Abstract
A variant of somatic nuclear autoantigenic sperm protein (sNASP) was identified from the murine lupus susceptibility locus Sle2c1 by whole exome sequencing (WES). Previous studies have shown that mutant sNASP could synergize with the Faslpr mutation in exacerbating autoimmunity and aggravating end-organ inflammation. In the current study, the sNASP mutation was introduced into Sle1.Yaa mice to detect whether it has a synergistic effect with Sle1 or Yaa loci. As expected, compared with Sle1.Yaa mice, Sle1.Yaa.ΔsNASP mice showed enlarged lymph nodes, aggravated renal inflammation, and shortened survival time. The proportions of CD3+ T cells, activated CD19+CD86+ B cells, Th1 cells in the spleen and lymph nodes, and Th17 cells in lymph nodes in Sle1.Yaa.ΔsNASP mice were increased compared to those in Sle1.Yaa mice. The levels of IFN-γ and TNF-α in the serum of Sle1.Yaa.ΔsNASP mice were higher than those of Sle1.Yaa mice. The above results show that mutant sNASP can interact with different lupus susceptibility genes and promote the disease process of systemic lupus erythematosus.
Highlights
Systemic lupus erythematosus (SLE) is a highly heterogeneous autoimmune disorder that causes damage to multiple organ systems
To confirm whether the mutant somatic nuclear autoantigenic sperm protein (sNASP) has epistatic interactions with the Sle1 and Y-linked autoimmune accelerator (Yaa) loci, we analyzed the pathological alterations of the Sle1.Yaa.ΔsNASP strain compared to the control Sle1.Yaa mice at 6 months of age
We revealed a novel mutant sNASP in the Sle2c1 locus, which can cooperate with Faslpr mutation to amplify autoimmunity and greatly exacerbate kidney and lung damage in the B6.lpr strain [5]
Summary
Systemic lupus erythematosus (SLE) is a highly heterogeneous autoimmune disorder that causes damage to multiple organ systems. Because the clinical manifestations of spontaneous lupus mice are comparable to those of human SLE patients, various mouse models have been developed to dissect the genetic and cellular mechanisms of SLE [2], as well as to identify and validate therapeutic targets [3]. A nonsynonymous mutation of two adjacent bases on the sNASP gene resulted in changes of the 281 and 282 amino acids in the histone binding region from valine and leucine to isoleucine and phenylalanine. We revealed that the mutant sNASP has a greater affinity to the H4 histone or H3.1/H4 tetramer than the normal sNASP protein in vitro, suggesting that the amino acid changes alter its threedimensional structure and function. Our results demonstrate that the variant of sNASP in the B6.lpr strain was responsible for aggravating inflammatory pathology alterations in the kidney and lung and the majority of the cellular dysfunction in the spleen and lymph nodes
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