Reactivity of Autoantibodies in Systemic &lt;i&gt;Lupus etythematosu&lt;/i&gt;&lt;i&gt;s&lt;/i&gt; with Synthetic Core Histone Peptides

Muller, Sylviane; Bonnier, Dominique; Thiry, Marc; Regenmortel, M.H.V. Van

doi:10.1159/000234962

Cited by 53 publications

(20 citation statements)

References 19 publications

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“…In the current study, using a whole panel of overlapping H2B peptides, we showed that the N-terminal region of this protein encompasses a dominant target for autoantibodies produced by NZB/W lupus mice inthecourseofthe disease.Ourfindings confirmearlierdata describing the presence of a major B cell epitope in the N-terminal peptide of H2B recognized by the Abs from patients or mice with lupus (34,35), juvenile chronic arthritis (36) and graft-versus-host disease [murine lupus model; (37)]. Using the two large cleavage H2B fragments 1-59 and 63-125 and sera from lupus patients, Hardin and Thomas also drew the same conclusion (22).…”

Section: Discussionsupporting

confidence: 85%

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

Lacotte

Dumortier

Décossas

et al. 2010

The Journal of Immunology

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An important hallmark of systemic lupus erythematosus is the production of autoantibodies specific for nuclear Ags, among which nucleosomes and their constituents, DNA and histones. It is widely admitted that some of these autoantibodies contribute largely in lupus pathogenesis because of their nephritogenic potential. However, the underlying mechanisms are still debated. In this study, we analyzed the autoimmune response against histone H2B during the course of the disease in lupus-prone (NZBxNZW)F1 mice, both in lymphoid organs and kidneys, and we assessed its potential involvement in lupus pathogenicity. We found that the N-terminal region of histone H2B represents a preferential target for circulating autoantibodies, which kinetics of appearance positively correlates with disease development. Furthermore, immunization of preautoimmune (NZBxNZW)F1 mice with H2B peptide 1–25 accelerates the disease. Kidney eluates from diseased (NZBxNZW)F1 mice do contain IgG Abs reacting with this peptide, and this H2B sequence was found to be accessible to specific Ab probes in Ag-containing deposits detected in nephritic kidneys. Finally, compared with control normal mice and to young preautoimmune (NZBxNZW)F1 animals, the frequency of cells secreting autoantibodies reacting with peptide 1–25 was significantly raised in the spleen and bone marrow and most importantly on a pathophysiological point of view, locally, in nephritic kidneys of diseased (NZBxNZW)F1 mice. Altogether our results demonstrate the existence in (NZBxNZW)F1 mice of both a systemic and local B cell response targeting the N-terminal region of histone H2B, and highlight the potential implication of this nuclear domain in lupus pathology.

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Section: Discussionsupporting

confidence: 85%

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

Lacotte

Dumortier

Décossas

et al. 2010

The Journal of Immunology

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“…Altogether, the region 53-85 of H3 seems to contain important Th cell epitopes in BW mice (this work) and lupus patients. In the present study, we further confirm that this region as well as the N-terminal region 1-21 and the C terminus of H3 also contain B cell epitopes recognized by IgG Abs from BW mice and lupus patients (43,44). Moreover, the domain 53-70 of H3 has been shown to be accessible at the surface of free mononucleosomes and nucleosomes in long chains of chromatin (30).…”

Section: Discussionsupporting

confidence: 84%

CD4+ T Cells from (New Zealand Black × New Zealand White)F1 Lupus Mice and Normal Mice Immunized Against Apoptotic Nucleosomes Recognize Similar Th Cell Epitopes in the C Terminus of Histone H3

