THE ROLE OF AN AUTOANTIGEN, HISTIDYL-TRANSFER RNA-SYNTHETASE, IN THE INDUCTION AND MAINTENANCE OF AUTOIMMUNITY
THE ROLE OF AN AUTOANTIGEN, HISTIDYL-TRANSFER RNA-SYNTHETASE, IN THE INDUCTION AND MAINTENANCE OF AUTOIMMUNITY
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DOI：
10.1073/pnas.87.24.9933
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发表时间：
1990-12-01
影响因子：
11.1
通讯作者：
PLOTZ, PH
中科院分区：
文献类型：
--
作者：
MILLER, FW;WAITE, KA;PLOTZ, PH
全身性自身免疫性疾病的患者会产生针对自身结构的特定自身抗体。根据一种观点，这些自身抗体的产生是对外来抗原的免疫反应的结果，例如通过分子模仿与宿主蛋白质共享共同结构的感染性病原体。另一种观点认为，靶自身抗原本身启动、选择和维持自身抗体的合成。我们在这里表明，在人类自身免疫性肌肉疾病多发性肌炎中，针对组氨酰-tRNA合成酶的抗Jo-1自身抗体，除了谱型拓宽和类别转换外，还经历了对靶抗原的免疫反应的必要条件-对该抗原的亲和力成熟。我们进一步证明，与异种抗原免疫的小鼠诱导的抗合成酶抗体不同，这些自身抗体只与天然人类合成酶3上的非线性表位结合，当酶与tRNAHis络合时，这些表位仍然暴露。这些数据表明，天然靶自身抗原本身在选择和维持自身抗体反应方面发挥了直接作用，并严格限制了分子模拟物激发自身抗体的时间和方式。
Patients with systemic autoimmune diseases make specific autoantibodies that are directed against self structures. According to one view, these autoantibodies arise as a result of an immune response to foreign antigens such as infectious agents that share, by molecular mimicry, common structures with host proteins. An alternative view is that the target autoantigen itself initiates, selects, and sustains autoantibody synthesis. We show here that anti-Jo-1 autoantibodies directed against histidyl-tRNA synthetase in the human autoimmune muscle disease polymyositis undergo, in addition to spectrotype broadening and class switching, the sine qua non of an immune response to the target antigen-affinity maturation to that antigen. We demonstrate further that these autoantibodies, unlike anti-synthetase antibodies induced in mice immunized with heterologous antigen, bind only nonlinear epitopes on the native human synthetase 3 that remain exposed when the enzyme is complexed to tRNAHis. These data suggest that the native target autoantigen itself has played a direct role in selecting anhd sustaining the autoantibody response and sharply restrict the time and the way in which a molecular mimic might act to provoke autoantibodies.