Immune response to hn and snRNP in autoimmune mice. A model for the development of lupus autoimmunity by a single initiator T helper epitope?
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KeywordsPeptide Systemic Lupus Erythematosus Cell Response Heterogeneous Nuclear Ribonucleoprotein Ribonucleoprotein Particle
Systemic lupus erythematosus is characterised by the presence of high titers of autoantibodies reacting with various components of the small and heterogeneous nuclear ribonucleoprotein particle. It has been suggested that these antibodies are produced by an antigen-driven mechanism under the dependence of antigen-specific T cells. To investigate the role of T cell help in this process, we sought with twenty overlapping peptides the Th epitopes on the U1-70K snRNP in unprimed H-2k MRL/lpr lupus mice and immunised CBA normal mice. The peptide 131-151 was recognized by both IgG autoantibodies and CD4+ T cells from 7-9 week-old MRL/lpr mice. In this test, APCs from MRL/lpr mice were required, APCs from naive CBA mice failed to stimulate CD4+ cells from MRL/lpr mice. Peptide 131-151 bound both I-Ak and I-Ek class II molecules and favoured an IL-2 positive T cell response but not IFN-γ, IL-6 and IL-10 secretion. Segment 131-151 is localised within the RNP80 motif and contains residues that are highly conserved in many nuclear, nucleolar and cytoplasmic RNA binding proteins. In parallel, we studied the Ab response to the A2/B1 hnRNP in different murine models of lupus, and found in residues 50-70 a major epitope recognized very early during the course of the disease by Abs from most of MRL/lpr mice. Peptide 50-70 generated in CBA/J mice an effective Th cell response with IL-2 and IFN-γ secretion. Interestingly, this peptide also contains the highly conserved sequence present in peptide 131-151 of the 70K protein. It is possible that starting from a single Th epitope, the sequence of which is repeated in several self-proteins involved in the same complex or close cellular components, a larger, diversified Th response is generated, which extends via intra-and inter-molecular spreading of the T and B cell responses.