title: T cells of lupus and molecular targets for immunotherapy.
abstract: A major advance in understanding the basic mechanism driving the pathogenic autoimmune response in SLE has been the identification of nucleosome as a primary immunogen. The production of pathogenic antinuclear antibodies in SLE is mediated by a MHC class II restricted, cognate interaction between select populations of autoimmune T helper cells and autoimmune B cells that recognize epitopes in the different molecular components of the nucleosome particle: a form of intermolecular-intrastructural help. In the SNF1 model, we have localized the critical peptide autoepitopes for lupus nephritis-inducing Th cells in the core histones of nucleosomes, at amino acid positions 10-33 of H-2B and 16-39 and 71-94 of H4. Remarkabely, the nephritogenic epitopes are located in the regions of histones that are also targeted by lupus B cells, as well as the sites where the histones contact DNA in the nucleosome, indicating that they are specially protected during antigen processing. Identification of the peptide epitopes is a basic step toward defining how the pathogenic Th cells emerge in lupus. In addition, we found that the pathogenic Th cells and B cells of lupus have a regulatory defect in the expression of CD40 ligand (CD40L or gp39), which results in abnormal costimulatory signals that sustain the production of pathogenic autoantibodies. Specific immunotherapy that blocks the pathogenic T and B cell interaction in lupus can be designed based on the knowledge of these disease mechanisms.
authors.affiliation: Department of Medicine, Northwestern University Medical School, Chicago, Illinois 60611, USA.
authors.forename: S K
authors.initials: SK
authors.lastname: Datta
authors.forename: A
authors.initials: A
authors.lastname: Kaliyaperumal
authors.forename: A
authors.initials: A
authors.lastname: Desai-Mehta
mesh_terms: D000818:Animals; D006801:Humans; D008180:Lupus Erythematosus, Systemic / Q000276:immunology* / Q000628:therapy*; D013601:T-Lymphocytes / Q000276:immunology*