Lack of IL-17 Receptor A signaling aggravates lymphoproliferation in C57BL/6 lpr mice

Sci Rep. 2019 Mar 11;9(1):4032. doi: 10.1038/s41598-019-39483-w.

Abstract

Defects in Fas function correlate with susceptibility to systemic autoimmune diseases like autoimmune lymphoproliferative syndrome (ALPS) and systemic lupus erythematosus (SLE). C57BL/6 lpr (B6/lpr) mice are used as an animal model of ALPS and develop a mild SLE phenotype. Involvement of interleukin-17A (IL-17A) has been suggested in both phenotypes. Since IL-17 receptor A is part of the signaling pathway of many IL-17 family members we investigated the role of IL-17 receptor signaling in disease development in mice with a B6/lpr background. B6/lpr mice were crossed with IL-17 receptor A deficient (IL-17RA KO) mice and followed over time for disease development. IL-17RA KO/lpr mice presented with significantly enhanced lymphoproliferation compared with B6/lpr mice, which was characterized by dramatic lymphadenomegaly/splenomegaly and increased lymphocyte numbers, expansion of double-negative (DN) T-cells and enhanced plasma cell formation. However, the SLE phenotype was not enhanced, as anti-nuclear antibody (ANA) titers and induction of glomerulonephritis were not different. In contrast, levels of High Mobility Group Box 1 (HMGB1) and anti-HMGB1 autoantibodies were significantly increased in IL-17RA KO/lpr mice compared to B6/lpr mice. These data show that lack of IL-17RA signaling aggravates the lymphoproliferative phenotype in B6/lpr mice but does not affect the SLE phenotype.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Autoimmune Lymphoproliferative Syndrome / immunology*
  • B-Lymphocytes / immunology*
  • B-Lymphocytes / pathology
  • Cell Proliferation
  • HMGB1 Protein / metabolism
  • Kidney / immunology
  • Kidney / pathology
  • Lupus Erythematosus, Systemic / immunology*
  • Lymph Nodes / immunology
  • Lymph Nodes / pathology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Inbred MRL lpr
  • Mice, Knockout
  • Receptors, Interleukin-17 / genetics
  • Receptors, Interleukin-17 / physiology*
  • Spleen / immunology
  • Spleen / pathology
  • T-Lymphocytes / immunology*
  • T-Lymphocytes / pathology

Substances

  • HMGB1 Protein
  • HMGB1 protein, mouse
  • Il17ra protein, mouse
  • Receptors, Interleukin-17