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


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
Kaoshiung Medical University, Kaoshiung, Taiwan, Republic of China.
Jau-Ling
JL
Suen
Ya-Hui
YH
Chuang
Bor-Yu
BY
Tsai
Peter M
PM
Yau
Bor-Luen
BL
Chiang
D000818:Animals; D001324:Autoantigens / Q000276:immunology; D001853:Bone Marrow / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D004247:DNA / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology*; D004195:Disease Models, Animal; D018984:Epitopes, T-Lymphocyte / Q000032:analysis / Q000276:immunology*; D006657:Histones / Q000032:analysis; D007167:Immunotherapy / Q000379:methods; D008180:Lupus Erythematosus, Systemic / Q000276:immunology* / Q000628:therapy; D051379:Mice; D008815:Mice, Inbred Strains; D009707:Nucleosomes / Q000276:immunology*
D001324:Autoantigens; D018984:Epitopes, T-Lymphocyte; D006657:Histones; D009707:Nucleosomes; D004247:DNA