Hirano Naoto, Butler Marcus O, Von Bergwelt-Baildon Michael S, Maecker Britta, Schultze Joachim L, O'Connor Kevin C, Schur Peter H, Kojima Seiji, Guinan Eva C, Nadler Lee M
Dana-Farber Cancer Institute, Department of Medical Oncology, 44 Binney St, Boston MA 02115, USA.
Blood. 2003 Dec 15;102(13):4567-75. doi: 10.1182/blood-2002-11-3409. Epub 2003 Aug 28.
Although accumulating evidence strongly suggests that aplastic anemia (AA) is a T cell-mediated autoimmune disease, no target antigens have yet been described for AA. In autoimmune diseases, target autoantigens frequently induce not only cellular T-cell responses but also humoral B-cell responses. We hypothesized that the presence of antigen-specific autoantibodies could be used as a "surrogate marker" for the identification of target T-cell autoantigens in AA patients. We screened a human fetal liver library for serologic reactivity against hematopoietic stem/progenitor cell antigens and isolated 32 genes. In 7 of 18 AA patients, an immunoglobulin G (IgG) antibody response was detected to one of the genes, kinectin, which is expressed in all hematopoietic cell lineages tested including CD34+ cells. No response to kinectin was detected in healthy volunteers, multiply transfused non-AA patients, or patients with other autoimmune diseases. Epitope mapping of IgG autoantibodies against kinectin revealed that the responses to several of the epitopes were shared by different AA patients. Moreover, CD8+ cytotoxic T cells raised against kinectin-derived peptides suppressed the colony formation of granulocyte macrophage colony-forming units (CFU-GMs) in an HLA class I-restricted fashion. These results suggest that kinectin may be a candidate autoantigen that is involved in the pathophysiology of AA.
尽管越来越多的证据强烈表明再生障碍性贫血（AA）是一种T细胞介导的自身免疫性疾病，但尚未发现AA的靶抗原。在自身免疫性疾病中，靶自身抗原不仅经常诱导细胞T细胞反应，还诱导体液B细胞反应。我们假设抗原特异性自身抗体的存在可作为识别AA患者靶T细胞自身抗原的“替代标志物”。我们筛选了一个人胎肝文库，以寻找针对造血干/祖细胞抗原的血清学反应性，并分离出32个基因。在18例AA患者中的7例中，检测到针对其中一个基因驱动蛋白的免疫球蛋白G（IgG）抗体反应，该基因在包括CD34+细胞在内的所有测试造血细胞谱系中均有表达。在健康志愿者、多次输血的非AA患者或其他自身免疫性疾病患者中未检测到对驱动蛋白的反应。针对驱动蛋白的IgG自身抗体的表位作图显示，不同AA患者对几个表位的反应是相同的。此外，针对驱动蛋白衍生肽产生的CD8+细胞毒性T细胞以HLA I类限制性方式抑制了粒细胞巨噬细胞集落形成单位（CFU-GM）的集落形成。这些结果表明，驱动蛋白可能是参与AA病理生理过程的自身抗原候选物。
