The fluorescence patterns are not absolutely specific for the type of antibody, and because many autoantibodies may be present, combinations of patterns are frequent. Attempts are ongoing to replace microscopic assays with quantitative assays for antibodies against specific nuclear and other antigens. Indeed, antibodies to double-stranded DNA and the so-called “Smith (Sm) antigen” can be detected by more quantitative assays and are virtually diagnostic of SLE. Nevertheless, the staining pattern has diagnostic value, and the test remains in use.
In addition to ANAs, lupus patients have a host of other autoantibodies. Some are directed against blood cells, such as red cells, platelets, and lymphocytes. Anti-phospholipid antibodies are present in 30% to 40% of lupus patients. They are actually directed against epitopes of various plasma proteins that are revealed when the proteins are in complex with phospholipids. Antibodies against the phospholipid– β2-glycoprotein complex also bind to cardiolipin antigen, used in syphilis serology, and therefore lupus patients may have a false-positive test result for syphilis. Because these antibodies bind to phospholipids, they may prolong the partial thromboplastin time, an in vitro clotting test that requires phospholipids. Therefore, these antibodies are sometimes referred to as lupus anti-coagulant. Despite the observed clotting delays in vitro, patients with antiphospholipid antibodies have complications related to excessive clotting (a hypercoagulable state), such as thrombosis (Chapter 4).
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Fig. 5.22 Stainingpatternsofanti-nuclearantibodies.(A)HomogeneousordiffusestainingofnucleiistypicalofantibodiesreactivewithdsDNA,nucleosomes,andhistones,andiscommoninSLE.(B)Aspeckledpatternisseenwithantibodiesagainstvariousnuclearantigens,includingSmandRNPs.(C)Thepatternofstainingofanti-centromereantibodiesisseeninsomecasesofsystemicsclerosis,Sjögrensyndrome,andotherdiseases.(D)Anucleolarpatternistypicalofantibodiesagainstnucleolarproteins.(From Wiik AS, Høier-Madsen M, Forslid J, et al: Antinuclear antibodies: a contemporary nomenclature using HEp-2 cells. J
Autoimm35:276, 2010.)
The fundamental defect in SLE is a failure of the mechanisms that maintain self-tolerance. Although what causes this failure of self-tolerance remains unknown, as is true of most autoimmune diseases, both genetic and environmental factors play a role.
Many lines of evidence support a genetic predisposition to SLE.
Familial association. Family members have an increased risk for the development of SLE, and up to 20% of unaffected first-degree relatives have autoantibodies. There is a higher rate of concordance in monozygotic twins (25%) than in dizygotic twins (1%–3%).
HLA association. The odds ratio (relative risk) for persons with HLA-DR2 or HLA-DR3 is 2 to 3, and if both haplotypes are present, the risk is about 5.
• Other genes. Genetic deficiencies of classical pathway complement proteins, especially C1q, C2, or C4, are seen in about 10% of patients with SLE. The complement deficiencies may result in defective clearance of immune complexes and apoptotic cells, and failure of B-cell tolerance. A polymorphism in the inhibitory Fc receptor, FcγRIIb, has been described in some patients; this may contribute to inadequate control of B-cell activation. Additional genes have been implicated by genome-wide association studies, but their contribution to the development of the disease remains unclear.