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The systemic lupus erythematosus-associated NCF190H allele synergizes with viral infection to cause mouse lupus but also limits virus spread

Li, Yanpeng ; Coelho, Ana ; Li, Zhilei ; Alsved, Malin LU orcid ; Li, Qixing ; Xu, Rui ; Luo, Huqiao ; Liang, Dongxia ; Xu, Jing and Nandakumar, Kutty Selva , et al. (2025) In Nature Communications 16(1).
Abstract

Studying how single nucleotide polymorphisms (SNPs) crosstalk with non-autologous factors to cause complex autoimmune diseases is challenging. An amino acid replacement in the neutrophil cytosolic factor 1 (NCF1-339/NCF1R90H) leading to lower reactive oxygen species induction has been reported as the major SNP for systemic lupus erythematosus (SLE). Here we show that infection with the murine norovirus (MNV) contributes to the induction of lupus in Ncf190H mice. Mutant NCF190H upregulates the IFN-α/JAK1/STAT1 pathway in macrophages and anti-MNV-antibody production. In parallel, the MNV infection of NCF190H mice upregulates Toll-like receptor 7 in macrophages, plasmacytoid dendritic cells and... (More)

Studying how single nucleotide polymorphisms (SNPs) crosstalk with non-autologous factors to cause complex autoimmune diseases is challenging. An amino acid replacement in the neutrophil cytosolic factor 1 (NCF1-339/NCF1R90H) leading to lower reactive oxygen species induction has been reported as the major SNP for systemic lupus erythematosus (SLE). Here we show that infection with the murine norovirus (MNV) contributes to the induction of lupus in Ncf190H mice. Mutant NCF190H upregulates the IFN-α/JAK1/STAT1 pathway in macrophages and anti-MNV-antibody production. In parallel, the MNV infection of NCF190H mice upregulates Toll-like receptor 7 in macrophages, plasmacytoid dendritic cells and B220+ splenocytes, thereby promoting germinal center formation and lupus-associated autoantibodies production. These compounded effects lead to protection against MNV infection but also glomerulonephritis with proteinuria and lupus arthritis in the absence of chemical inducers such as pristane. Our data thus suggest that this SLE-associated SNP, NCF190H, synergizes with MNV infection to induce the development of mouse lupus.

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Contribution to journal
publication status
published
subject
in
Nature Communications
volume
16
issue
1
article number
1593
publisher
Nature Publishing Group
external identifiers
  • pmid:39939342
  • scopus:85218452847
ISSN
2041-1723
DOI
10.1038/s41467-025-56857-z
language
English
LU publication?
yes
id
ff7bdcb4-b7fe-43e3-bf8f-06caede9e77a
date added to LUP
2025-06-10 08:47:25
date last changed
2025-07-08 11:44:49
@article{ff7bdcb4-b7fe-43e3-bf8f-06caede9e77a,
  abstract     = {{<p>Studying how single nucleotide polymorphisms (SNPs) crosstalk with non-autologous factors to cause complex autoimmune diseases is challenging. An amino acid replacement in the neutrophil cytosolic factor 1 (NCF1-339/NCF1<sup>R90H</sup>) leading to lower reactive oxygen species induction has been reported as the major SNP for systemic lupus erythematosus (SLE). Here we show that infection with the murine norovirus (MNV) contributes to the induction of lupus in Ncf1<sup>90H</sup> mice. Mutant NCF1<sup>90H</sup> upregulates the IFN-α/JAK1/STAT1 pathway in macrophages and anti-MNV-antibody production. In parallel, the MNV infection of NCF1<sup>90H</sup> mice upregulates Toll-like receptor 7 in macrophages, plasmacytoid dendritic cells and B220<sup>+</sup> splenocytes, thereby promoting germinal center formation and lupus-associated autoantibodies production. These compounded effects lead to protection against MNV infection but also glomerulonephritis with proteinuria and lupus arthritis in the absence of chemical inducers such as pristane. Our data thus suggest that this SLE-associated SNP, NCF1<sup>90H</sup>, synergizes with MNV infection to induce the development of mouse lupus.</p>}},
  author       = {{Li, Yanpeng and Coelho, Ana and Li, Zhilei and Alsved, Malin and Li, Qixing and Xu, Rui and Luo, Huqiao and Liang, Dongxia and Xu, Jing and Nandakumar, Kutty Selva and Meng, Liesu and Löndahl, Jakob and Holmdahl, Rikard}},
  issn         = {{2041-1723}},
  language     = {{eng}},
  number       = {{1}},
  publisher    = {{Nature Publishing Group}},
  series       = {{Nature Communications}},
  title        = {{The systemic lupus erythematosus-associated NCF1<sup>90H</sup> allele synergizes with viral infection to cause mouse lupus but also limits virus spread}},
  url          = {{http://dx.doi.org/10.1038/s41467-025-56857-z}},
  doi          = {{10.1038/s41467-025-56857-z}},
  volume       = {{16}},
  year         = {{2025}},
}