% of patients will have reduced serum levels of C3 and C4 at the time of SLE flares, presumably because complement is being activated and consumed faster than it can be produced. However, people and rodents deficient in C1q are not protected from SLE and actually can spon- taneously develop SLE, raising the possibility that complement-independent mechanisms may also con- tribute to tissue damage. * Autoantibodies of different specificities contribute to the pathology and clinical manifestations of SLE (type II hyper- sensitivity). Autoantibodies against red cells, white cells, and platelets opsonize these cells and lead to their phagocy- tosis, resulting in cytopenias. Autoantibodies against various phospholipids lead to increased thrombosis in patients, with varied clinical consequences, including recurrent spontaneous aboion and thrombotic epi- sodes. These disorders are pa of the antiphospholipid syndrome. Paradoxically, these antibodies interfere with clotting tests and are actually called "lupus anticoagu- lants." Autoantibodies are also produced against clot- ting factors such as thrombin, and these too may contribute to clotting disorders. Autoantibodies against central nervous system receptors for various neurotransmit- ters have been implicated in the neuropsychiatric com- plications of the disease. * There is no evidence that ANAs can permeate intact cells. However, if cell nuclei are exposed, the ANAs can bind to them. In tissues, nuclei of damaged cells react with ANAs, lose their chromatin pattern, and become homogeneous, to produce so-called LE bodies or hema- toxylin bodies. An in vitro correlate of this is the LE cell, a neutrophil or macrophage that has engulfed the dena- tured nucleus of another injured cell. When blood is withdrawn and agitated, a number of leukocytes are sufficiently damaged to expose their nuclei to ANAs, with secondary complement activation; these antibody- and complement-opsonized nuclei are then readily phagocytosed. Although the LE cell test is positive in as many as 70% of patients with SLE, it is now largely of historical interest.