New insights into the role of antinuclear antibodies in systemic lupus erythematosus

Abstract

Systemic lupus erythematosus (SLE) is a prototypic autoimmune disease characterized by antinuclear antibodies (ANAs) that form immune complexes that mediate pathogenesis by tissue deposition or cytokine induction. Some ANAs bind DNA or associated nucleosome proteins, whereas other ANAs bind protein components of complexes of RNA and RNA-binding proteins (RBPs). Levels of anti-DNA antibodies can fluctuate widely, unlike those of anti-RBP antibodies, which tend to be stable. Because anti-DNA antibody levels can reflect disease activity, repeat testing is common; by contrast, a single anti-RBP antibody determination is thought to suffice for clinical purposes. Experience from clinical trials of novel therapies has provided a new perspective on ANA expression during disease, as many patients with SLE are ANA negative at screening despite previously testing positive. Because trial results suggest that patients who are ANA negative might not respond to certain agents, screening strategies now involve ANA and anti-DNA antibody testing to identify patients with so-called 'active, autoantibody-positive SLE'. Evidence suggests that ANA responses can decrease over time because of the natural history of disease or the effects of therapy. Together, these findings suggest that, during established disease, more regular serological testing could illuminate changes relevant to pathogenesis and disease status.

Fig. 1 |. Anti-DNA and anti-RBP antibodies in systemic lupus erythematosus.

Anti-DNA and anti-RNA binding protein (RBP) antibodies can arise from different B cell populations. This difference can account for the pattern of expression during the course of systemic lupus erythematosus and the apparent relationship to disease activity. Whereas titres of anti-RBP antibodies are consistent over time because they are produced by long-lived plasma cells, anti-DNA antibody titres can vary markedly because they arise from naive B cells that transition to plasmablasts, which can be short-lived. Once secreted, both anti-DNA and anti-RBP antibodies can mediate pathogenesis either as free antibodies or as components of immune complexes, although in some instances, the actual role of these antibodies is uncertain. Cells undergoing apoptosis are considered to be the most common source of nuclear antigens, which can be released in a free form or as constituents of microparticles. Extracellular nuclear molecules can also arise from cells undergoing other forms of cell death (such as necroptosis or necrosis) or from neutrophils releasing neutrophil extracellular traps, which can occur with cell death (known as NETosis) or without. The amount of this material that is extracellular is determined by the clearance of dead and dying cells, as well as by the digestion of released nucleic acids by nucleases. Anti-DNA antibodies can also contribute to neuropsychological manifestations by mediating neuronal cell death by cross-reactive binding to the N-methyl-d-aspartate (NMDA) receptor on neurons; activation of microglial cells can subsequently affect neurons by dendritic pruning. DNase 1L3, DNase 1 like 3.

Fig. 2 |. Mechanisms of glomerulonephritis induction in systemic lupus erythematosus.

Anti-DNA antibodies can promote nephritis by several different mechanisms in systemic lupus erythematosus. a | Nephritogenic anti-DNA antibodies can form immune complexes (ICs) with circulating DNA, as well as with DNA on microparticles (MPs); these ICs can then be deposited on the glomerular basement membrane and activate complement to induce damage and recruit inflammatory cells. In this process, the charge of the antigen present might influence renal localization. b | During in situ IC formation, complexes can form with DNA or MPs that have bound to the glomerular basement membrane; such antigens are termed ‘planted’. These ICs can then activate complement. c | Anti-DNA antibodies can bind to fixed sites on the glomerular basement membrane, attracting circulating DNA in a free form or as MPs. The assembly of ICs in this mechanism requires that antibody bound to the glomerular basement membrane is, nevertheless, able to interact with circulating antigen to serve as a nidus for IC formation.