Major pathogenic steps in human lupus can be effectively suppressed by nucleosomal histone peptide epitope-induced regulatory immunity (original) (raw)
Related papers
The Journal of Immunology, 2008
A peptide, designated human CDR1 (hCDR1), that is based on the CDR1 of an anti-DNA Ab ameliorates systemic lupus erythematosus (SLE) in murine models via the induction of CD4 ؉ CD25 ؉ regulatory T cells (Tregs). In the present study, the involvement of CD8 Tregs in the mode of action of hCDR1 was investigated in SLE-afflicted (NZB ؋ NZW)F1 mice and in SJL mice following immunization with the lupus-inducing anti-DNA mAb that bears a common Id, 16/6Id. Treatment with hCDR1 up-regulated Foxp3-expressing CD8 ؉ CD28 ؊ Tregs in association with clinical amelioration of lupus manifestations. Furthermore, the in vivo depletion of the latter cells diminished the clinical improvement and the inhibitory effects of hCDR1 on the secretion of IFN-␥ and resulted in the up-regulation of IL-10. However, the stimulatory effect of hCDR1 on the secretion of TGF- was not affected by the CD8 Tregs. In the absence of CD8 Tregs, CD4 ؉ CD25 ؉ Tregs were unable to expand in the hCDR1-treated mice, and the expression of Foxp3 was reduced, thereby interfering further with the suppressive function of CD4 ؉ CD25 ؉ Tregs as determined in the in vitro assays. However, CD8 cells from hCDR1-treated mice that were adoptively transferred into SLEafflicted mice led to up-regulation of CD4 ؉ CD25 ؉ cells with intensified Foxp3 expression in the recipient mice. Thus, a functional link between two subsets of Tregs is demonstrated in which CD8 ؉ CD28 ؊ Tregs are required for both the optimal expansion and function of lupus ameliorating hCDR1-induced CD4 ؉ CD25 ؉
Histone Peptide-Induced Nasal Tolerance: Suppression of Murine Lupus
The Journal of Immunology, 2002
Induced mucosal tolerance has been shown to be beneficial in preventing or treating a number of murine and human autoimmune disorders. However, this particular form of therapy has not been thoroughly tested in systemic lupus erythematosus. In this study, we investigated the conditions for induction of nasal tolerance using a histone peptide named H471 expressing a dominant T cell epitope in the histone protein H4 of mononucleosome in lupus-prone SNF1 female mice. We also tested the effect of chronic peptide nasal treatment on the development of autoimmune reactivities in these mice. Results demonstrated that a dose-dependent nasal tolerance to peptide H471 can be achieved before or after peptide sensitization in SNF1 mice. In addition, tolerance to mononucleosomes was induced by nasal instillation of SNF1 mice with H471. This was accompanied by an increase in IL-10 and suppression of IFN-γ production by lymph node cells. Suppression of Th1-type cytokines was also observed in SNF1 mi...
Annals of the Rheumatic Diseases, 2010
Objectives In systemic lupus erythematosus (SLE) apoptotic chromatin is present extracellularly, which is most likely the result of disturbed apoptosis and/or insuffi cient removal. Released chromatin, modifi ed during apoptosis, activates the immune system resulting in the formation of autoantibodies. A study was undertaken to identify apoptosis-induced histone modifi cations that play a role in SLE. Methods The lupus-derived monoclonal antibody BT164, recently established by selection using apoptotic nucleosomes, was analysed by ELISA, western blot analysis and immunofl uorescence staining using chromatin, cells, plasma and renal sections. Random peptide phage display and peptide inhibition ELISA were used to identify precisely the epitope of BT164. The reactivity of plasma samples from lupus mice and patients with SLE with the epitope of BT164 was investigated by peptide ELISA. Results The epitope of BT164 was mapped in the N-terminal tail of histone H3 (27-KSAPAT-32) and included the apoptosis-induced trimethylation of K27. siRNA-mediated silencing of histone demethylases in cultured cells resulted in hypermethylation of H3K27 and increased nuclear reactivity of BT164. This apoptosisinduced H3K27me3 is a target for autoantibodies in patients and mice with SLE and is present in plasma and in glomerular deposits. Conclusion In addition to previously identifi ed acetylation of histone H4, H2A and H2B, this study shows that trimethylation of histone H3 on lysine 27 is induced by apoptosis and associated with autoimmunity in SLE. This fi nding is important for understanding the autoimmune response in SLE and for the development of translational strategies.
