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

Lopez-Hoyos, Marcos
Marquina, Regina
Tamayo, Esther
Gonzalez-Rojas, Jovanna
Merino, Ramon
Merino, Jesus
Published in Arthritis and Rheumatism. 2003, vol. 48, no. 8, p. 2353-2361
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 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.
Keywords AnimalsApoptosis/ immunologyArthritis, Rheumatoid/ immunologyAutoantibodies/ immunology/metabolismB-Lymphocytes/ cytology/ immunologyCell Communication/immunologyCitrulline/ immunologyGene Expression/immunologyHumansMiceMice, Inbred BALB CMice, Inbred C57BLMice, Inbred DBAMice, Inbred MRL lprMice, Inbred NZBMice, TransgenicPeptides/immunologyProto-Oncogene Proteins c-bcl-2/geneticsSpecies SpecificityT-Lymphocytes/cytology/immunology
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PMID: 12905491
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