Autoimmune bone marrow environment severely inhibits B cell development by inducing extensive cell death and inhibiting proliferation

Autoimmunity. 2012 May;45(3):210-7. doi: 10.3109/08916934.2011.632455. Epub 2012 Feb 7.

Abstract

The spontaneous scurfy (sf) mutation in mice results in a complete loss of Tregs, leading to a lethal, multi-system autoimmune syndrome. We have carefully examined B lymphopoiesis in sf mice. Paradoxically, the B cell numbers at all developmental stages including pro-B, pre-B, immature and mature B cells are significantly decreased in the BM and spleen of sf mice, compared to that of wild-type littermate controls. The developing B cells in sf mice exhibit profoundly elevated cell death induced by down-regulation of Bcl-XL expression and up-regulation of Fas expression. In addition, the clonal expansion of pre-B and immature B cells in sf mice is significantly reduced compared to wild-type controls. Foxp3 expression is not detectable in all stages of developing B cells in wild-type mice, indicating that the defects are B-cell extrinsic, which is further supported by the recovery of B cell maturation in BM chimeric mice. Remarkably, IFN-γ production is significantly elevated in numerous cell types in the BM of sf mice. Taken together, these results indicate that the autoimmune inflammatory marrow environment has dramatic inhibitory effects on B cell development by inducing apoptosis and suppressing proliferation of developing B cells.

MeSH terms

  • Animals
  • Autoimmunity* / genetics
  • B-Lymphocytes / immunology*
  • B-Lymphocytes / metabolism
  • Bone Marrow / immunology*
  • Cell Death / genetics
  • Cell Death / immunology
  • Cell Differentiation / genetics
  • Cell Differentiation / immunology
  • Cellular Microenvironment / immunology*
  • Female
  • Forkhead Transcription Factors / genetics
  • Interferon-gamma / biosynthesis
  • Lymphopoiesis / genetics
  • Lymphopoiesis / immunology*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • bcl-X Protein / metabolism
  • fas Receptor / metabolism

Substances

  • Forkhead Transcription Factors
  • Foxp3 protein, mouse
  • bcl-X Protein
  • fas Receptor
  • Interferon-gamma