Characterization of DNA-protein complexes by nanoparticle tracking analysis and their association with systemic lupus erythematosus.

Autor:	Juul-Madsen K; Department of Biomedicine, Aarhus University, DK-8000 Aarhus C, Denmark., Troldborg A; Department of Biomedicine, Aarhus University, DK-8000 Aarhus C, Denmark.; Department of Rheumatology, Aarhus University Hospital, DK-8200 Aarhus N, Denmark., Wittenborn TR; Department of Biomedicine, Aarhus University, DK-8000 Aarhus C, Denmark., Axelsen MG; Department of Biomedicine, Aarhus University, DK-8000 Aarhus C, Denmark., Zhao H; Dynamics of Macromolecular Assembly Section, National Institute of Biomedical Imaging and Bioengineering, Bethesda, MD 20892., Klausen LH; Interdisiciplinary Nanoscience Center, Aarhus University, DK-8000 Aarhus C, Denmark., Luecke S; Department of Biomedicine, Aarhus University, DK-8000 Aarhus C, Denmark.; Department for Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, CA 90095., Paludan SR; Department of Biomedicine, Aarhus University, DK-8000 Aarhus C, Denmark., Stengaard-Pedersen K; Department of Rheumatology, Aarhus University Hospital, DK-8200 Aarhus N, Denmark., Dong M; Interdisiciplinary Nanoscience Center, Aarhus University, DK-8000 Aarhus C, Denmark., Møller HJ; Department of Clinical Biochemistry, Aarhus University Hospital, DK-8200 Aarhus N, Denmark., Thiel S; Department of Biomedicine, Aarhus University, DK-8000 Aarhus C, Denmark.; Center for Cellular Signal Patterns, Aarhus University, 8000 Aarhus C, Denmark., Jensen H; Department of Pharmacy, University of Copenhagen, DK-2100 Copenhagen Ø, Denmark.; FIDA Biosystems Aps, DK-2100 Copenhagen Ø, Denmark., Schuck P; Dynamics of Macromolecular Assembly Section, National Institute of Biomedical Imaging and Bioengineering, Bethesda, MD 20892., Sutherland DS; Interdisiciplinary Nanoscience Center, Aarhus University, DK-8000 Aarhus C, Denmark.; Center for Cellular Signal Patterns, Aarhus University, 8000 Aarhus C, Denmark., Degn SE; Department of Biomedicine, Aarhus University, DK-8000 Aarhus C, Denmark.; Center for Cellular Signal Patterns, Aarhus University, 8000 Aarhus C, Denmark., Vorup-Jensen T; Department of Biomedicine, Aarhus University, DK-8000 Aarhus C, Denmark; vorup-jensen@microbiology.au.dk.; Interdisiciplinary Nanoscience Center, Aarhus University, DK-8000 Aarhus C, Denmark.
Jazyk:	angličtina
Zdroj:	Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2021 Jul 27; Vol. 118 (30).
DOI:	10.1073/pnas.2106647118
Abstrakt:	Nanotechnology enables investigations of single biomacromolecules, but technical challenges have limited the application in liquid biopsies, for example, blood plasma. Nonetheless, tools to characterize single molecular species in such samples represent a significant unmet need with the increasing appreciation of the physiological importance of protein structural changes at nanometer scale. Mannose-binding lectin (MBL) is an oligomeric plasma protein and part of the innate immune system through its ability to activate complement. MBL also serves a role as a scavenger for cellular debris, especially DNA. This may link functions of MBL with several inflammatory diseases in which cell-free DNA now appears to play a role, but mechanistic insight has been lacking. By making nanoparticle tracking analysis possible in human plasma, we now show that superoligomeric structures of MBL form nanoparticles with DNA. These oligomers correlate with disease activity in systemic lupus erythematosus patients. With the direct quantification of the hydrodynamic radius, calculations following the principles of Taylor dispersion in the blood stream connect the size of these complexes to endothelial inflammation, which is among the most important morbidities in lupus. Mechanistic insight from an animal model of lupus supported that DNA-stabilized superoligomers stimulate the formation of germinal center B cells and drive loss of immunological tolerance. The formation involves an inverse relationship between the concentration of MBL superoligomers and antibodies to double-stranded DNA. Our approach implicates the structure of DNA-protein nanoparticulates in the pathobiology of autoimmune diseases. Competing Interests: Competing interest statement: K.J.-M., A.T., K.S.-P., H.J.M., and T.V.-J. are inventors on a submitted patent application (PCT/EP2020/082837) related to the discoveries of the present paper and owned by Aarhus University.
Databáze:	MEDLINE
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