Lu L, Kaliyaperumal A, Boumpas D T, Datta S K
Department of Medicine, Northwestern University Medical School, Chicago, Illinois 60611, USA.
J Clin Invest. 1999 Aug;104(3):345-55. doi: 10.1172/JCI6801.
We tested 154 peptides spanning the entire length of core histones of nucleosomes for the ability to stimulate an anti-DNA autoantibody-inducing T helper (Th) clone, as well as CD4(+) T-cell lines and T cells, in fresh PBMCs from 23 patients with lupus erythematosus. In contrast to normal T cells, lupus T cells responded strongly to certain histone peptides, irrespective of the patient's disease status. Nucleosomal peptides in histone regions H2B(10-33), H4(16-39) (and overlapping H4(14-28)), H4(71-94), and H3(91-105) (and overlapping H3(100-114)) were recurrently recognized by CD4 T cells from the patients with lupus. Remarkably, these same peptides overlap with major epitopes for the Th cells that induce anti-DNA autoantibodies and nephritis in lupus-prone mice. We localized 2 other recurrent epitopes for human lupus T cells in H2A(34-48) and H4(49-63). All the T-cell autoepitopes have multiple HLA-DR binding motifs, and the epitopes are located in histone regions recognized by lupus autoantibodies, suggesting a basis for their immunodominance. Native nucleosomes and their peptides H4(16-39), H4(71-94), and H3(91-105) induced a stronger IFN-gamma response, whereas others, particularly, H2A(34-48), favored an IL-10- and/or IL-4-positive T-cell response. The major autoepitopes may reveal the mechanism of autoimmune T-cell expansion and lead to antigen-specific therapy of human lupus.
我们检测了154种跨越核小体核心组蛋白全长的肽段，以评估其刺激抗DNA自身抗体诱导性辅助性T（Th）克隆以及来自23例红斑狼疮患者新鲜外周血单个核细胞（PBMC）中的CD4(+) T细胞系和T细胞的能力。与正常T细胞不同，狼疮T细胞对某些组蛋白肽段反应强烈，且与患者的疾病状态无关。来自狼疮患者的CD4 T细胞反复识别组蛋白区域H2B(10 - 33)、H4(16 - 39)（以及重叠的H4(14 - 28)）、H4(71 - 94)和H3(91 - 105)（以及重叠的H3(100 - 114)）中的核小体肽段。值得注意的是，这些相同的肽段与易患狼疮小鼠中诱导抗DNA自身抗体和肾炎的Th细胞的主要表位重叠。我们在H2A(34 - 48)和H4(49 - 63)中定位了另外两个针对人类狼疮T细胞的反复出现的表位。所有T细胞自身表位都有多个HLA - DR结合基序，且这些表位位于狼疮自身抗体识别的组蛋白区域，这表明了它们免疫显性的基础。天然核小体及其肽段H4(16 - 39)、H4(71 - 94)和H3(91 - 105)诱导更强的γ干扰素反应，而其他肽段，特别是H2A(34 - 48)，则倾向于诱导白细胞介素-10和/或白细胞介素-4阳性的T细胞反应。主要自身表位可能揭示自身免疫性T细胞扩增的机制，并为人类狼疮的抗原特异性治疗提供线索。
