Study Tells How Anti-dsDNA Antibodies Promote Lupus Severity

Researchers at Sun Yat-sen University in China have found that a group of anti-nuclear antibodies that target double stranded DNA, anti-dsDNA, may cause inflammation in systemic lupus erythomatosus (SLE) patients, through the activation of a particular molecular inflammasome.

The findings were revealed in the study “Anti-dsDNA antibodies bind to TLR4 and activate NLRP3 inflammasome in lupus monocytes/macrophages,” published in the Journal of Translational Medicine.

SLE is a systemic autoimmune disease that affects multiple organs in the body. Dysregulation of the immune system plays a crucial role in the development and progression of the disease. Interluekin-1 (IL-1β) is a proinflammatory cytokine extensively linked to SLE. Not only is it expressed in the anti-body rich blood of SLE patients, its depletion in mice causes resistance to the induction of experimental lupus.

The NLRP3 inflammasome is a mulltiprotien complex that when activated, leads to the production and secretion of the active form of IL-1β. Inflammasomes are expressed in monocytes and macrophages that are activated by infection signals that trigger the production of pro-inflammatory cytokines to boost the immune response.

Niansheng Yang and his team have shown that anti-dsDNA antibodies, found in the blood of SLE patients before disease onset and known to play a role in the pathogenesis of SLE, can stimulate the expression and secretion of IL-1β from mononuclear cells and monocytes through the activation of the NLRP3 inflammasome.

The results suggest that anti-dsDNA antibodies might promote disease initiation and progression by inducing IL-1β production and enhancing the inflammatory response in a NLRP3-dependent manner.

The  investigators also found that anti-dsDNA antibodies induced NLRP3 inflammasome activation by binding to TLR4, then induced the production of mitochondrial reactive oxygen species (ROS).

When anti-dsDNA antibodies were injected into an SLE mouse model, activation of the inflammasome in the monocytes was stimulated. The activation may be involved in the differentiation of Th17 cells, a newly identified subpopulation of CD4 T-cells that play major roles in SLE pathogenesis – because the mice presented increased levels of Th17 cells and decreased the amount of regulatory T cells.

These results suggest that anti-dsDNA antibodies-mediated NLRP3 activation may lead to increased disease severity by disrupting the balance of Th17/Treg cells.