Nucleosomal Peptide Epitopes for Nephritis-inducing T Helper Cells of Murine Lupus (original) (raw)
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Nucleosome: A Major Immunogen for Pathogenic Autoantibody-inducing T Cells of Lupus
Only a fraction (12%) of 268 "autoreactive" T cell clones derived from lupus-prone mice can selectively induce the production of pathogenic anti-DNA autoantibodies in vitro and accelerate the development of lupus nephritis when transferred in vivo. The CDR3 loops of T cell receptor B chains expressed by these pathogenic T helper (Th) clones contain a recurrent motif of anionic residues suggesting that they are selected by autoantigens with cationic residues. Herein, we found that =50% of these pathogenic Th clones were specific for nucleosomal antigens, but none of them responded to cationic idiopeptides shared by variable regions of pathogenic anti-DNA autoantibodies. Nucleosomes did not stimulate the T cells as a nonspecific mitogen or superantigen. Only the pathogenic Th cells of lupus responded to nucleosomal antigens that were processed and presented via the major histocompatibility class II pathway. Although the presentation of purified mononucleosomes to the Th clones could be blocked by inhibitors of endosomal proteases, neither of the two components of the nucleosomes-free DNA or histones by themselves-could stimulate the Th clones. Thus critical peptide epitopes for the Th cells were probably protected during uptake and processing of the nucleosome particle as a whole. The nucleosome-specific Th clones preferentially augmented the production of IgG autoantibodies to histone-DNA complex in vitro. In vivo, nucleosome-specific, CD4 + T cells were not detectable in normal mice, but they were found in the spleens of lupus-prone mice as early as I mo of age, long before other autoimmune manifestations. Immunization of young, preautoimmune lupus mice with nucleosomes augmented the production of autoantibodies and markedly accelerated the development of severe glomerulonephritis. Previously, crude preparations containing nucleosomes were shown by others to have polyclonal mitogenic activity for B cells from normal as well as lupus mice. Identification here of pure mononucleosome as a lupus-specific immunogen for the Th cells that selectively help the pathogenic anti-DNA autoantibody producing B cells of lupus could lead to the design of specific therapy against this pathogenic autoimmune response. J. Exp.
Nucleosomes in the pathogenesis of systemic lupus erythematosus
Rheumatic Disease Clinics of North America, 2004
Antibodies that are directed against components of the cell nucleus almost always accompany systemic lupus erythematosus (SLE). Formation of antibodies against double-stranded DNA is a hallmark of SLE. For many years, the development of antibodies against cell components that normally are sequestered into the nucleus remained puzzling to researchers who were working in this field of rheumatology. A decade ago, it became clear that these intracellular antigens could become exposed at the cell surface during physiologic cell death (apoptosis), and, under particular conditions, become immunogenic. The primary antigen in SLE has been believed to be naked DNA. DNA is a poor immunogen, however, and recent evidence suggests that nucleosomes, that comprise DNA and histones, constitute the primary inciting antigen in SLE. We review up-to-date data on the mechanisms by which nucleosomes and other lupus autoantigens may become immunogenic in lupus and the role of antinucleosome antibodies in the development of glomerulonephritis, a common and severe complication that occurs in approximately 60% of patients who have SLE. The apoptotic cell: a source of lupus antigens Human and murine SLE are characterized by the appearance in the blood of an array of autoantibodies that are directed against nuclear components. Frequently-targeted antigens include nucleosomes (the elementary unit of chroma
Specificity of Monoclonal Anti-nucleosome Auto-antibodies Derived from Lupus Mice
Journal of Autoimmunity, 1996
