Anti-double Stranded DNA Antibodies: Origin, Pathogenicity, and Targeted Therapies

Abstract

Systemic lupus erythematosus (SLE) is characterized by high-titer serological autoantibodies, including antibodies that bind to double-stranded DNA (dsDNA). The origin, specificity, and pathogenicity of anti-dsDNA antibodies have been studied from a wider perspective. These autoantibodies have been suggested to contribute to multiple end-organ injuries, especially to lupus nephritis, in patients with SLE. Moreover, serum levels of anti-DNA antibodies fluctuate with disease activity in patients with SLE. By directly binding to self-antigens or indirectly forming immune complexes, anti-dsDNA antibodies can accumulate in the glomerular and tubular basement membrane. These autoantibodies can also trigger the complement cascade, penetrate into living cells, modulate gene expression, and even induce profibrotic phenotypes of renal cells. In addition, the expression of suppressor of cytokine signaling 1 is reduced by anti-DNA antibodies simultaneously with upregulation of profibrotic genes. Anti-dsDNA antibodies may even participate in the pathogenesis of SLE by catalyzing hydrolysis of certain DNA molecules or peptides in cells. Recently, anti-dsDNA antibodies have been explored in greater depth as a therapeutic target in the management of SLE. A substantial amount of data indicates that blockade of pathogenic anti-dsDNA antibodies can prevent or even reverse organ damage in murine models of SLE. This review focuses on the recent research advances regarding the origin, specificity, classification, and pathogenicity of anti-dsDNA antibodies and highlights the emerging therapies associated with them.

Keywords: anti-dsDNA antibody; catalysis; lupus nephritis; peptide; suppressor of cytokine signaling 1 (SOCS1); systemic lupus erythematosus (SLE).

Figure 1

The pathogenic mechanism of anti-dsDNA antibodies in LN. After binding to DNA and non-DNA antigens, the penetrating anti-dsDNA antibodies relocate to the cytosol and cell nucleus, cause DNA fragmentation (accompanied by dysfunction of DNase), and induce apoptosis by regulating the gene expression of p53, Fas, or c-myc. The internalized anti-dsDNA antibodies enhance the expression of IL-6, IL-1β, TNF-α, and TGF-β1, activate the PKC, MAPK, TWEAK/Fn14, and EMT signaling pathways, and trigger the fibrotic process. Local deposition of anti-dsDNA IgG—in combination with the secretion of inflammatory or profibrogenic cytokines as well as the recruitment of immune cells—is sufficient for the initiation of renal fibrosis in LN.

Figure 2

The catalytic properties of anti-dsDNA IgG. Anti-dsDNA IgG binds to DNA at the thymine repetitive sequences via tyrosine side chains within a hydrophobic pocket. Hydrolysis of DNA is an energy-intensive process and can be activated by the binding of Ca²⁺ and Mg²⁺. After binding to DNA, the active site of IgG is converted to a transition state, and the DNA fragments are produced and released. At this point, the free IgG binds to another DNA molecule and begins its new cycle, in which IgG stabilizes the transition state of the reaction and lowers the activation energy, and thereby increases the rate of the reaction.