The systemic lupus erythematosus-associated NCF1^90H allele synergizes with viral infection to cause mouse lupus but also limits virus spread.

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/NCF1^R90H) 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 Ncf1^90H mice. Mutant NCF1^90H upregulates the IFN-α/JAK1/STAT1 pathway in macrophages and anti-MNV-antibody production. In parallel, the MNV infection of NCF1^90H 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, NCF1^90H, synergizes with MNV infection to induce the development of mouse lupus.