Dnase1-deficient mice spontaneously develop a systemic lupus erythematosus-like disease

Eur J Immunol. 2019 Apr;49(4):590-599. doi: 10.1002/eji.201847875. Epub 2019 Feb 21.

Abstract

Systemic lupus erythematosus (SLE) is an autoimmune disease that has high morbidity and can result in multi-organ damage. SLE is characterized by dysregulated activation of T- and B-lymphocytes and the production of autoantibodies directed against nuclear components. The endonuclease deoxyribonuclease 1 (DNase1) is abundant in blood and a subset of SLE patients have mutations in DNASE1. Furthermore, a report showed that Dnase1-deficient mice develop an SLE-like disease, but these mice also carry a deletion of the gene adjacent to Dnase1, which encodes the chaperone TRAP1/HSP75. We generated a murine strain deficient in Dnase1 with an intact Trap1 gene to examine if a lack of DNase1 is responsible for the development of a spontaneous SLE-like disease. We show that the Dnase1-deficient mice do indeed develop an SLE-like phenotype with elevated autoantibody production by 9 months and kidney damage by 12 months. Notably, this model recapitulates the female bias seen in human SLE patients since female Dnase1-deficient mice produced the highest concentrations of autoantibodies and had more severe kidney damage than males. Since there is currently no cure for SLE the protective role of DNase1 as demonstrated in our study remains of great therapeutic interest.

Keywords: DNase1; Systemic lupus erythematosus; autoantibodies; murine models; nephritis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Autoantibodies / immunology
  • B-Lymphocytes / immunology
  • B-Lymphocytes / metabolism
  • Biomarkers
  • Biopsy
  • Deoxyribonuclease I / deficiency*
  • Disease Models, Animal
  • Female
  • Genetic Association Studies* / methods
  • Genetic Predisposition to Disease*
  • HSP90 Heat-Shock Proteins / genetics
  • HSP90 Heat-Shock Proteins / metabolism
  • Lupus Erythematosus, Systemic / etiology*
  • Lupus Erythematosus, Systemic / metabolism
  • Lupus Erythematosus, Systemic / pathology
  • Lupus Nephritis / etiology
  • Lupus Nephritis / metabolism
  • Lupus Nephritis / pathology
  • Male
  • Mice
  • Mice, Knockout
  • Sex Factors

Substances

  • Autoantibodies
  • Biomarkers
  • HSP90 Heat-Shock Proteins
  • Deoxyribonuclease I