Recently, anti-nucleosome antibodies, which do not bind to DNA or to individual histones, have been identified in longitudinal studies in lupus mice. These anti-nucleosome antibodies occur early in spontaneous SLE and are formed prior to other anti-nuclear specificities. However, nucleosomal epitopes are yet to be fully characterized. We selected a panel of six monoclonal anti-nucleosome antibodies (mAbs) (#2, #32, #34, PL2-6, LG8-1 and LG10-1) derived from lupus mice. These mAbs were tested in ELISA on subnucleosome structures and on a panel of 53 histone peptides, covering the entire sequence of the five histones. Two mAbs reacted with one of these peptides, but the reactivity hardly exceeded the background reactivity. Based on the nucleosome and subnucleosome ELISA we identified different recognition patterns. Three mAbs showed the highest reactivity towards the intact nucleosome. For two of them (#32 and LG8-1) the nucleosomal epitope was primarily located on H2A-H2B/DNA, whereas for mAb #34 this primary epitope was located on H3/H4/DNA. Two mAbs (#2 and PL2-6) showed the highest reactivity with H2A-H2B/DNA and one mAb (LG10-1) recognized H3-H4/DNA. In the subnucleosome ELISA all but one (mAb #32) recognized more than one epitope, including DNA complexed to a variety of cationic molecules. Comparing these reactivities we identified for all mAbs one specific nucleosomal epitope, whereas reactivity with other subnucleosomes was comparable to the reactivity towards DNA complexed with cationic molecules. In inhibition experiments both in ELISA and in immunofluorescence it was found that only one of the mAbs (i.e. PL2-6), recognizing an epitope on H2A-H2B/DNA as primary epitope, could be inhibited by H2A-H2B/DNA in fluid phase. The two mAbs recognizing an epitope on H3-H4/DNA as primary epitope could be inhibited by H3-H4/DNA in fluid phase. From these analyses, we conclude first that for these nucleosome specific mAbs linear histone peptides are not very important. Second, that these mAbs all recognize different epitopes on both H2A/H2B-DNA and H3/H4-DNA and third that some solid phase H2A/H2B-DNA epitopes are not expressed on fluid phase H2A/H2B-DNA. Our findings suggest that in SLE the nucleosome can act as auto-antigen and that there is no immunodominant cell epitope within the nucleosome.
Lupus Nephritis: Role of Antinucleosome Autoantibodies
Seminars in Nephrology, 2011
The discovery of autoantigen clustering in blebs at the surface of apoptotic cells boosted research on the role of apoptosis in systemic lupus erythematosus (SLE) and led to the discovery of autoantigen modification during apoptosis. Normally, apoptotic cells are cleared efficiently and swiftly. However, it became clear that in SLE insufficient removal of apoptotic material leads to the release of these modified autoantigens. This creates the danger that these modified autoantigens are recognized by the immune system. Indeed, dendritic cells, the professional antigen-presenting cells, phagocytose these modified autoantigens, which leads to maturation and induction of a proinflammatory state of these dendritic cells. As a consequence, they present these modified autoantigens to T cells in an immunogenic way, which become activated and stimulate autoreactive B cells to secrete autoantibodies. In this review the currently available evidence for the sequential steps in the pathogenesis of SLE is discussed. Furthermore, the mechanisms responsible for the nephritogenicity of antinucleosome antibodies are reviewed. This will reveal that nucleosomes are not only a major driving force in the formation of antinuclear antibodies, but also play a pivotal role in the development of tissue lesions by mediating binding of autoantibodies to basement membranes as exemplified for the kidney. Semin Nephrol 31:376-389
Clinical Immunology, 2013
Low-dose tolerance therapy with nucleosomal histone peptide epitopes blocks lupus disease in mouse models, but effect in humans is unknown. Herein, we found that CD4 + CD25 high FoxP3 + or CD4 + CD45RA + FoxP3 low T-cells, and CD8 + CD25 + FoxP3 + T-cells were all induced durably in PBMCs from inactive lupus patients and healthy subjects by the histone peptide/s themselves, but in active lupus, dexamethasone or hydroxychloroquine unmasked Treg-induction by the peptides. The peptide-induced Treg depended on TGFβ/ALK-5/ pSmad 2/3 signaling, and they expressed TGF-β precursor LAP. Lupus patients' sera did not inhibit Treg induction. The peptide epitopeinduced T cells markedly suppressed type I IFN related gene expression in lupus PBMC. Finally, the peptide epitopes suppressed pathogenic autoantibody production by PBMC from active lupus patients to baseline levels by additional mechanisms besides Treg induction, and as potently as anti-IL6 antibody. Thus, low-dose histone peptide epitopes block pathogenic autoimmune response in human lupus by multiple mechanisms to restore a stable immunoregulatory state.
Arthritis & Rheumatism, 2003
Objective. Antinuclear autoantibodies complexed to nucleosomes can bind to heparan sulfate (HS) in the glomerular basement membrane. This binding is due to the binding of the positively charged histones to the strongly anionic HS. Nucleosomes and histones have been identified in glomerular deposits in human lupus nephritis. We investigated whether nucleosomes are present in the basement membrane of nonlesional skin of lupus patients.