Major peptide autoepitopes for nucleosome-specific T cells of human lupus

Lu, Liping; Kaliyaperumal, Arunan; Boumpas, Dimitrios T.; Datta, Somnath

doi:10.1172/jci6801

Cited by 151 publications

(166 citation statements)

References 49 publications

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“…Due to intrinsic defects in lupus immune system, nucleosomes from apoptotic cells become major immunogens initiating cognate interactions between autoimmune CD4 ϩ Th cells and B cells leading to production of somatically mutated, class-switched autoantibodies that form pathogenic immune complexes with diverse nuclear Ags (6 -11). Certain peptides in nucleosomal histones are dominant autoepitopes and spontaneous priming to these occurs in preclinical lupus (12,13). These epitopes are cross-reactively recognized by autoimmune Th cells, as well as B cells of lupus, and they can be promiscuously presented in the context of diverse MHC class II (MHC II) 4 alleles, like "universal epitopes" (2,(12)(13)(14).…”

Section: Low-dose Peptide Tolerance Therapy Of Lupus Generates Plasmamentioning

confidence: 99%

Low-Dose Peptide Tolerance Therapy of Lupus Generates Plasmacytoid Dendritic Cells That Cause Expansion of Autoantigen-Specific Regulatory T Cells and Contraction of Inflammatory Th17 Cells

Kang

Liu

Datta

2007

The Journal of Immunology

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186

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Subnanomolar doses of an unaltered, naturally occurring nucleosomal histone peptide epitope, H471–94, when injected s.c. into lupus-prone mice, markedly prolong lifespan by generating CD4+25+ and CD8+ regulatory T cells (Treg) producing TGF-β. The induced Treg cells suppress nuclear autoantigen-specific Th and B cells and block renal inflammation. Splenic dendritic cells (DC) captured the s.c.-injected H471–94 peptide rapidly and expressed a tolerogenic phenotype. The DC of the tolerized animal, especially plasmacytoid DC, produced increased amounts of TGF-β, but diminished IL-6 on stimulation via the TLR-9 pathway by nucleosome autoantigen and other ligands; and those plasmacytoid DC blocked lupus autoimmune disease by simultaneously inducing autoantigen-specific Treg and suppressing inflammatory Th17 cells that infiltrated the kidneys of untreated lupus mice. Low-dose tolerance with H471–94 was effective even though the lupus immune system is spontaneously preprimed to react to the autoepitope. Thus, H471–94 peptide tolerance therapy that preferentially targets pathogenic autoimmune cells could spare lupus patients from chronically receiving toxic agents or global immunosuppressants and maintain remission by restoring autoantigen-specific Treg cells.

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Section: Low-dose Peptide Tolerance Therapy Of Lupus Generates Plasmamentioning

confidence: 99%

Low-Dose Peptide Tolerance Therapy of Lupus Generates Plasmacytoid Dendritic Cells That Cause Expansion of Autoantigen-Specific Regulatory T Cells and Contraction of Inflammatory Th17 Cells

Kang

Liu

Datta

2007

The Journal of Immunology

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186

206

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“…Erythematosus, Induces Direct Dendritic Cell Activation via a MyD88-Independent Pathway: Consequences on Inflammation 1 S ystemic lupus erythematosus (SLE) 3 is an inflammatory autoimmune disease of unknown etiology that is characterized by a large amount of circulating autoantibodies with diverse specificities. Among the targets recognized by these autoantibodies is the nucleosome, a complex composed of 180 bp of DNA and the five histone molecules (H1, H2A, H2B, H3, and H4).…”

Section: Nucleosome the Main Autoantigen In Systemic Lupusmentioning

confidence: 99%

“…Among the targets recognized by these autoantibodies is the nucleosome, a complex composed of 180 bp of DNA and the five histone molecules (H1, H2A, H2B, H3, and H4). The nucleosome is the main lupus autoantigen and is believed to play a key role in disease development because it is found as a circulating complex in patient sera (1) and because both autoreactive nucleosome-specific B and Th lymphocytes are detected in patients (2,3). Moreover, the levels of both anti-nucleosome autoantibodies and circulating nucleosomes have been shown to be associated with disease activity (4 -6).…”

