The Journal of Experimental Medicine
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Published 15 April 2002. doi:10.1084/jem.20011941
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© Rockefeller University Press, 0022-1007/2002/4/1071/ $5.00
The Journal of Experimental Medicine, Volume 195, Number 8, April 15, 2002 1071-1077

Brief Definitive Report

Arthritogenic Monoclonal Antibodies from K/BxN Mice

Mariana Maccioni1, Gabrielle Zeder-Lutz3, Haochu Huang2, Claudine Ebel1, Philippe Gerber1,2, Josiane Hergueux1, Patricia Marchal1,2, Veronique Duchatelle4, Claude Degott4, Marc van Regenmortel3, Christophe Benoist1,2 and Diane Mathis1,2

1 Institut de Génétique et de Biologie Moléculaire et Cellulaire (CNRS/INSERM/ULP), 67000 Strasbourg, France
2 Section on Immunology and Immunogenetics, Joslin Diabetes Center, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02215
3 Institut de Biologie Moléculaire and Cellulaire (CNRS), 67084 Strasbourg, France
4 Service d'Anatomie Pathologique, Hopital Beaujon, 92110 Clichy, France

Address correspondence to C. Benoist and D. Mathis, Joslin Diabetes Center, Harvard Medical School, One Joslin Place, Boston, MA 02215. Phone: 617-264-2743. Fax: 617-264-2744; E-mail: dm{at}joslin.harvard.edu

Arthritis in the K/BxN mouse model is provoked by pathogenic antibodies (Abs) directed against a ubiquitously expressed protein, glucose-6-phosphate isomerase (GPI). To begin dissecting the repertoire of arthritogenic immunoglobulins (Igs) in the K/BxN model, and to provide a basis for comparison with RA patientswe have generated anti-GPI monoclonal Abs (mAbs) from spontaneously activated B cells in the lymphoid organs of arthritic mice. B cell clones with anti-GPI specificities were present at extraordinarily high frequencies in the spleen, and less frequently in other lymphoid organs and in the synovial fluid. None of the anti-GPI mAbs induced arthritis when injected individually into healthy recipients, but most were effective when combined in pairs or larger pools. Arthritogenic combinations depended on mAbs of the IgG1 isotype, which bound to GPI with Kd in the 10-9 M range, with no indication of cooperative binding between complementing pairs. Pathogenicity was not associated with recognition of a particular epitope, but the ability to form mAb/GPI multimers by simultaneous recognition of different epitopes was clearly required, consistent with the known role of complement and FcRs in this model. Sequence analysis revealed structural similarities amongst the mAbs, indicating that a particular subset of B cells may evade tolerance in K/BxN mice, and that affinity maturation by somatic mutation likely takes place. These results confirm that GPI itself, rather than a cross-reactive molecule, is the target of pathogenic Igs.

Key Words: autoimmunity • arthritis • autoantibodies • glucose-6-phosphate isomerase • mouse model


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