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,§,§
*
Institut de Biologie Moléculaire et Cellulaire, Unité Propre de Recherche, Centre National de la Recherche Scientifique, Strasbourg, France;
Division of Rheumatology, Department of Internal Medicine III, University of Vienna, Vienna, Austria;
Division of Rheumatology and Immunology, University of North Carolina, Chapel Hill, NC 27599; and
§
Ludwig-Boltzmann-Institute for Rheumatology, Vienna, Austria
Autoantibodies directed against spliceosomal heterogeneous nuclear
ribonucleoproteins (hnRNPs) are a typical feature of rheumatoid
arthritis, systemic lupus erythematosus, and mixed-connective tissue
disease. With the aim of investigating a potential pathogenic role of
these Abs, we have studied the Ab response to A2/B1 hnRNPs in different
murine models of lupus. The specificity of anti-A2/B1 Abs was
tested with a series of 14 overlapping synthetic peptides covering the
region 1–206 of A2 that contains most of the epitopes recognized by
patients’ Abs. A major epitope recognized very early during the course
of the disease by Abs from most of MRL lpr/lpr mice but
not from other lupus mice and from mice of different MHC haplotypes
immunized against B1 was identified in residues 50–70. This peptide
contains a highly conserved sequence RGFGFVTF also present in other
hnRNPs and small nuclear ribonucleoproteins. Abs reacting with a second
A2 epitope identified in residues 35–55 were detectable several weeks
later, suggesting an intramolecular B cell epitope spreading during the
course of the disease. We identified several T cell epitopes within the
region 35–175 that generated an effective Th cell response with IL-2
and IFN-
secretion in nonautoimmune CBA/J mice sharing the same MHC
haplotype H-2k as MRL/lpr mice. None of the peptides
stimulated T cells primed in vivo with B1. Because Abs to peptide
50–70 were detected significantly earlier than Abs reacting with other
A2 peptides and the protein itself, it is possible that within the
protein, this segment contains residues playing an initiator role in
the induction of the anti-A2/B1 and antispliceosome Ab
response.
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