Section: Nucleosome the Main Autoantigen In Systemic Lupusmentioning

confidence: 99%

“…After 24 and 48 h, supernatants were collected and frozen at Ϫ80°C until use and replaced by fresh medium. At day 4, cell proliferation was measured by 3 [H]thymidine (Amersham Biosciences) incorporation (with 1 Ci/well for the last 18 h) using a scintillation counter (Microbeta; Wallac). Supernatants were tested for the presence of IL-2 using the CTLL-2 cell line, the growth of which is dependent on the presence of IL-2.…”

Section: Mixed Leukocyte Reactionsmentioning

confidence: 99%

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Nucleosome, the Main Autoantigen in Systemic Lupus Erythematosus, Induces Direct Dendritic Cell Activation via a MyD88-Independent Pathway: Consequences on Inflammation

Decker

Singh‐Jasuja

Haager

et al. 2005

The Journal of Immunology

107

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Nucleosome is the major autoantigen in systemic lupus erythematosus. It is found as a circulating complex in the sera of patients and seems to play a key role in disease development. In this study, we show for the first time that physiologic concentrations of purified nucleosomes directly induce in vitro dendritic cell (DC) maturation of mouse bone marrow-derived DC, human monocyte-derived DC (MDDC), and purified human myeloid DC as observed by stimulation of allogenic cells in MLR, cytokine secretion, and CD86 up-regulation. Importantly, nucleosomes act as free complexes without the need for immune complex formation or for the presence of unmethylated CpG DNA motifs, and we thus identified a new mechanism of DC activation by nucleosomes. We have clearly demonstrated that this activation is nucleosome-specific and endotoxin-independent. Particularly, nucleosomes induce MDDC to secrete cytokines known to be detected in high concentrations in the sera of patients. Moreover, activated MDDC secrete IL-8, a neutrophil chemoattractant also detected in patient sera, and thus might favor the inflammation observed in patients. Both normal and lupus MDDC are sensitive to nucleosome-induced activation. Finally, injection of purified nucleosomes to normal mice induces in vivo DC maturation. Altogether, these results strengthen the key role of nucleosomes in systemic lupus erythematosus and might explain how peripheral tolerance is broken in patients.

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“…After AHSCT, however, IFN-γ production by CD4 + T cells is completely abrogated. It is noteworthy that CD4 + T cells of patients in clinical remission and treated with conventional approaches still exhibit a propensity for IFN-γ production under similar conditions [20]. In contrast, a significant upregulation of interleukin (IL)-13 synthesis occurred with post-AHSCT CD4 + T cells.…”

Section: Introductionmentioning

confidence: 99%

Immune Mechanisms Underlying the Beneficial Effects of Autologous Hematopoietic Stem Cell Transplantation in Multiple Sclerosis

Gosselin

Rivest

2011

Neurotherapeutics

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A recent phase I/II clinical trial drew serious attention to the therapeutic potential of autologous hematopoietic stem cell transplantation (AHSCT) in multiple sclerosis. However, questions were raised as to whether these beneficial effects should be attributed to the newly reconstituted immune system per se, or to the lymphoablative conditioning regimeninduced immunosuppression, given that T-cell depleting combinational drug therapies were used in the study. We discuss here the possibility that both AHSCT and T-cell depleting therapies may re-program alternatively the immune system, and why transplantation of CD34 + hematopoietic stem cells may offer AHSCT a possible advantage regarding longterm remission.

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Major peptide autoepitopes for nucleosome-specific T cells of human lupus

Cited by 151 publications

References 49 publications

Low-Dose Peptide Tolerance Therapy of Lupus Generates Plasmacytoid Dendritic Cells That Cause Expansion of Autoantigen-Specific Regulatory T Cells and Contraction of Inflammatory Th17 Cells

Low-Dose Peptide Tolerance Therapy of Lupus Generates Plasmacytoid Dendritic Cells That Cause Expansion of Autoantigen-Specific Regulatory T Cells and Contraction of Inflammatory Th17 Cells

Nucleosome, the Main Autoantigen in Systemic Lupus Erythematosus, Induces Direct Dendritic Cell Activation via a MyD88-Independent Pathway: Consequences on Inflammation

Immune Mechanisms Underlying the Beneficial Effects of Autologous Hematopoietic Stem Cell Transplantation in Multiple Sclerosis

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