Induction of anti-RA33 hnRNP autoantibodies and transient spread to U1-A snRNP complex of spliceosome by idiotypic manipulation with anti-RA33 antibody preparation in mice

G. Steiner, O. Shovman, K. Skriner, B. Gilburd, P. Langevitz, M. Miholits, R. Hoet, Y. Levy, G. Zandman-Goddard, E. Hoefler, J. S. Smolen, Yehuda Shoenfeld

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Abstract

Objective. Anti-RA33 antibodies occur in patients with rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and mixed connective tissue disease (MCTD) and target the A2/B1 protein of the heterogeneous nuclear ribonucleoprotein (hnRNP) complex 4 which forms part of the spliceosome. The aim of the present study was to evaluate the immune response and pathological features induced in mice immunized with anti-RA33 antibodies or patient-derived recombinant single-chain variable fragments (scFv) of anti-RA33 antibodies. Methods. In the first set of the experiment, two strains of mice (C57BL/6J and BALB/c) were immunized with IgG preparations obtained from two patients with RA and one normal donor. One of the patients had high titer anti-RA33 antibodies; the other one showed weak borderline reactivity. In the second set of the experiment three groups of C57BL/6J mice were immunized, respectively, with affinity-purified (AP) anti-RA33 antibodies, scFv of anti-RA33 antibodies and normal human IgG. The immunological response induced in immunized mice was studied by immunoblotting and line immunoassay (LIA). The presence of arthritis, serositis or myositis was assessed six-months following initial immunization. Results. While anti-RA33 antibodies developed in only two of the mice immunized with different human IgG fractions, anti-RA33 antibodies were clearly detected in 7 sera of 13 mice immunized with AP anti-RA33 antibodies three months after the boost immunization and, moreover, also in 2 sera of 13 mice immunized with scFv of anti-RA33 antibodies. In contrast, mice immunized with normal human IgG did not develop anti-RA33 antibodies. Interestingly, transient autoantibody production against another nuclear autoantigen, U1 snRNP, was observed in 3 C57BL/6J mice immunized with scFv and in 1 mouse immunized with AP autoantibodies. However, these immunological responses were not associated with pathological findings. Conclusions. Active immunization of naive mice with AP anti-RA33 antibodies and scFv of anti-RA33 antibodies resulted on the one hand in the production of murine anti-RA33 antibodies and led, on the other hand, to transient "autoantibody spread" to snRNP component of the spliceosome and other nuclear autoantigens. This "autoantibody spread" probably reflected disregulation of the idiotypic anti-idiotypic cascade.

Original languageEnglish
Pages (from-to)517-524
Number of pages8
JournalClinical and Experimental Rheumatology
Volume20
Issue number4
StatePublished - 2002

Keywords

  • Affinity purified anti-RA33 antibodies
  • Mixed connective tissue disease
  • Recombinant single-chain variable fragments of anti-RA33 antibodies
  • Rheumatoid arthritis
  • Systemic lupus erythematosus
  • hnRNP complex

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