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

Abstract

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 doublestranded 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.

Identification of New Pathogenic Players in Lupus: Autoantibody-Secreting Cells Are Present in Nephritic Kidneys of (NZBxNZW)F1 Mice

“…In NZB/W mice, we cannot exclude that the H2B peptide 1-25 does contain a Th cell epitope in addition to one or several B cell epitopes. However, studies by Suen et al (27) and by us (not shown) using NZB/W-derived CD4 + T cells do not support this hypothesis. Autoimmune responses in lupus are usually analyzed at the systemic level but very rarely at the level of affected target organs.…”

“…It contains a number of potential sites for posttranslational modifications, including apoptosis-specific ones (1). Using overlapping peptides covering the whole sequence of H2B, CD4 + T cell epitopes have been identified in lupus mice and patients, among which one that is disease-relevant present in residues 10-33 (25,26), and a second one encompassing residues 31-50 (27). Strikingly, however, although a few B cell epitopes recognized by circulating autoantibodies have been identified (28), a systematic identification of H2B B cell epitopes is not available in lupus, neither in mice nor in humans.…”

Very Low-Dose Tolerance with Nucleosomal Peptides Controls Lupus and Induces Potent Regulatory T Cell Subsets

“…Nucleosome is one of the major immunogens driving lupus autoimmunity in murine and human SLE (2,5,7,24,25). Critical peptide epitopes from nucleosomal histones are recognized by autoimmune T cells of lupus patients, irrespective of their MHC haplotypes (5-7).…”

Low-Dose Peptide Tolerance Therapy of Lupus Generates Plasmacytoid Dendritic Cells That Cause Expansion of Autoantigen-Specific Regulatory T Cells and Contraction of Inflammatory Th17 Cells

“…Importantly, H4 71-94 also binds strongly to common HLA-DR alleles. T cells reactive to this epitope can be detected in almost all lupus patients, as well as SNF 1 and BWF 1 mice (2,12,13,19,20).…”