In solid organ transplantation (SOT), the clinical relevance of donor‐specific antibodies (DSA) directed at anti‐HLA‐A, ‐B, ‐DR and ‐DQ antigens is largely recognized while it is still a matter of debate for DSA directed at HLA‐C. In this review, we summarize the peculiarities of HLA‐C among class I HLA antigens as well as their immunogenicity, which underlie the clinical relevance of HLA‐C locus and anti‐HLA‐C DSA in SOT. Many factors, both intrinsic and extrinsic to the HLA‐C gene and HLA‐C protein, explain its lower expression in comparison with HLA‐A and ‐B. This lower expression can explain the apparent lower immunogenicity of HLA‐C leading to a lower prevalence and strength of anti‐HLA‐C antibodies. Nevertheless, HLA‐C antigens are truly immunogenic and preformed anti‐HLA‐C DSA are clinically relevant. Indeed, anti‐HLA‐C DSA are able to bind donor cells and to activate the complement pathway both ex vivo and in vivo. In line with this, numerous clinical studies now show that preformed DSA directed at native HLA‐C molecules induce poorer graft outcomes. We then plead for the inclusion of HLA‐C in all transplant allocation systems and we propose a strategy to cope with anti‐HLA‐C DSA in SOT. Beyond SOT, anti‐HLA‐C antibodies generate a growing interest in the allo‐HCT, transfusion and obstetrics fields, while new concepts such as the role of the “missing‐self” in solid organ rejection places HLA‐C as an inescapable actor in transplant tolerance.

中文翻译：

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针对 HLA-C 的供体特异性抗体的临床相关性：接受的漫长道路

在实体器官移植 (SOT) 中，针对抗 HLA-A、-B、-DR 和 -DQ 抗原的供体特异性抗体 (DSA) 的临床相关性已得到广泛认可，但针对 DSA 仍存在争议在 HLA-C。在这篇综述中，我们总结了 I 类 HLA 抗原中 HLA-C 的特性及其免疫原性，这构成了 SOT 中 HLA-C 基因座和抗 HLA-C DSA 的临床相关性。许多因素，包括 HLA-C 基因和 HLA-C 蛋白的内在和外在因素，解释了其与 HLA-A 和 -B 相比较低的表达。这种较低的表达可以解释 HLA-C 的免疫原性明显较低，导致抗 HLA-C 抗体的流行率和强度较低。尽管如此，HLA-C 抗原确实具有免疫原性，并且预先形成的抗 HLA-C DSA 具有临床相关性。的确，抗 HLA-C DSA 能够结合供体细胞并在体外和体内激活补体途径。与此一致，现在许多临床研究表明，针对天然 HLA-C 分子的预制 DSA 会导致较差的移植结果。然后，我们呼吁将 HLA-C 纳入所有移植分配系统，并提出一种应对 SOT 中抗 HLA-C DSA 的策略。除了 SOT，抗 HLA-C 抗体在 allo-HCT、输血和产科领域引起了越来越多的兴趣，而诸如“缺失自我”在实体器官排斥反应中的作用等新概念使 HLA-C 成为不可避免的参与者在移植耐受性方面。然后，我们呼吁将 HLA-C 纳入所有移植分配系统，并提出一种应对 SOT 中抗 HLA-C DSA 的策略。除了 SOT，抗 HLA-C 抗体在 allo-HCT、输血和产科领域引起了越来越多的兴趣，而诸如“缺失自我”在实体器官排斥反应中的作用等新概念使 HLA-C 成为不可避免的参与者在移植耐受性方面。然后，我们呼吁将 HLA-C 纳入所有移植分配系统，并提出一种应对 SOT 中抗 HLA-C DSA 的策略。除了 SOT，抗 HLA-C 抗体在 allo-HCT、输血和产科领域引起了越来越多的兴趣，而诸如“缺失自我”在实体器官排斥反应中的作用等新概念使 HLA-C 成为不可避免的参与者在移植耐受性方面。