Treatment of murine lupus using nucleosomal T cell epitopes identified by bone marrow-derived dendritic cells.

Systemic lupus erythematosus (SLE) is characterized by the existence of a heterogeneous group of autoantibodies directed against intact nuclear structures, such as nucleosomes. The most prominent of these autoantibodies are those directed against double-stranded DNA (dsDNA) and histones. The majority are of the IgG isotype and show affinity maturation, both of which are known hallmarks of T cell help. Much evidence suggests that the nucleosome is a major candidate autoantigen in SLE. In this study, a novel strategy was used to identify the critical CD4+ T cell autoepitopes in nucleosomes. In addition, peptide-based therapy was then performed in a lupus animal model. Bone marrow (BM)-derived dendritic cells (DCs) were used to examine the self-T cell responses against nucleosomes and to characterize the T cell epitope(s) of nucleosomes in (NZB x NZW)F1 (BWF1) mice. Several potential auto-T cell epitopes of core histone proteins (H2A, H2B, H3, and H4) were identified. Nucleosome-pulsed BM-derived DCs elicited release of interleukin-4 and interferon-gamma, representing a Th0 (i.e., mixed Th1 and Th2) pattern of cytokine production. In addition, intradermal immunization of BWF1 mice with the H3(111-130) peptide not only suppressed the level of anti-dsDNA and anti-single-stranded DNA IgG, but also significantly delayed the progress of glomerulonephritis in lupus-prone BWF1 mice. These results will help in understanding how pathogenic autoimmune responses develop in spontaneous SLE. This may potentially open the way to T cell-based immunotherapy for lupus.

Suen JL ，Chuang YH ，Tsai BY ，Yau PM ，Chiang BL ... -  《ARTHRITIS AND RHEUMATISM》

Specificity of monoclonal anti-nucleosome auto-antibodies derived from lupus mice.

Kramers K ，Stemmer C ，Monestier M ，van Bruggen MC ，Rijke-Schilder TP ，Hylkema MN ，Smeenk RJ ，Muller S ，Berden JH ... -  《JOURNAL OF AUTOIMMUNITY》

Dendritic cells pulsed with apoptotic cells activate self-reactive T-cells of lupus mice both in vitro and in vivo.

Tzeng TC ，Suen JL ，Chiang BL 《RHEUMATOLOGY》

Nucleosomes are major T and B cell autoantigens in systemic lupus erythematosus.

Bruns A ，Bläss S ，Hausdorf G ，Burmester GR ，Hiepe F ... -  《ARTHRITIS AND RHEUMATISM》

Apoptosis-induced acetylation of histones is pathogenic in systemic lupus erythematosus.

Dieker JW ，Fransen JH ，van Bavel CC ，Briand JP ，Jacobs CW ，Muller S ，Berden JH ，van der Vlag J ... -  《ARTHRITIS AND RHEUMATISM》