en
Scientific article
English

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

Publication date1993
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
  • Animals
  • Antibodies, Monoclonal/ immunology/toxicity
  • Base Sequence
  • Cloning, Molecular
  • Crosses, Genetic
  • Cryoglobulins/biosynthesis
  • Enzyme-Linked Immunosorbent Assay
  • Female
  • Glomerulonephritis/ immunology/pathology
  • Immunoglobulin Constant Regions/ immunology/toxicity
  • Immunoglobulin Fab Fragments/immunology/toxicity
  • Immunoglobulin G/classification/ immunology/toxicity
  • Immunoglobulin Heavy Chains/ immunology/toxicity
  • Kidney/immunology/pathology
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred Strains
  • Molecular Sequence Data
  • Oligodeoxyribonucleotides
  • Polymerase Chain Reaction
  • Rheumatoid Factor/ immunology
  • Skin/ immunology/pathology
  • Vasculitis, Leukocytoclastic, Cutaneous/ immunology/pathology
Affiliation Not a UNIGE publication
Citation (ISO format)
FULPIUS, Thierry et al. Immunoglobulin heavy chain constant region determines the pathogenicity and the antigen-binding activity of rheumatoid factor. In: Proceedings of the National Academy of Sciences of the United States of America, 1993, vol. 90, n° 6, p. 2345–2349. doi: 10.1073/pnas.90.6.2345
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Identifiers
ISSN of the journal0027-8424
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