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, Sylvie; Neichel, Sarah; Dali, Hayet; Farci, Sandrine; Maillère, Bernard; Briand, Jean‐Paul; Muller, Sylviane

doi:10.4049/jimmunol.171.2.636

Cited by 32 publications

(18 citation statements)

References 51 publications

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“…In contrast to these B cell epitopes, histone H3-specific T cell epitopes have so far been identified mainly outside the N-terminal tail of H3 31–33…”

Section: Discussionmentioning

confidence: 99%

Apoptosis-induced histone H3 methylation is targeted by autoantibodies in systemic lupus erythematosus

Bavel

Dieker

Kroeze

et al. 2010

Annals of the Rheumatic Diseases

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ObjectivesIn 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.

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“…In contrast to these B cell epitopes, histone H3-specific T cell epitopes have so far been identified mainly outside the N-terminal tail of H3 31–33…”

Section: Discussionmentioning

confidence: 99%

Apoptosis-induced histone H3 methylation is targeted by autoantibodies in systemic lupus erythematosus

Bavel

Dieker

Kroeze

et al. 2010

Annals of the Rheumatic Diseases

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“…Sera of SNF 1 mice also contained high titers of IdLNF1 + IgG antibodies, which peaked at 22-24 weeks and coincided with an increase in the CD4 to CD8 ratio of IdLNF1-reactive T cells and IdLNF1 Ig (IgG + IgM) deposition in the kidneys (Uner et al, 1998). The presence of pathogenic autoantibody-inducing T h cells specific for chromatin subparticles or histones has also been described in human patients with lupus as well as lupus-like SNF 1 mice (Fournel et al, 2003). These data suggest the possibility that early onset of autoimmune nephritis in SNF 1 mice after TCDD could result from a T cell lesion.…”

Section: Introductionmentioning

confidence: 89%

An enhanced postnatal autoimmune profile in 24 week-old C57BL/6 mice developmentally exposed to TCDD

Mustafa

Holladay

Goff

et al. 2008

Toxicology and Applied Pharmacology

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Developmental exposure of mice to the environmental contaminant and AhR agonist, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), causes persistent postnatal suppression of T cell-mediated immune responses. The extent to which prenatal TCDD may induce or exacerbate postnatal autoimmune disease remains unknown. In the present study, time-pregnant high affinity AhR C57BL/ 6 mice received a single oral administration of 0, 2.5, or 5 µg/kg TCDD on gestation day (gd) 12. Offspring of these mice (n=5/gender/treatment) were evaluated at 24 weeks-of-age and showed considerable immune dysregulation that was often gender-specific. Decreased thymic weight and percentages of CD4 + CD8 + thymocytes, and increased CD4 + CD8 − thymocytes, were present in the female but not male offspring. Males but not females showed decreased CD4 − CD8 + T cells, and increased Vβ3 + and Vβ17a + T cells, in the spleen. Males but not females also showed increased percentages of bone marrow CD24 − B220 + B cell progenitors. Antibody titers to dsDNA, ssDNA and cardiolipin displayed increasing trends in both male and female mice, reaching significance for anti-dsDNA in both genders and for ssDNA in males at 5 µg/kg TCDD. Immunofluorescent staining of IgG and C3 deposition in kidney glomeruli increased in both genders of prenatal TCDD-exposed mice, suggestive of early stages of autoimmune glomerulonephritis. Collectively, these results show that exposure to TCDD during immune system development causes persistent humoral immune dysregulation as well as altered cell mediated responses, and induces an adult profile of changes suggestive of increased risk for autoimmune disease.

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“…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).…”

Section: Discussionmentioning

confidence: 99%

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

Kang

Michaels

Berner

et al. 2005

The Journal of Immunology

161

176

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We induced very low-dose tolerance by injecting lupus prone (SWR × NZB)F1 (SNF1) mice with 1 μg nucleosomal histone peptide autoepitopes s.c. every 2 wk. The subnanomolar peptide therapy diminished autoantibody levels and prolonged life span by delaying nephritis, especially by reducing inflammatory cell reaction and infiltration in kidneys. H471–94 was the most effective autoepitope. Low-dose tolerance therapy induced CD8+, as well as CD4+CD25+ regulatory T (Treg) cell subsets containing autoantigen-specific cells. These adaptive Treg cells suppressed IFN-γ responses of pathogenic lupus T cells to nucleosomal epitopes at up to a 1:100 ratio and reduced autoantibody production up to 90–100% by inhibiting nucleosome-stimulated T cell help to nuclear autoantigen-specific B cells. Both CD4+CD25+ and CD8+ Treg cells produced and required TGF-β1 for immunosuppression, and were effective in suppressing lupus autoimmunity upon adoptive transfer in vivo. The CD4+CD25+ T cells were partially cell contact dependent, but CD8+ T cells were contact independent. Thus, low-dose tolerance with highly conserved histone autoepitopes repairs a regulatory defect in systemic lupus erythematosus by generating long-lasting, TGF-β-producing Treg cells, without causing allergic/anaphylactic reactions or generalized immunosuppression.

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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

Cited by 32 publications

References 51 publications

Apoptosis-induced histone H3 methylation is targeted by autoantibodies in systemic lupus erythematosus

Apoptosis-induced histone H3 methylation is targeted by autoantibodies in systemic lupus erythematosus

An enhanced postnatal autoimmune profile in 24 week-old C57BL/6 mice developmentally exposed to TCDD

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

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