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

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Abstract
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 × B6)F1‐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 × B6)F1‐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.
Funding Information
  • Swiss National Foundation
  • Fondo de Investigación Sanitaria (Spain) (FIS 00/0413)
  • Ministerio de Ciencia y Tecnología (Spain) (SAF00/0176)
  • Fundación Marqués de Valdecilla (Spain)

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