The Pathogenesis of Systemic Lupus Erythematosus

Lisa G. Criscione, MD 
Division of Rheumatology, Department of Medicine, Duke University Medical Center 
Durham, NC

David S. Pisetsky, MD, PhD 
Division of Rheumatology, Department of Medicine, Duke University Medical Center 
Durham, NC
Medical Research Service, Durham Veterans Affairs Medical Center
Durham, NC

Summary Points

• The hallmark of systemic lupus erythematosus (SLE) is autoantibody production.
• Autoantibodies may directly attack organs or cause injury by combining with antigens and inciting inflammation.
• SLE likely involves a set of unlinked genes that operate to induce SLE. 
• The generation of autoantibodies may occur because of an abnormality in apoptosis and phagocytosis of cell debris allowing nuclear antigens to become antigenic.

Introduction 

Systemic lupus erythematosus (SLE) is a prototypic autoimmune disease characterized by multisystem involvement in association with a diverse array of autoantibodies. Similar to other autoimmune diseases, SLE appears to arise from a combination of genetic and environmental factors that interact to cause a state of immune hyperactivity.

The serological hallmark of SLE is autoantibody production, with antibodies directed to components of the cell nucleus the most characteristic. These antinuclear antibodies (ANA) bind to a variety of nuclear macromolecules that include DNA, RNA, histones, and a series of protein-RNA complexes called snRNPS (small nuclear ribonucleoproteins). In SLE, ANAs target molecules that are ubiquitously expressed among all cells.  In normal cells, these antigens are inaccessible to the external milieu since they are located in the nucleus and thereby protected from the immune system. An important issue in the pathogenesis of SLE concerns the manner in which antibodies to ubiquitous intracellular molecules mediate organ-specific manifestations (1).

While ANAs are almost always present in the sera of SLE patients, these antibodies are not unique to SLE. Rather, ANAs occur commonly in patients with connective tissues diseases such as rheumatoid arthritis and Sjögren's syndrome. Furthermore, ANAs can be detected in up to 5% of normal individuals; it is unclear whether the frequency of this reactivity reflects the vagaries of current assays or an underlying predisposition to autoimmunity that is widespread in the population. Although ANA expression occurs in many diseases, certain ANAs are found essentially only in patients with SLE and can serve as disease markers. Thus, anti-DNA and anti-Sm have been identified as criteria in the classification of patients with SLE. Other autoantibodies, such as anti-RNP, while frequent in patients with SLE, also occur outside this setting and lack diagnostic significance.

In view of the heterogeneity of SLE, diagnosis is established on the basis of a set of criteria that include clinical and serological findings. While designed for classification and enrollment of patients into studies, these criteria are commonly used for diagnosis. In the use of these criteria, serology has a major impact since the presence of an antinuclear antibody represents one criterion while the specific autoantibodies (anti-DNA, anti-Sm) are another. 

The serological findings in SLE, such as hyperglobulinemia, point strongly to global immune system disturbances in disease pathogenesis. Patients with autoimmune diseases have defects in tolerance, the processes by which normal immune systems prevent the emergence or activity of autoreactive cells (2).