NUCLEOSOMAL PEPTIDE EPITOPES FOR NEPHRITIS-INDUCING T-HELPER CELLS OFMURINE LUPUS

Nucleosome-specific T helper (Th) cells provide major histocompatibili ty complex class II-restricted, cognate help to nephritogenic antinucl ear autoantibody-producing B cells in lupus. However, the lupus Th cel ls do not respond when components of the nucleosome, such as free DNA or histones, are individually presented by antigen-presenting cells. T hus critical peptide epitopes for the pathogenic Th cells are probably protected during uptake and processing of the native nucleosome parti cle as a whole. Therefore, herein we tested 145 overlapping peptides s panning all four core histones in the nucleosome. We localized three r egions in core histones, one in H2B at amino acid position 10-33 (H2B( 10-33)), and two in H4, at position 16-39 (H4(16-39)) and position 71- 94 (H4(71-94)), that contained the peptide epitopes recognized by the pathogenic autoantibody-inducing Th cells of lupus. The peptide autoep itopes also triggered the pathogenic Th cells of (SWR X NZB)F-1 lupus mice in vivo to induce the development of severe lupus nephritis. The nucleosomal autoepitopes stimulated the production of Th1-type cytokin es, consistent with immunoglobulin IgG2a, IgG2b, and IgG3 being the is otypes of nephritogenic autoantibodies induced in the lupus mice. Inte restingly, the Th cell epitopes overlapped with regions in histones th at contain B cell epitopes targeted by autoantibodies, as well as the sites where histones contact with DNA in the nucleosome. Identificatio n of the disease-relevant autoepitopes in nucleosomes will help in und erstanding how the pathogenic Th cells of spontaneous systemic lupus e rythematosus emerge, and potentially lead to the development of peptid e-based tolerogenic therapy for this major autoimmune disease.