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<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 (<i>NCF1</i>-339/<i>NCF1</i><sup><i>R90H</i></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 <i>Ncf1</i><sup><i>90H</i></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 glomeruloneph ritis 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>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年2月13日

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  • Yanpeng Li,
  • Ana Coelho,
  • Zhilei Li,
  • Malin Alsved,
  • Qixing Li,
  • Rui Xu,
  • Huqiao Luo,
  • Dongxia Liang,
  • Jing Xu,
  • Kutty Selva Nandakumar,
  • Liesu Meng,
  • Jakob Löndahl,
  • Rikard Holmdahl

摘要

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 glomeruloneph ritis 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.