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Specific post-translational histone modifications of neutrophil extracellular traps as immunogens and potential targets of lupus autoantibodies
INTRODUCTION: Autoreactivity to histones is a pervasive feature of several human autoimmune disorders, including systemic lupus erythematosus (SLE). Specific post-translational modifications (PTMs) of histones within neutrophil extracellular traps (NETs) may potentially drive the process by which to...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2012
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3392818/ https://www.ncbi.nlm.nih.gov/pubmed/22300536 http://dx.doi.org/10.1186/ar3707 |
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author | Liu, Chih Long Tangsombatvisit, Stephanie Rosenberg, Jacob M Mandelbaum, Gil Gillespie, Emily C Gozani, Or P Alizadeh, Ash A Utz, Paul J |
author_facet | Liu, Chih Long Tangsombatvisit, Stephanie Rosenberg, Jacob M Mandelbaum, Gil Gillespie, Emily C Gozani, Or P Alizadeh, Ash A Utz, Paul J |
author_sort | Liu, Chih Long |
collection | PubMed |
description | INTRODUCTION: Autoreactivity to histones is a pervasive feature of several human autoimmune disorders, including systemic lupus erythematosus (SLE). Specific post-translational modifications (PTMs) of histones within neutrophil extracellular traps (NETs) may potentially drive the process by which tolerance to these chromatin-associated proteins is broken. We hypothesized that NETs and their unique histone PTMs might be capable of inducing autoantibodies that target histones. METHODS: We developed a novel and efficient method for the in vitro production, visualization, and broad profiling of histone-PTMs of human and murine NETs. We also immunized Balb/c mice with murine NETs and profiled their sera on autoantigen and histone peptide microarrays for evidence of autoantibody production to their immunogen. RESULTS: We confirmed specificity toward acetyl-modified histone H2B as well as to other histone PTMs in sera from patients with SLE known to have autoreactivity against histones. We observed enrichment for distinctive histone marks of transcriptionally silent DNA during NETosis triggered by diverse stimuli. However, NETs derived from human and murine sources did not harbor many of the PTMs toward which autoreactivity was observed in patients with SLE or in MRL/lpr mice. Further, while murine NETs were weak autoantigens in vivo, there was only partial overlap in the immunoglobulin G (IgG) and IgM autoantibody profiles induced by vaccination of mice with NETs and those seen in patients with SLE. CONCLUSIONS: Isolated in vivo exposure to NETs is insufficient to break tolerance and may involve additional factors that have yet to be identified. |
format | Online Article Text |
id | pubmed-3392818 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2012 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-33928182012-07-11 Specific post-translational histone modifications of neutrophil extracellular traps as immunogens and potential targets of lupus autoantibodies Liu, Chih Long Tangsombatvisit, Stephanie Rosenberg, Jacob M Mandelbaum, Gil Gillespie, Emily C Gozani, Or P Alizadeh, Ash A Utz, Paul J Arthritis Res Ther Research Article INTRODUCTION: Autoreactivity to histones is a pervasive feature of several human autoimmune disorders, including systemic lupus erythematosus (SLE). Specific post-translational modifications (PTMs) of histones within neutrophil extracellular traps (NETs) may potentially drive the process by which tolerance to these chromatin-associated proteins is broken. We hypothesized that NETs and their unique histone PTMs might be capable of inducing autoantibodies that target histones. METHODS: We developed a novel and efficient method for the in vitro production, visualization, and broad profiling of histone-PTMs of human and murine NETs. We also immunized Balb/c mice with murine NETs and profiled their sera on autoantigen and histone peptide microarrays for evidence of autoantibody production to their immunogen. RESULTS: We confirmed specificity toward acetyl-modified histone H2B as well as to other histone PTMs in sera from patients with SLE known to have autoreactivity against histones. We observed enrichment for distinctive histone marks of transcriptionally silent DNA during NETosis triggered by diverse stimuli. However, NETs derived from human and murine sources did not harbor many of the PTMs toward which autoreactivity was observed in patients with SLE or in MRL/lpr mice. Further, while murine NETs were weak autoantigens in vivo, there was only partial overlap in the immunoglobulin G (IgG) and IgM autoantibody profiles induced by vaccination of mice with NETs and those seen in patients with SLE. CONCLUSIONS: Isolated in vivo exposure to NETs is insufficient to break tolerance and may involve additional factors that have yet to be identified. BioMed Central 2012 2012-02-02 /pmc/articles/PMC3392818/ /pubmed/22300536 http://dx.doi.org/10.1186/ar3707 Text en Copyright ©2012 Liu et al.; licensee BioMed Central Ltd. http://creativecommons.org/licenses/by/2.0 This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Research Article Liu, Chih Long Tangsombatvisit, Stephanie Rosenberg, Jacob M Mandelbaum, Gil Gillespie, Emily C Gozani, Or P Alizadeh, Ash A Utz, Paul J Specific post-translational histone modifications of neutrophil extracellular traps as immunogens and potential targets of lupus autoantibodies |
title | Specific post-translational histone modifications of neutrophil extracellular traps as immunogens and potential targets of lupus autoantibodies |
title_full | Specific post-translational histone modifications of neutrophil extracellular traps as immunogens and potential targets of lupus autoantibodies |
title_fullStr | Specific post-translational histone modifications of neutrophil extracellular traps as immunogens and potential targets of lupus autoantibodies |
title_full_unstemmed | Specific post-translational histone modifications of neutrophil extracellular traps as immunogens and potential targets of lupus autoantibodies |
title_short | Specific post-translational histone modifications of neutrophil extracellular traps as immunogens and potential targets of lupus autoantibodies |
title_sort | specific post-translational histone modifications of neutrophil extracellular traps as immunogens and potential targets of lupus autoantibodies |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3392818/ https://www.ncbi.nlm.nih.gov/pubmed/22300536 http://dx.doi.org/10.1186/ar3707 |
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