Murine models of systemic lupus erythematosus: B and T cell responses to spliceosomal ribonucleoproteins in MRL/Faslpr and (NZB x NZW)F1 lupus mice

Abstract

(NZB × NZW)F1 and MRL/Faslpr lupus mice present a similar phenotype with a spectrum of autoantibodies associated with very severe nephritis. It is thought, however, that in contrast to other lupus-prone mice such as MRL/Faslpr mice, (NZB × NZW)F1 mice do not generate autoantibodies to ribonucleoproteins (RNP) Sm/RNP. In this study, we demonstrate that contrary to previous reports, the autoimmune response directed against Sm/RNP antigens also occurs in NZB × NZW mice. CD4+ T cells from unprimed 10-week-old NZB × NZW mice proliferate and secrete IL-2 in response to peptide 131-151 of the U1-70K protein, which is known to contain a Th epitope recognized by CD4+ T cells from MRL/Faslpr mice. Peptide 131-151, which was found to bind I-Ak and I-Ek class II MHC molecules, also bound both I-Ad and I-Ed molecules. This result led us to also re-evaluate longitudinally the anti-Sm/RNP antibody response in NZB × NZW mice. We found that 25-week-old mice do produce antibodies reacting with several small nuclear and heterogeneous nuclear (hn) RNP proteins, such as SmD1, U1-70K and hnRNP A2/B1 proteins. The fine specificity of these antibodies was studied with overlapping synthetic peptides. The same antigenically positive and negative peptides were characterized in MRL/Faslpr and NZB × NZW mice in the three proteins. This new finding can help to understand the mechanisms involved in the development of the anti-Sm/RNP antibody response and, particularly, the role played by non-MHC genes in this autoimmune response.