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

Marcos López-Hoyos, Regina Marquina, Esther Tamayo, Jovanna González-Rojas, Shozo Izui, Ramón Merino, Jesús Merino

Laboratorio de Immunologia del Trasplante, Unidad de Investigación, Hospital Universitario Marqués de Valdecilla, Departamento de Medicina y Psiquiatría, Av. Valdecilla s/n, 39008 Santander, Spain.

Arthritis and rheumatism 2003 Aug

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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. 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. 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. 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.

Citation

Marcos López-Hoyos, Regina Marquina, Esther Tamayo, Jovanna González-Rojas, Shozo Izui, Ramón Merino, Jesús Merino. Defects in the regulation of B cell apoptosis are required for the production of citrullinated peptide autoantibodies in mice. Arthritis and rheumatism. 2003 Aug;48(8):2353-61