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Monoclonal anti-dsDNA antibody 2C10 escorts DNA to intracellular DNA sensors in normal mononuclear cells and stimulates secretion of multiple cytokines implicated in lupus pathogenesis.

08:00 EDT 11th October 2019 | BioPortfolio

Summary of "Monoclonal anti-dsDNA antibody 2C10 escorts DNA to intracellular DNA sensors in normal mononuclear cells and stimulates secretion of multiple cytokines implicated in lupus pathogenesis."

There have been many studies on mechanisms of internalization of DNA-anti-DNA immune complexes by cells, including the one used rheumatoid factor expressing mouse B cells. In parallel, studies on the role of intracellular DNA sensors in the pathogenesis of systemic lupus erythematosus (SLE) have been conducted including the one using a mouse model lacking one of the sensors. These and other data have established a framework for understanding the pathogenic role of anti-DNA antibodies, but studies on normal cells are limited. Here, we used the monoclonal anti-dsDNA antibody 2C10, 2 kbp dsDNA, and healthy human peripheral blood mononuclear cells (PBMCs) to test whether and how 2C10 and/or DNA cause pathology in normal cells. We found that on culture with PBMCs, 2C10 preferentially entered monocytes and that DNA enhanced this internalization. In contrast, DNA alone was not significantly internalized by monocytes, but 2C10 facilitated its internalization. This was suppressed by cytochalasin D, but not by methyl-β-cyclodextrin, chloroquine, or an Fc blocker, suggesting the involvement of macropinocytosis in this process. Internalization of 2C10 and DNA together resulted in production of IFN-α, IFN-γ, TNF-α, MCP-1, IL-1β, IL-6, IL-10 and IL-33 by PBMCs. Cytokine production was suppressed by chloroquine and shikonin, but not by RU.521, suggesting dependence on activation of the TLR9 and AIM2 pathways. These results established a simple model to demonstrate that anti-DNA antibodies can cause dysregulation of cytokine network mimicking SLE in culture of normal PBMCs, and emphasize again the importance of maintaining anti-DNA antibodies at low levels by treatment.

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Name: Clinical and experimental immunology
ISSN: 1365-2249
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