AUTHOR=Ju Jiyu , Xu Jia , Zhu Yaoqiang , Fu Xiaoyan , Morel Laurence , Xu Zhiwei 

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

JOURNAL=Frontiers in Immunology

VOLUME=10

YEAR=2019

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2019.00637

DOI=10.3389/fimmu.2019.00637

ISSN=1664-3224

ABSTRACT=<p>The <italic>Sle2c1rec1c</italic> (<italic>rec1c</italic>) sublocus is derived from the mouse lupus susceptibility 2 (<italic>Sle2</italic>) locus identified in the NZM2410 model. Our current study dissected the functional characters and the genetic basis of the <italic>rec1c</italic> locus relative to lupus when co-expressed with the Fas<sup><italic>lpr</italic></sup> 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 <italic>rec1c</italic> amplifies <italic>lpr</italic>-induced autoimmune pathogenesis. A variant of somatic nuclear autoantigenic sperm protein (sNASP) was identified from the <italic>rec1c</italic> 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 <italic>sNASP rec1c</italic> allele in mouse lupus, a novel strain was generated by introducing the <italic>rec1c</italic> mutations into the B6 genome. In this transgenic model, the <italic>sNASP</italic> allele synergized with the <italic>lpr</italic> 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 <italic>sNASP</italic> allele is a pathogenic genetic element in the <italic>rec1c</italic> 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 <italic>Sle2c</italic> locus, initially mapped as the major locus associated with B1a cell expansion. In addition to <italic>Cdkn2c</italic>, which regulates this expansion, we have now identified in the same locus a protective allele of <italic>Csf3r</italic>, a variant of Skint6 associated with T cell activation, and now a variant of <italic>sNASP</italic> that amplifies autoimmunity and tissue damage.</p>