Expansion of polyreactive B cells cross-reactive to HLA and self in the blood of a patient with kidney graft rejection.
Expansion of polyreactive B cells cross-reactive to HLA and self in the blood of a patient with kidney graft rejection.
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DOI：
10.1111/j.1600-6143.2012.04053.x
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发表时间：
2012-08
期刊：
影响因子：
--
通讯作者：
Zorn E
中科院分区：
文献类型：
--
作者：
Porcheray F;DeVito J;Helou Y;Dargon I;Fraser JW;Nobecourt P;Ferdman J;Germana S;Girouard TC;Kawai T;Saidman SL;Wong W;Colvin RB;Leguern C;Zorn E
抗体排斥通常伴随着非供体 HLA 特异性抗体 (NDSA) 和与供体特异性抗体 (DSA) 一起产生的自身反应性抗体。为了确定这些抗体的来源，我们对来自患有体液排斥的肾移植受者的 107 个 B 细胞克隆进行了永生化。其中两个克隆对 I 类 HLA 或 MICA 产生反应。两个克隆也对自身抗原和肾细胞系裂解物有反应，因此揭示了多反应性模式。通过鉴定每个克隆的单个重排免疫球蛋白重链可变区（VH）序列来验证单克隆性。通过追踪其独特的 CDR3 序列，我们发现一种这样的多反应性克隆在患者血液中高度扩增，约占循环 B 细胞的 0.2%。该克隆的 VH 序列显示了与其记忆表型及其扩展一致的体细胞突变的证据。最后，在排斥反应时患者血清中发现了扩增的多反应性 B 细胞克隆的反应性。总之，我们在此提供克隆水平的原理证明，即人类抗体可以与 HLA 和自身发生交叉反应。我们的研究结果强烈表明，多反应性抗体有助于移植受者的 DSA、NDSA 以及自身抗体。
Antibody rejection is often accompanied by non-donor HLA specific antibodies (NDSA) and self-reactive antibodies that develop alongside donor-specific antibodies (DSA). To determine the source of these antibodies, we immortalized 107 B cell clones from a kidney transplant recipient with humoral rejection. Two of these clones reacted to HLA class I or MICA. Both clones were also reactive to self antigens and a lysate of a kidney cell line, hence revealing a pattern of polyreactivity. Monoclonality was verified by the identification of a single rearranged immunoglobulin heavy chain variable region (VH) sequence for each clone. By tracking their unique CDR3 sequence, we found that one such polyreactive clone was highly expanded in the patient blood, representing ~0.2% of circulating B cells. The VH sequence of this clone showed evidence of somatic mutations that were consistent with its memory phenotype and its expansion. Lastly, the reactivity of the expanded polyreactive B cell clone was found in the patient serum at time of rejection. In conclusion, we provide here proof of principle at the clonal level that human antibodies can cross-react to HLA and self. Our findings strongly suggest that polyreactive antibodies contribute to DSA, NDSA as well as autoantibodies, in transplant recipients.
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