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Scientific article
English

Cryoglobulinemia induced by a murine IgG3 rheumatoid factor: skin vasculitis and glomerulonephritis arise from distinct pathogenic mechanisms

Contributors

Reininger, Luc; Berney, Thierry; Shibata, T.; Spertini, F.; Merino, Ramon; Izui, Shozo

Published in

Proceedings of the National Academy of Sciences of the United States of America, vol. 87, no. 24, p. 10038-10042

Publication date

1990

Abstract

MRL-lpr/lpr mice spontaneously develop a lupus-like syndrome characterized by immunopathological manifestations such as necrotizing vascular lesions of ear tips and severe glomerulonephritis. Similar skin vascular and glomerular lesions associated with cryoglobulinemia can be induced in normal mice by injection of a monoclonal antibody (mAb)--6-19 (gamma 3 heavy chain and kappa light chain), exhibiting both cryoglobulin and anti-IgG2a rheumatoid factor (RF) activities--derived from the MRL-lpr/lpr autoimmune mouse. To determine the role of RF and/or IgG3 Fc fragment-associated cryoglobulin activities in 6-19 mAb-induced tissue lesions, a 6-19-J558L hybrid mAb (gamma 3 heavy chain and lambda 1 light chain) was produced by fusion between the 6-19 hybridoma and the J558L myeloma. Here we report that the 6-19-J558L hybrid mAb, which loses the RF activity but retains the cryoglobulin activity, fails to induce skin vascular lesions. However, it is still able to provoke glomerular lesions identical to those caused by the 6-19 mAb. Further, we have observed that the depletion of the corresponding autoantigen, IgG2a, in mice by treatment with anti-IgM antisera from birth also prevents the development of skin but not glomerular lesions. Our results indicate that both RF and cryoglobulin activities of the 6-19 mAb are required for the development of skin vasculitis, but its cryoglobulin activity alone is sufficient to cause glomerular lesions. In addition, cDNA cloning and sequencing of the 6-19 mAb has revealed that the 6-19 kappa light chain variable region amino acid sequence is encoded in a germ-line configuration, suggesting that immunoglobulin variable region germ-line genes could contribute to the generation of pathogenic autoantibodies.

Keywords

  • Animals
  • Antibodies, Monoclonal/administration & dosage/ genetics
  • Autoimmune Diseases/immunology
  • Base Sequence
  • Cloning, Molecular
  • Cryoglobulinemia/genetics/immunology/ pathology
  • Glomerulonephritis/genetics/immunology/ pathology
  • Hybridomas/immunology
  • Immunoglobulin G/administration & dosage/ genetics
  • Immunoglobulin Variable Region/ genetics
  • Mice
  • Mice, Inbred BALB C
  • Mice, Mutant Strains
  • Molecular Sequence Data
  • Oligonucleotide Probes
  • Rheumatoid Factor/ administration & dosage/isolation & purification
  • Skin/ blood supply/pathology
  • Vasculitis/genetics/immunology/ pathology

UNIGE affiliation entities

Citation (ISO format)

REININGER, Luc et al. Cryoglobulinemia induced by a murine IgG3 rheumatoid factor: skin vasculitis and glomerulonephritis arise from distinct pathogenic mechanisms. In: Proceedings of the National Academy of Sciences of the United States of America, 1990, vol. 87, n° 24, p. 10038–10042. doi: 10.1073/pnas.87.24.10038

Main files (1)

Article

Identifiers

Additional URL for this publication

http://www.pnas.org/content/87/24/10038.full.pdf

Journal ISSN

0027-8424
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Technical informations

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27/08/2010 13:35:56

First validation

27/08/2010 13:35:56

Update

14/03/2023 16:04:59

Status update

14/03/2023 16:04:59

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