Lupus resistance is associated with marginal zone abnormalities in an NZM murine model

Lab Invest. 2007 Jan;87(1):14-28. doi: 10.1038/labinvest.3700497. Epub 2006 Nov 27.

Abstract

The NZM2410 and NZM TAN (TAN) are two of 27 inbred strains derived from an intercross between the NZW and NZB strains. NZM2410 mice develop a highly penetrant lupus nephritis mediated by three susceptibility loci, Sle1, Sle2 and Sle3. These three loci have been combined on a C57BL/6 background in a triple congenic strain that reconstitutes the NZM2410 autoimmune phenotype. Remarkably, inspite of the presence of Sle1, Sle2 and Sle3, TAN mice display a mild autoimmune phenotype reminiscent of NZW. Contrary to the lupus-prone strains, the majority of TAN CD4(+) T cells are in a naïve-inactivated stage. TAN mice show B-cell developmental abnormalities similar to lupus-prone mice, such an accumulation of transitional T1 cells and peritoneal B-1a cells. TAN mice show, however, a unique expansion of the splenic marginal zone, in which B cells express high levels of CD5 and CD9, fail to migrate to the follicles in response to LPS, and show sub-optimal binding of T-independent type 2 antigens. Therefore, TAN mice present a functional silencing of marginal zone B cells, which have been previously implicated with autoimmune process. The TAN strain thus provides a novel model for the analysis of the genetic determinants of B-cell autoreactivity.

Publication types

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

MeSH terms

  • Animals
  • Autoantibodies / immunology
  • Autoantibodies / metabolism
  • B-Lymphocyte Subsets / immunology*
  • B-Lymphocytes / immunology
  • Disease Models, Animal
  • Genetic Predisposition to Disease / genetics*
  • Immunoglobulin G / immunology
  • Immunoglobulin G / metabolism
  • Kidney Cortex / pathology
  • Lupus Erythematosus, Systemic / genetics*
  • Lupus Erythematosus, Systemic / immunology
  • Lupus Nephritis / genetics
  • Lymph Nodes / cytology
  • Lymph Nodes / immunology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Inbred NZB
  • Mice, Inbred Strains / genetics*
  • Mice, Inbred Strains / immunology
  • Microsatellite Repeats / genetics*
  • Spleen / cytology
  • Spleen / immunology

Substances

  • Autoantibodies
  • Immunoglobulin G