Impaired clearance of apoptotic cells induces the activation of autoreactive anti-Sm marginal zone and B-1 B cells

J Immunol. 2004 Jan 1;172(1):625-35. doi: 10.4049/jimmunol.172.1.625.

Abstract

Since apoptotic cell Ags are thought to be a source of self-Ag in systemic lupus erythematosus, we have examined the role of apoptotic cells in the regulation and activation of B cells specific for Sm, a ribonucleoprotein targeted in human and murine lupus. Using Ig-transgenic mice that have a high frequency of anti-Sm B cells, we find that apoptotic cell injection induces a transient splenic B cell response, while simultaneously causing extensive splenic and peritoneal anti-Sm B cell death. In contrast, mice deficient in the clearance of apoptotic cells develop a chronic anti-Sm response beginning at 1-2 mo of age. These mice have expanded marginal zone and B-1 B cell populations and anti-Sm B cells of both types are activated to form Ab-secreting cells. This activation appears to be Ag-specific, suggesting that activation is due to increased availability of apoptotic cell Ags. Since marginal zone and B-1 cells are positively selected, these data suggest a loss of ignorance rather than a loss of tolerance.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Apoptosis / genetics
  • Apoptosis / immunology*
  • Autoantigens / immunology*
  • B-Lymphocyte Subsets / cytology
  • B-Lymphocyte Subsets / immunology*
  • B-Lymphocyte Subsets / metabolism
  • B-Lymphocyte Subsets / pathology
  • Cell Death / immunology
  • Epitopes, B-Lymphocyte / genetics
  • Epitopes, B-Lymphocyte / immunology
  • Lymphocyte Activation / genetics
  • Lymphocyte Activation / immunology*
  • Lymphopenia / genetics
  • Lymphopenia / immunology
  • Lymphopenia / pathology
  • Mice
  • Mice, Transgenic
  • Mutation
  • Peritoneum / cytology
  • Peritoneum / immunology
  • Peritoneum / pathology
  • Phosphatidylcholines / immunology
  • Proto-Oncogene Proteins*
  • Receptor Protein-Tyrosine Kinases / genetics
  • Ribonucleoproteins, Small Nuclear / immunology*
  • Spleen / cytology*
  • Spleen / immunology*
  • Spleen / metabolism
  • c-Mer Tyrosine Kinase
  • snRNP Core Proteins

Substances

  • Autoantigens
  • Epitopes, B-Lymphocyte
  • Phosphatidylcholines
  • Proto-Oncogene Proteins
  • Ribonucleoproteins, Small Nuclear
  • Snrpb protein, mouse
  • snRNP Core Proteins
  • Mertk protein, mouse
  • Receptor Protein-Tyrosine Kinases
  • c-Mer Tyrosine Kinase