Altered selection processes of B lymphocytes in autoimmune NZB/W mice, despite intact central tolerance against DNA

Eur J Immunol. 2001 Sep;31(9):2800-10. doi: 10.1002/1521-4141(200109)31:9<2800::aid-immu2800>3.0.co;2-e.

Abstract

Anti-DNA autoantibodies are the hallmark of systemic lupus erythematosus and the (NZBxNZW)F1 (NZB/W) murine model. To investigate potential defects in B cell tolerance, we followed the development of anti-DNA-specific B cells in 2-5-month-old mice transgenic for an unmutated muH chain in the normal C57BL/6 and in the NZB/W background. When the transgenic H chain was combined with a random kappa L chain repertoire about 60% of the antibodies bound to DNA. The analysis of the B cell repertoire in the spleen showed extensive receptor editing and a deletion of DNA reactivity in the C57BL/6 as well as in the autoimmune NZB/W background. NZB/W compared to C57BL/6 transgenic mice had a higher frequency of anti-DNA B cells among follicular B cells that were not censored by central tolerance mechanisms. Furthermore, positive selection of B cells with a recurrent rearrangement into the marginal zone compartment was more pronounced in NZB/W mice. Serum levels of transgenic IgM and of anti-DNA autoantibodies indicate a polyclonal activation of hyperactive B cells in the transgenic NZB/W mice. We propose different B cell receptor signaling thresholds for the NZB/W compared to C57BL/6 B cells. This could explain the quantitative differences in the B cell repertoire as well as the hyperactivity of B cells from NZB/W mice.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Antinuclear / immunology*
  • B-Lymphocytes / immunology*
  • Bone Marrow / immunology
  • DNA / immunology*
  • Gene Rearrangement, B-Lymphocyte, Light Chain
  • Hybridomas
  • Immunoglobulin Heavy Chains / genetics
  • Immunoglobulin M / blood
  • Immunoglobulin M / genetics
  • Immunoglobulin Variable Region
  • Lupus Erythematosus, Systemic / genetics
  • Lupus Erythematosus, Systemic / immunology*
  • Lymphocyte Count
  • Mice
  • Mice, Inbred C57BL
  • Mice, Inbred NZB
  • Mice, Transgenic
  • Self Tolerance*
  • Spleen / immunology
  • Tumor Cells, Cultured

Substances

  • Antibodies, Antinuclear
  • Immunoglobulin Heavy Chains
  • Immunoglobulin M
  • Immunoglobulin Variable Region
  • DNA