Concise communication t cell epitope mapping of u1‐a rnp

Okubo, Mitsuo; Kokubun, Masae; Nishimaki, Tomoe; Kasukawa, Reiji; Ohto, Hitoshi; Yamamoto, Kazuhiko; Muller, Sylviane

doi:10.1002/art.1780380823

Cited by 12 publications

(16 citation statements)

References 11 publications

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“…The murine and human U1A proteins are 96% identical at the amino acid level, with the main difference occurring at the N‐terminus 26 . Therefore, the sequence of murine U1A 201−220 , which was identified in the present study, is exactly the same as the human U1A 196−215 sequence, which overlaps the 201–241 region at the C‐terminus of human U1A 24 . It suggests that U1A‐specific T cells from either human lupus or BWF 1 mice may recognize the same auto‐T‐cell epitope.…”

Section: Discussionsupporting

confidence: 53%

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Characterization of self‐T‐cell response and antigenic determinants of U1A protein with bone marrow‐derived dendritic cells in NZB × NZW F₁ mice

Suen

Chen

et al. 2001

Immunology

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SUMMARYSystemic lupus erythematosus (SLE) is characterized by the existence of a heterogeneous group of autoantibodies directed against nuclear intact structures, such as nucleosomes and small nuclear ribonucleoproteins (snRNPs). Autoantibodies against snRNPs are of special interest because they are detectable in the majority of SLE patients. Although the B-cell antigenic determinants have been well characterized, very limited data have been reported in regard to the T-cell epitopes of snRNPs. Furthermore, several studies have demonstrated that determination of the auto-T-cell epitopes recognized by freshly isolated T cells is dif®cult from unprimed lupus mice when self-antigen-pulsed B cells or macrophages are used as antigen-presenting cells (APCs) in vitro. In the present study, we showed a novel approach for determining the auto-T-cell epitopes, using bone marrow-derived dendritic cells (BMDCs) pulsed with the murine U1A protein ± an immunodominant antigen of the U1 snRNPs ± which is capable of activating freshly isolated T cells from unprimed (NZBrNZW) F 1 (BWF 1 ) mice in vitro. The T-cell epitope area was found to be located at the C-terminus of U1A, overlapping the T-cell epitope of human U1A that has been reported in human SLE. Identi®cation of the autoreactive T-cell epitope(s) in snRNPs will help to elucidate how reciprocal T±B determinant spreading of snRNPs emerges in lupus. The results presented here also indicate that it is feasible to use this approach to further explore strategies to design immunotherapy for patients with lupus.

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Section: Discussionsupporting

confidence: 53%

“…U1A may be an initial target when an anti‐snRNP response develops in MRL‐ lpr / lpr mice 4 . Two major T‐cell epitopes on U1A RNP have been identified in human lupus 24 . However, only limited studies have been carried out on the antigenic determinant of U1A in BWF 1 mice.…”

Section: Discussionmentioning

confidence: 99%

Characterization of self‐T‐cell response and antigenic determinants of U1A protein with bone marrow‐derived dendritic cells in NZB × NZW F₁ mice

Suen

Chen

et al. 2001

Immunology

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“…2B). The region 201±241 as well as the C-terminal sequence 242±282 were subsequently reported to contain major T-cell epitopes recognized by CD4 1 T cells from patients with MCTD [48].…”

Section: U1a Epitopesmentioning

confidence: 99%

Key Sequences Involved in the Spreading of the Systemic Autoimmune Response to Spliceosomal Proteins

Monneaux

Muller

2001

Scand J Immunol

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Immune spreading to multiple intracellular antigens is likely to be of primary importance in organ-specific and systemic autoimmune diseases. A number of mechanisms by which immune spreading may occur from only a single autoreactive epitope have been proposed. Search for an initiator or early epitope thus represents an important area of investigation. For example, many studies have focused on the identification of epitopes recognized by the antibodies from both patients with systemic lupus erythematosus (SLE) and lupus-prone mice. Recently, an autoepitope present in the 70K U1 ribonucleo protein (RNP) and recognized by CD4 1 T cells from lupus mice has also been identified. Here, we analyze the results of B-and T-cell-epitope mapping studies of several RNPs present in the spliceosome and propose a model of epitope spreading. In this model, a consensus sequence (the RNP motif) conserved in many nuclear, nucleolar and cytoplasmic antigens, might play a role as`driver' epitope. This hypothesis is based on the observation that this sequence is recognized by CD4 1 T cells from lupus mice and is often targeted by autoantibodies, very early during the course of the disease. Targeting this region that is repeated in different self-antigens, might represent an interesting strategy to interfere with the continuous T-cell stimulation and exposure to specific antigens.

