Sh3bp2 Gain-Of-Function Mutation Ameliorates Lupus Phenotypes in B6.MRL- Fas lpr Mice

Cells. 2019 Apr 30;8(5):402. doi: 10.3390/cells8050402.

Abstract

SH3 domain-binding protein 2 (SH3BP2) is an adaptor protein that is predominantly expressed in immune cells, and it regulates intracellular signaling. We had previously reported that a gain-of-function mutation in SH3BP2 exacerbates inflammation and bone loss in murine arthritis models. Here, we explored the involvement of SH3BP2 in a lupus model. Sh3bp2 gain-of-function (P416R knock-in; Sh3bp2KI/+) mice and lupus-prone B6.MRL-Faslpr mice were crossed to yield double-mutant (Sh3bp2KI/+Faslpr/lpr) mice. We monitored survival rates and proteinuria up to 48 weeks of age and assessed renal damage and serum anti-double-stranded DNA antibody levels. Additionally, we analyzed B and T cell subsets in lymphoid tissues by flow cytometry and determined the expression of apoptosis-related molecules in lymph nodes. Sh3bp2 gain-of-function mutation alleviated the poor survival rate, proteinuria, and glomerulosclerosis and significantly reduced serum anti-dsDNA antibody levels in Sh3bp2KI/+Faslpr/lpr mice. Additionally, B220+CD4-CD8- T cell population in lymph nodes was decreased in Sh3bp2KI/+Faslpr/lpr mice, which is possibly associated with the observed increase in cleaved caspase-3 and tumor necrosis factor levels. Sh3bp2 gain-of-function mutation ameliorated clinical and immunological phenotypes in lupus-prone mice. Our findings offer better insight into the unique immunopathological roles of SH3BP2 in autoimmune diseases.

Keywords: Fas; SH3 domain–binding protein 2; anti-dsDNA antibody; dendritic cells; double-negative T cells; lpr mutation; macrophages; murine lupus model; systemic lupus erythematosus; tumor necrosis factor.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics*
  • Animals
  • Antibodies, Antinuclear / blood
  • Apoptosis
  • B-Lymphocytes / immunology
  • Caspase 3 / metabolism
  • Cell Differentiation
  • Dendritic Cells / metabolism
  • Gain of Function Mutation / genetics*
  • Lupus Erythematosus, Systemic / blood
  • Lupus Erythematosus, Systemic / genetics*
  • Lupus Erythematosus, Systemic / pathology*
  • Lymph Nodes / pathology
  • Macrophages / metabolism
  • Mice, Inbred C57BL
  • Mice, Inbred MRL lpr
  • Phagocytosis
  • Phenotype
  • Survival Analysis
  • T-Lymphocytes / immunology
  • Tumor Necrosis Factor-alpha / metabolism
  • fas Receptor / metabolism

Substances

  • Adaptor Proteins, Signal Transducing
  • Antibodies, Antinuclear
  • Fas protein, mouse
  • Sh3bp2 protein, mouse
  • Tumor Necrosis Factor-alpha
  • fas Receptor
  • Caspase 3