Defects in the regulation of B cell apoptosis are required for the production of citrullinated peptide autoantibodies in mice

Arthritis Rheum. 2003 Aug;48(8):2353-61. doi: 10.1002/art.11107.


Objective: Protein deimination, a process to modify arginine residues to citrulline by the addition of a neutral oxygen group, is associated with apoptosis. The presence of autoantibodies recognizing citrullinated peptides is highly specific to rheumatoid arthritis (RA) and is therefore a useful marker for the early diagnosis of RA. In this study, we explored whether anti-cyclic citrullinated peptide (anti-CCP) autoantibodies are produced in several experimental models of autoimmune diseases in mice.

Methods: The levels of anti-CCP autoantibodies were analyzed by enzyme-linked immunosorbent assay in several lupus-prone strains of mice, in animals with type II collagen (CII)-induced arthritis, and after induction of neonatal tolerance to alloantigens.

Results: We observed the production of these autoantibodies in 2 different lupus-prone mice, MRL-lpr/lpr and (NZW x B6)F(1)-hbcl-2 transgenic mice, characterized by the presence of abnormalities in the regulation of B cell apoptosis. Other genetic defects, determining autoimmune susceptibility, present in MRL and NZW mice were additionally required for anti-CCP autoantibody production. The induction of autoantibodies in normal BALB/c mice injected at birth with semiallogeneic spleen cells from (BALB/c x B6)F(1)-hbcl-2 transgenic mice suggested that these additional autoimmune defects may be related, at least in part, to the establishment of abnormal interactions between T cells and B cells. In addition, anti-CCP autoantibodies were not produced in the course of CII-induced arthritis, an experimental model of RA in mice.

Conclusion: Our study provides evidence for the association between defects in the regulatory cell death machinery of B lymphocytes and the production of certain autoantibody specificities.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / immunology*
  • Arthritis, Rheumatoid / immunology*
  • Autoantibodies / immunology*
  • Autoantibodies / metabolism
  • B-Lymphocytes / cytology*
  • B-Lymphocytes / immunology*
  • Cell Communication / immunology
  • Citrulline / immunology*
  • Gene Expression / immunology
  • Humans
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, Inbred DBA
  • Mice, Inbred MRL lpr
  • Mice, Inbred NZB
  • Mice, Transgenic
  • Peptides / immunology
  • Proto-Oncogene Proteins c-bcl-2 / genetics
  • Species Specificity
  • T-Lymphocytes / cytology
  • T-Lymphocytes / immunology


  • Autoantibodies
  • Peptides
  • Proto-Oncogene Proteins c-bcl-2
  • Citrulline