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Immunoglobulin heavy chain constant region determines the pathogenicity and the antigen-binding activity of rheumatoid factor

Fulpius, Thierry
Spertini, F.
Reininger, Luc
Published in Proceedings of the National Academy of Sciences. 1993, vol. 90, no. 6, p. 2345-2349
Abstract An IgG3 monoclonal antibody, 6-19, derived from unmanipulated MRL/MpJ-lpr/lpr mice, exhibiting cryoglobulin and anti-IgG2a rheumatoid factor activities, induces skin leukocytoclastic vasculitis and glomerulonephritis when injected into normal mice. To determine the role of the gamma 3 heavy chain constant region in the generation of cryoglobulins and associated tissue lesions, we have established an IgG1 class switch variant, clone SS2F8, from the 6-19 hybridoma by sequential sublining. Here we report that the SS2F8 monoclonal antibody, which loses the cryoglobulin activity but retains the rheumatoid factor activity, fails to generate skin and glomerular lesions. The lack of pathogenicity of the IgG1 SS2F8 switch variant is not due to mutations in variable regions, since nucleotide sequence analysis shows no differences between both clones. In addition, we have observed that the IgG1 SS2F8 switch variant exhibits < 10% of the rheumatoid factor activity, as compared with the IgG3 6-19 monoclonal antibody, suggesting that the self-associating property of the gamma 3 isotype promotes antibody-binding activity. The present study indicates that the cryoglobulin activity associated with the gamma 3 isotype is critically involved in the pathogenicity of 6-19 anti-IgG2a rheumatoid factor monoclonal antibody and highlights the pathogenic relevance of autoantibodies of the IgG3 subclass in murine systemic lupus erythematosus.
Keywords AnimalsAntibodies, Monoclonal/ immunology/toxicityBase SequenceCloning, MolecularCrosses, GeneticCryoglobulins/biosynthesisEnzyme-Linked Immunosorbent AssayFemaleGlomerulonephritis/ immunology/pathologyImmunoglobulin Constant Regions/ immunology/toxicityImmunoglobulin Fab Fragments/immunology/toxicityImmunoglobulin G/classification/ immunology/toxicityImmunoglobulin Heavy Chains/ immunology/toxicityKidney/immunology/pathologyMaleMiceMice, Inbred BALB CMice, Inbred StrainsMolecular Sequence DataOligodeoxyribonucleotidesPolymerase Chain ReactionRheumatoid Factor/ immunologySkin/ immunology/pathologyVasculitis, Leukocytoclastic, Cutaneous/ immunology/pathology
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PMID: 8460145
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