Among ANAs, anti-DNA antibodies are linked to active disease, especially lupus nephritis, and fluctuate with disease activity, suggesting they arise from newly activated B cells. Meanwhile, antibodies to RNA binding proteins (RBPs), such as Sm, RNP, Ro and La, are more stable and are produced by long-lived plasma cells.
“Despite differences in expression over time and relationship to disease activity, both anti-DNA and anti-Sm antibodies are criteria for the classification of patients with SLE. Antibodies to other RBPs (e.g., RNP, Ro and La) can be present in other diseases,” Dr. Pisetsky writes. “The lack of specificity of these antibodies for classification or diagnosis should in no way minimize their importance for pathogenesis.”
Anti-DNA antibodies can bind to DNA in the blood, forming immune complexes that lead to renal deposition, provoking nephritis and “stimulating cytokine production following uptake into innate immune cells and interaction with internal nucleic acid sensors,” Dr. Pisetsky explains. These nucleic acid sensors contribute to an internal host defense system in the cytoplasm that “can respond to DNA from infecting organisms. During cell stress, DNA from nuclear and mitochondrial sources can also trigger these sensors,” he writes.
A source of immunologically active, extracellular DNA is needed to form immune complexes. Patients with SLE have abnormal neutrophil populations predisposed to a distinct type of death, termed NETosis, which forms an extended mesh-like structure called a neutrophil extracellular trap (NET). NETs contain high molecular weight DNA. In SLE, “the combination of ANAs and immunologically active DNA can create new structures that can promote inflammation throughout the body, as well as drive organ inflammation and damage,” Dr. Pisetsky explains.
Further, SLE research has shown that type 1 interferon plays a central role in the pathogenesis. Studies show that sera of patients with SLE can induce interferon production “by immune cells in vitro, with immune complexes of ANAs and their cognate nuclear autoantigens driving these responses,” Dr. Pisetsky writes.
Genetics
Around 200 different gene loci have been associated with SLE. Genetic polymorphisms can influence the immune system by affecting B and T cell response thresholds. “Because of aberrant signaling during steps of tolerance, the B cell repertoire in patients with SLE can contain precursors for DNA and other autoantigens that, in otherwise healthy individuals, would be removed or anergized,” Dr. Pisetsky writes.
Mutations of single genes can provoke SLE, notably by involving complement and clearance systems for nucleic acids. The review provides a table of selected single-gene systems associated with SLE or related conditions.