Fournel

Neichel

Dali

et al. 2003

The Journal of Immunology

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We have previously reported that peptide 88-99 of histone H4 represents a minimal T cell epitope recognized by Th cells from nonautoimmune BALB/c (H-2d/d) mice immunized with nucleosomes. In this study, we tested a panel of overlapping peptides spanning the whole sequences of H4 and H3 for recognition by CD4+ T cells from unprimed (New Zealand Black (NZB) × New Zealand White (NZW))F1 lupus mice (H-2d/z). None of the 11 H4 peptides was recognized by CD4+ T cells from (NZB × NZW)F1 mice. In contrast, these cells proliferated and secreted IL-2, IL-10, and IFN-γ upon ex vivo stimulation with H3 peptides representing sequences 53-70, 64-78, and 68-85. Peptides 56-73 and 61-78 induced the production of IFN-γ and IL-10, respectively, without detectable proliferation, suggesting that they may act as partial agonist of the TCR. Th cells from unprimed BALB/c mice and other lupus-prone mice such as SNF1 (H-2d/q) and MRL/lpr (H-2k/k) mice did not recognize any peptides present within the H3 region 53-85. We further demonstrated that immunization of normal BALB/c mice with syngeneic liver nucleosomes and spleen apoptotic cells, but not with nonapoptotic syngeneic cells, induced Th cell responses against several peptides of the H3 region 53-85. Moreover, we found that this conserved region of H3, which is accessible at the surface of nucleosomes, is targeted by Abs from (NZB × NZW)F1 mice and lupus patients, and contains motifs recognized by several distinct HLA-DR molecules. It might thus be important in the self-tolerance breakdown in lupus.

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“…the amino-and carboxyl-terminal domains [21]. Since during the course of some autoimmune diseases like systemic lupus erythematosus (SLE) the elicited anti-histone antibodies are directed mainly against the histone 'tails' exposed on the nucleosomes [34], it has been suggested that chromatin cores rather than free histones would be responsible for the triggering of the humoral response [35]. Taking into account the equivalent locations of the antigenic determinants of the histones which are recognized by both SLE and VL sera, it is likely that a similar mechanism of epitope selection must operate during both pathological processes.…”

Section: Discussionmentioning

confidence: 99%

Characterization of the antigenic determinants of the Leishmania infantum histone H3 recognized by antibodies elicited during canine visceral leishmaniasis

Soto

Requena

Quijada

et al. 1996

Clinical and Experimental Immunology

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SUMMARYIn the present study we show that sera from dogs naturally infected with the protozoan parasite Leishmania infantum contain antibodies that specifically react with the parasite histone H3. Using synthetic peptides covering the complete sequence of the protein we located the linear antigenic determinants within the 40 amino-terminal amino acids of the molecule. In addition to the complete form of the protein (rLiH3), two regions of the Leishmania histone H3 were expressed as recombinant proteins: the rLiH3-Nt fragment containing the 39 amino-terminal amino acids and the rLiH3-Ct fragment containing the 90 carboxyl-terminal residues. Competition experiments using the protein fragment rLiH3-Nt as competitor confirmed that the antigenic determinants of histone H3 are confined to the amino-terminal domain. This domain, which is believed to be exposed on the nucleosome surface, is also the most evolutionarily divergent region of the L. infantum histone H3. Visceral leishmaniasis (VL) sera do not react with mammalian histones, an indication that the anti-histone response elicited during Leishmania infection is triggered by the parasite histone. The results of the prevalence of antihistone H3 antibodies in canine VL sera together with the sequence-specific characteristics of the amino-terminal region of L. infantum histone H3 indicate that the recombinant protein rLiH3-Nt may be of use for diagnosis of canine VL.

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Reactivity of Autoantibodies in Systemic <i>Lupus etythematosu</i><i>s</i> with Synthetic Core Histone Peptides

Cited by 53 publications

References 19 publications

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

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

CD4+ T Cells from (New Zealand Black × New Zealand White)F1 Lupus Mice and Normal Mice Immunized Against Apoptotic Nucleosomes Recognize Similar Th Cell Epitopes in the C Terminus of Histone H3

Characterization of the antigenic determinants of the Leishmania infantum histone H3 recognized by antibodies elicited during canine visceral leishmaniasis

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