PloS one, 2016
Persistent exposure of the immune system to death cell debris leads to autoantibodies against chromatin in patients with systemic lupus erythematosus (SLE). Deposition of anti-chromatin/chromatin complexes can instigate inflammation in multiple organs including the kidney. Previously we identified specific cell death-associated histone modifications as targets of autoantibodies in SLE. In this study we addressed, in a large cohort of SLE patients and controls, the question whether plasma reactivities with specific histone peptides associated with serology and clinical features. Plasma from SLE patients with and without lupus nephritis, disease controls, and healthy controls, were tested in ELISA with histone H4 peptide acetylated at lysines 8, 12 and 16 (H4pac), H2B peptide acetylated at lysine 12 (H2Bpac), H3 peptide trimethylated at lysine 27 (H3pme), and their unmodified equivalents. SLE patients displayed a higher reactivity with the modified equivalent of each peptide. Reactivi...
Autoimmunity to isomerized histone H2B in systemic lupus erythematosus
Autoimmunity, 2012
Histone H2B is a common target of autoantibodies in both spontaneous and drug-induced systemic lupus erythematosus (SLE). Recent studies demonstrate that Asp 25 of histone H2B (H2B) spontaneously converts to an isoaspartic acid (isoAsp) in vivo. Our laboratory has demonstrated that the posttranslational modification of an aspartic acid to an isoaspartic acid within self-peptides renders otherwise ignored peptides immunogenic. Analysis of serum from lupus-prone mice and histone antibody positive SLE patients revealed antibodies specific to the Asp and isoAsp H2B 21-35 peptide, and that the expression of these antibodies is dependent on TLR9. IsoAsp H2B 21-35 is immunogenic in non-autoimmune prone mice and mice lacking the ability to repair isoAsp have significantly reduced levels of antibodies to H2B. Asp H2B 21-35 incubated at physiological temperatures and pH acquires the isoAsp modification, demonstrating that H2B 21-35 is prone to spontaneous isoAsp formation in vivo. Autoimmunity to isoAsp H2B suggests that this form of the autoantigen may be critical in the induction of anti-histone autoantibodies in human SLE and in murine models of disease.
Molecular Immunology, 1990
The antigenic domains of histone 5 (H5), a highly conserved variant of histone I (Hl), were studied in relation to their reactivity with autoantibodies found in the sera of patients with systemic lupus erythematosus (SLE) and drug-induced lupus (DIL). While some H5 antibodies cross-react with HI, adsorption and immunoblotting studies have identified HS-specific antibodies as well. After proteolytic cleavage of H5 peptides, the reactivity of sera from these patients was tested by Western immunoblotting. All SLE (9/S) and DIL (7/7) sera bound an antigenic determinant in the carboxyl (C) terminus of H5 while none of the sera bound to the amino (N) terminus or the central hydrophobic domain. Although the reactivity of DIL sera with the purified H5 peptides was weaker than that of SLE sera, the antigenic domains bound by both groups of sera were the same. These observations demonstrate that the HS domains reacting with DIL sera are restricted to the carboxyl terminus and are therefore no less restricted than those reacting with SLE sera. Further, the potential epitopes in the carboxyl terminus of H5 do not have a high degree of sequence identity with known mammalian peptides.
Nucleosomal Peptide Epitopes for Nephritis-inducing T Helper Cells of Murine Lupus
1996
Nucleosome-specific T helper (Th) cells provide major histocompatibility complex class IIrestricted, cognate help to nephritogenic antinuclear autoantibody-producing B cells in lupus. However, the lupus Th cells do not respond when components of the nucleosome, such as free DNA or histones, are individually presented by antigen-presenting cells. Thus critical peptide epitopes for the pathogenic Th cells are probably protected during uptake and processing of the native nucleosome particle as a whole. Therefore, herein we tested 145 overlapping peptides spanning all four core histones in the nucleosome. We localized three regions in core histones, one in H2B at amino acid position 10-33 (H2BI0_33), and two in H4, at position 16-39 (H41t~_39) and position 71-94 (H471.,~4), that contained the peptide epitopes recognized by the pathogenic autoantibody-inducing Th cells of lupus. The peptide autoepitopes also triggered the pathogenic Th cells of(SWR • NZB)FI lupus mice in vivo to induce the development of severe lupus nephritis. The nucleosomal autoepitopes stimulated the production ofThl-type cytokines, consistent with immunoglobulin IgG2a, IgG2b, and IgG3 being the isotypes of nephritogenic autoantibodies induced in the lupus mice. Interestingly, the Th cell epitopes overlapped with regions in histories that contain B cell epitopes targeted by autoantibodies, as well as the sites where histones contact with DNA in the nucleosome. Identification of the disease-relevant autoepitopes in nucleosomes will help in understanding how the pathogenic Th cells of spontaneous systemic lupus erythematosus emerge, and potentially lead to the development of peptide-based tolerogenic therapy for this major autoimmune disease.