B and T cell responses to the spliceosomal heterogeneous nuclear ribonucleoproteins A2 and B1 in normal and lupus mice

Autoantibodies directed against spliceosomal heterogeneous nuclear ribonucl eoproteins (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 speci ficity of anti-A2/B1 Abs was tested with a series of 14 overlapping synthet ic peptides covering the region 1-206 of A2 that contains most of the epito pes recognized by patients' Abs, A major epitope recognized very early duri ng the course of the disease by Abs from most of MRL lpr/lpr mice but not f rom other lupus mice and from mice of different MHC haplotypes immunized ag ainst B1 was identified in residues 50-70, This peptide contains a highly c onserved sequence RGFGFVTF also present in other hnRNPs and small nuclear r ibonucleoproteins. Abs reacting with a second A2 epitope identified in resi dues 35-55 were detectable several weeks later, suggesting an intramolecula r B cell epitope spreading during the course of the disease. We identified several T cell epitopes within the region 35-175 that generated an effectiv e Th cell response with IL-2 and IFN-gamma secretion in nonautoimmune CBA/J mice sharing the same MHC haplotype H-2(k) as MRL/lpr mice. None of the pe ptides stimulated T cells primed in vivo with B1, Because Abs to peptide 50 -70 were detected significantly earlier than Abs reacting with other A2 pep tides 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.