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


CONCLUSIONS
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.
López-Hoyos
Marcos
M
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.
Marquina
Regina
R
Tamayo
Esther
E
González-Rojas
Jovanna
J
Izui
Shozo
S
Merino
Ramón
R
Merino
Jesús
J
D000818:Animals; D017209:Apoptosis / Q000276:immunology*; D001172:Arthritis, Rheumatoid / Q000276:immunology*; D001323:Autoantibodies / Q000276:immunology* / Q000378:metabolism; D001402:B-Lymphocytes / Q000166:cytology* / Q000276:immunology*; D002450:Cell Communication / Q000276:immunology; D002956:Citrulline / Q000276:immunology*; D015870:Gene Expression / Q000276:immunology; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D019463:Mice, Inbred MRL lpr; D008814:Mice, Inbred NZB; D008822:Mice, Transgenic; D010455:Peptides / Q000276:immunology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics; D013045:Species Specificity; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology
D001323:Autoantibodies; D010455:Peptides; D019253:Proto-Oncogene Proteins c-bcl-2; D002956:Citrulline