Major peptide autoepitopes for nucleosome-centered T and B cell interaction in human and murine lupus
Major peptide autoepitopes for nucleosome-centered T and B cell interaction in human and murine lupus
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DOI：
10.1111/j.1749-6632.2003.tb06035.x
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发表时间：
2003-01-01
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影响因子：
--
通讯作者：
Datta, SK
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文献类型：
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作者：
Datta, SK
正常T和B细胞对核抗原的潜在交叉反应是巨大的，可能是由于它们被生殖性淋巴器官中的凋亡细胞抗原“教育”所致。尽管如我们所说的“核心库”，但外周免疫系统通常对细胞凋亡的产物保持耐受性或无知。然而，狼疮患者的辅助性T细胞(Th)和B细胞在CD40配体(CD40L)的表达上存在调节缺陷。亚阈值刺激可触发狼疮T细胞持续高表达CD40L，并与T细胞信号转导中的关键下调分子Cbl-b的磷酸化受损有关。这种CD40L的高表达异常延长了对自身免疫B细胞的共刺激信号，并可能刺激APC(树突状细胞、静止抗DNA B细胞和巨噬细胞)以免疫原性方式递送凋亡细胞自身抗原。我们已经确定了主要的核小体表位，这些表位对于狼疮自身免疫Th细胞和抗DNA B细胞之间的同源相互作用至关重要。通过重叠合成多肽的扫描和自然加工多肽的质谱分析，确定了核小体历史上的5个主要表位，即H1‘(22-42)、H2B10-33、H3(85-105)、H4(16-39)和H4(71-94)。狼疮的自身免疫T细胞和B细胞识别这些表位，随着年龄的增长，针对这些表位的自身抗体与核自身抗原发生交叉反应。此外，在不同的MHC等位基因背景下，多肽自身表位可以被狼疮T细胞混杂地呈现和识别。这种交叉反应为开发用于人类狼疮治疗的“普遍的”耐受性多肽打开了可能性，尽管它们的MHC具有多样性。事实上，使用单一组蛋白多肽表位的耐受性疗法可以通过“耐受性传播”共同灭活广泛的自身免疫T细胞和B细胞来阻止狼疮易感小鼠已建立的肾小球肾炎的进展。
The potential cross-reactivity of normal T and B cells to nuclear antigens is vast, probably due to their "education" by apoptotic cell antigens in generative lymphoid organs. Despite this "nucleocentric repertoire," as we call it, the peripheral immune system normally remains tolerant or ignorant of the products of apoptosis. However, the T helper (Th) cells, and also B cells of lupus, have a regulatory defect in the expression of CD40 ligand (CD40L). A sustained hyper-expression of CD40L by lupus T cells can be triggered by subthreshold stimuli, and is associated with impaired phosphorylation of Cbl-b, a critical downregulatory molecule in T cell signal transduction. This CD40L hyper-expression abnormally prolongs co-stimulatory signals to autoimmune B cells, and it probably instigates APC (dendritic cells, resting anti-DNA B cells, and macrophages) to present apoptotic cell autoantigens in an immunogenic fashion. We have identified the dominant nucleosomal epitopes that are critical for cognate interactions between autoimmune Th cells and anti-DNA B cells in lupus. By scanning of overlapping synthetic peptides, and by mass spectrometry of naturally processed peptides, five major epitopes in nucleosomal histories were localized, namely H1'(22-42), H2B10-33, H3(85-105), H4(16-39), and H4(71-94). The autoimmune T cells as well as B cells of lupus recognize these epitopes, and with age, autoantibodies against the peptide epitopes cross-react with nuclear autoantigens. Moreover, the peptide autoepitopes can be promiscuously presented and recognized by lupus T cells in the context of diverse MHC alleles. This cross-reactivity opens up the possibility of developing "universally" tolerogenic peptides for therapy of lupus in humans despite their MHC diversity. Indeed, tolerogenic therapy with a single histone peptide epitope can halt the progression of established glomerulonephritis in lupus-prone mice by "tolerance spreading" that inactivates a broad spectrum of autoimmune T and B cells in concert.