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“…esides intrinsic dysfunctions of B lymphocytes that characterize systemic lupus erythematosus (SLE), 3 numerous abnormalities also affect T cell response, the production of T cell cytokines, and the T-B cell dialogue. T cells appear to have a central role in the pathogenesis of SLE.…”

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confidence: 99%

“…ϩ T cell epitopes of a number of nuclear Ags have been characterized in human lupus as well as in mixed-connective tissue disease and Sjögren's syndrome using either short-term T cell lines, T cell clones and cloned Th hybridomas, or PBMC (2)(3)(4)(5)(6)(7). By testing a series of overlapping peptides, we previously identified an epitope present in residues 131-151 of the spliceosomal U1-70K small nuclear ribonucleoprotein, recognized very early by IgG Abs and CD4 ϩ lymph node T cells from both H-2 k MRL/lpr and H-2 d/z (NZB ϫ NZW)F 1 lupus-prone mice (8,9).…”

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confidence: 99%

Selective Modulation of CD4+ T Cells from Lupus Patients by a Promiscuous, Protective Peptide Analog

Monneaux

Hoebeke

Sordet

et al. 2005

The Journal of Immunology

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A peptide encompassing residues 131–151 of the spliceosomal U1-70K protein and its analog phosphorylated at Ser140 were synthesized as potential candidates for the treatment of patients with lupus. Studies in the MRL/lpr and (NZB × NZW)F1 lupus models have demonstrated that these sequences contain a CD4+ T cell epitope but administration of the phosphorylated peptide only ameliorates the clinical manifestations of treated MRL/lpr mice. Binding assays with soluble HLA class II molecules and molecular modeling experiments indicate that both peptides behave as promiscuous epitopes and bind to a large panel of human DR molecules. In contrast to normal T cells and T cells from non-lupus autoimmune patients, we found that PBMCs from 40% of lupus patients selected randomly and CFSE-labeled CD4+ T cells proliferate in response to peptide 131–151. Remarkably, however, we observed that phosphorylation of Ser140 prevents CD4+ T cells proliferation but not secretion of regulatory cytokines, suggesting a striking immunomodulatory effect of phosphorylated analog on lupus CD4+ T cells that was unique to patients. The analog might act as an activator of regulatory T cells or as a partial agonist of TCR.

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Concise communication t cell epitope mapping of u1‐a rnp

Cited by 12 publications

References 11 publications

Characterization of self‐T‐cell response and antigenic determinants of U1A protein with bone marrow‐derived dendritic cells in NZB × NZW F₁ mice

Characterization of self‐T‐cell response and antigenic determinants of U1A protein with bone marrow‐derived dendritic cells in NZB × NZW F₁ mice

Key Sequences Involved in the Spreading of the Systemic Autoimmune Response to Spliceosomal Proteins

Selective Modulation of CD4+ T Cells from Lupus Patients by a Promiscuous, Protective Peptide Analog

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Concise communication t cell epitope mapping of u1‐a rnp

Cited by 12 publications

References 11 publications

Characterization of self‐T‐cell response and antigenic determinants of U1A protein with bone marrow‐derived dendritic cells in NZB × NZW F1 mice

Characterization of self‐T‐cell response and antigenic determinants of U1A protein with bone marrow‐derived dendritic cells in NZB × NZW F1 mice

Key Sequences Involved in the Spreading of the Systemic Autoimmune Response to Spliceosomal Proteins

Selective Modulation of CD4+ T Cells from Lupus Patients by a Promiscuous, Protective Peptide Analog

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Characterization of self‐T‐cell response and antigenic determinants of U1A protein with bone marrow‐derived dendritic cells in NZB × NZW F₁ mice

Characterization of self‐T‐cell response and antigenic determinants of U1A protein with bone marrow‐derived dendritic cells in NZB × NZW F₁ mice