title: Arthritogenic monoclonal antibodies from K/BxN mice.
abstract: 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 patients we 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.
authors.affiliation: Institut de Génétique et de Biologie Moléculaire et Cellulaire (CNRS/INSERM/ULP), 67000 Strasbourg, France.
authors.forename: Mariana
authors.initials: M
authors.lastname: Maccioni
authors.forename: Gabrielle
authors.initials: G
authors.lastname: Zeder-Lutz
authors.forename: Haochu
authors.initials: H
authors.lastname: Huang
authors.forename: Claudine
authors.initials: C
authors.lastname: Ebel
authors.forename: Philippe
authors.initials: P
authors.lastname: Gerber
authors.forename: Josiane
authors.initials: J
authors.lastname: Hergueux
authors.forename: Patricia
authors.initials: P
authors.lastname: Marchal
authors.forename: Veronique
authors.initials: V
authors.lastname: Duchatelle
authors.forename: Claude
authors.initials: C
authors.lastname: Degott
authors.forename: Marc
authors.initials: M
authors.lastname: van Regenmortel
authors.forename: Christophe
authors.initials: C
authors.lastname: Benoist
authors.forename: Diane
authors.initials: D
authors.lastname: Mathis
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology*; D000915:Antibody Affinity; D001172:Arthritis, Rheumatoid / Q000276:immunology*; D001402:B-Lymphocytes / Q000276:immunology; D002999:Clone Cells; D004195:Disease Models, Animal; D005260:Female; D005956:Glucose-6-Phosphate Isomerase / Q000276:immunology*; D007700:Kinetics; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic
chemical_list: D000911:Antibodies, Monoclonal; D005956:Glucose-6-Phosphate Isomerase