Anti-nucleosome antibodies and T-cell response in systemic lupus erythematosus

Evidence accumulated in recent years suggests that nucleosomes play a pivotal role in the induction phase and pathogenesis of systemic lupus erythematosus (SLE). Apoptotic cells are an important source of nucleosomes and apoptosis defects have been described in patients with SLE as well as in lupus mice. Moreover, it has been demonstrated that the intravenous injection of apoptotic cells in normal mice generated the production of anti-nuclear antibodies and led to the development of symptoms associated with lupus disease. In this review, we briefly summarize these results and describe recent findings on the characterization of histone T-cell epitopes recognized by CD4(+) cells from different strains of lupus mice. We have tested a panel of overlapping peptides spanning the whole sequences of H4 and H3 histones for recognition by CD4(+) T cells from unprimed (NZBxNZW) F1 and MRL/lpr lupus mice. We have also immunized naïve BALB/c mice with nucleosomes or syngeneic apoptotic and non-apoptotic spleen cells, and tested the activation of Th cells reacting ex vivo with H4 and H3 peptides. Our results suggest that nucleosomes and apoptotic cells may effectively act as initiator of autoreactive Th cell development in lupus mice. In the BW lupus model, the region 53-85 of H3, which also contains B-cell epitopes recognized by antibodies from (NZBxNZW) F1 mice and lupus patients, might be important.