A Variant of the Histone-Binding Protein sNASP Contributes to Mouse Lupus

• Published in: Frontiers in immunology Vol. 10; p. 637
• Main Authors: Ju, Jiyu, Xu, Jia, Zhu, Yaoqiang, Fu, Xiaoyan, Morel, Laurence, Xu, Zhiwei
• Format: Journal Article
• Language: English
• Published: Switzerland Frontiers Media S.A 02.04.2019
• Subjects: genetics; histone-binding protein; Immunology; lupus; lupus nephritis; mouse; NASP; mouse; lupus nephritis; genetics; NASP; histone-binding protein; lupus
• ISSN: 1664-3224; 1664-3224
• DOI: 10.3389/fimmu.2019.00637

The ( ) sublocus is derived from the mouse lupus susceptibility 2 ( ) locus identified in the NZM2410 model. Our current study dissected the functional characters and the genetic basis of the locus relative to lupus when co-expressed with the Fas mutation, an established inducer of autoimmunity. The rec1c.lpr mice exhibited mild expansion of lymph nodes and had a normal T cell cellularity, but developed significantly kidney and lung inflammation, indicating that the amplifies -induced autoimmune pathogenesis. A variant of somatic nuclear autoantigenic sperm protein (sNASP) was identified from the interval as a substitution of two consecutive amino acid residues in the histone-binding domain, resulting in an increased binding affinity to histone H4 and H3.1/H4 tetramer. To determine the role of the allele in mouse lupus, a novel strain was generated by introducing the mutations into the B6 genome. In this transgenic model, the allele synergized with the mutation leading to moderate autoimmune phenotypes and aggravating inflammatory pathology alterations in kidney and lung that were similar to those observed in the rec1c.lpr mice. These results establish that the allele is a pathogenic genetic element in the sublocus, which not only promotes autoimmunity, but also exacerbates the inflammation reaction of end organs in mouse lupus pathogenesis. It also shows the complexity of the locus, initially mapped as the major locus associated with B1a cell expansion. In addition to , which regulates this expansion, we have now identified in the same locus a protective allele of , a variant of Skint6 associated with T cell activation, and now a variant of that amplifies autoimmunity and tissue damage.