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

Kristian Juul-Madsen; Anne Troldborg; Thomas R Wittenborn; Mads G Axelsen; Huaying Zhao; Lasse H Klausen; Stefanie Luecke; Søren R Paludan; Kristian Stengaard-Pedersen; Mingdong Dong; Holger J Møller; Steffen Thiel; Henrik Jensen; Peter Schuck; Duncan S Sutherland; Søren E Degn; Thomas Vorup-Jensen

doi:10.1073/pnas.2106647118

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

Kristian Juul-Madsen, Anne Troldborg, Thomas R Wittenborn, Mads G Axelsen, Huaying Zhao, Lasse H Klausen, Stefanie Luecke, Søren R Paludan, Kristian Stengaard-Pedersen, Mingdong Dong, Holger J Møller, Steffen Thiel, Henrik Jensen, Peter Schuck, Duncan S Sutherland, Søren E Degn, Thomas Vorup-Jensen

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

9 Citations (Scopus)

Abstract

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.

Original language	English
Article number	e2106647118
Journal	Proceedings of the National Academy of Sciences (PNAS)
Volume	118
Issue	30
Number of pages	10
ISSN	0027-8424
DOIs	https://doi.org/10.1073/pnas.2106647118
Publication status	Published - Jul 2021

Keywords

Nanotechnology | autoimmunity | mannan-binding lectin | systemic lupus erythematosus
COMPLEMENT
ACTIVATION
SERINE PROTEASES
RECOGNITION
DISPERSION
POLYVALENT BINDING
mannan-binding lectin&nbsp
MANNAN-BINDING LECTIN
systemic lupus erythematosus
nanotechnology&nbsp
autoimmunity&nbsp
NANOSCIENCE
LIGAND
COLLECTINS

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10.1073/pnas.2106647118

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8325352/pdf/pnas.202106647.pdf

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Juul-Madsen, K., Troldborg, A., Wittenborn, T. R., Axelsen, M. G., Zhao, H., Klausen, L. H., Luecke, S., Paludan, S. R., Stengaard-Pedersen, K., Dong, M., Møller, H. J., Thiel, S., Jensen, H., Schuck, P., Sutherland, D. S., Degn, S. E., & Vorup-Jensen, T. (2021). Characterization of DNA-protein complexes by nanoparticle tracking analysis and their association with systemic lupus erythematosus. Proceedings of the National Academy of Sciences (PNAS), 118(30), Article e2106647118. https://doi.org/10.1073/pnas.2106647118

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abstract = "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.",

keywords = "Nanotechnology | autoimmunity | mannan-binding lectin | systemic lupus erythematosus, COMPLEMENT, ACTIVATION, SERINE PROTEASES, RECOGNITION, DISPERSION, POLYVALENT BINDING, mannan-binding lectin&nbsp, MANNAN-BINDING LECTIN, systemic lupus erythematosus, nanotechnology&nbsp, autoimmunity&nbsp, NANOSCIENCE, LIGAND, COLLECTINS",

author = "Kristian Juul-Madsen and Anne Troldborg and Wittenborn, {Thomas R} and Axelsen, {Mads G} and Huaying Zhao and Klausen, {Lasse H} and Stefanie Luecke and Paludan, {S{\o}ren R} and Kristian Stengaard-Pedersen and Mingdong Dong and M{\o}ller, {Holger J} and Steffen Thiel and Henrik Jensen and Peter Schuck and Sutherland, {Duncan S} and Degn, {S{\o}ren E} and Thomas Vorup-Jensen",

year = "2021",

month = jul,

doi = "10.1073/pnas.2106647118",

language = "English",

volume = "118",

journal = "Proceedings of the National Academy of Sciences (PNAS)",

issn = "0027-8424",

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Juul-Madsen, K , Troldborg, A , Wittenborn, TR, Axelsen, MG, Zhao, H, Klausen, LH, Luecke, S, Paludan, SR , Stengaard-Pedersen, K , Dong, M , Møller, HJ , Thiel, S, Jensen, H, Schuck, P, Sutherland, DS , Degn, SE & Vorup-Jensen, T 2021, 'Characterization of DNA-protein complexes by nanoparticle tracking analysis and their association with systemic lupus erythematosus', Proceedings of the National Academy of Sciences (PNAS), vol. 118, no. 30, e2106647118. https://doi.org/10.1073/pnas.2106647118

Characterization of DNA-protein complexes by nanoparticle tracking analysis and their association with systemic lupus erythematosus. / Juul-Madsen, Kristian ; Troldborg, Anne ; Wittenborn, Thomas R et al.
In: Proceedings of the National Academy of Sciences (PNAS), Vol. 118, No. 30, e2106647118, 07.2021.

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

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T1 - Characterization of DNA-protein complexes by nanoparticle tracking analysis and their association with systemic lupus erythematosus

AU - Juul-Madsen, Kristian

AU - Troldborg, Anne

AU - Wittenborn, Thomas R

AU - Axelsen, Mads G

AU - Zhao, Huaying

AU - Klausen, Lasse H

AU - Luecke, Stefanie

AU - Paludan, Søren R

AU - Stengaard-Pedersen, Kristian

AU - Dong, Mingdong

AU - Møller, Holger J

AU - Thiel, Steffen

AU - Jensen, Henrik

AU - Schuck, Peter

AU - Sutherland, Duncan S

AU - Degn, Søren E

AU - Vorup-Jensen, Thomas

PY - 2021/7

Y1 - 2021/7

N2 - 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.

AB - 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.

KW - Nanotechnology | autoimmunity | mannan-binding lectin | systemic lupus erythematosus

KW - COMPLEMENT

KW - ACTIVATION

KW - SERINE PROTEASES

KW - RECOGNITION

KW - DISPERSION

KW - POLYVALENT BINDING

KW - mannan-binding lectin&nbsp

KW - MANNAN-BINDING LECTIN

KW - systemic lupus erythematosus

KW - nanotechnology&nbsp

KW - autoimmunity&nbsp

KW - NANOSCIENCE

KW - LIGAND

KW - COLLECTINS

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U2 - 10.1073/pnas.2106647118

DO - 10.1073/pnas.2106647118

M3 - Journal article

C2 - 34301873

SN - 0027-8424

VL - 118

JO - Proceedings of the National Academy of Sciences (PNAS)

JF - Proceedings of the National Academy of Sciences (PNAS)

IS - 30

M1 - e2106647118

ER -

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

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