Immunogenetics of HLA null alleles: implications for blood stem cell transplantation
Immunogenetics of HLA null alleles: implications for blood stem cell transplantation
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DOI：
10.1111/j.1399-0039.2004.00322.x
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发表时间：
2004-12-01
期刊：
影响因子：
--
通讯作者：
Blasczyk, R
中科院分区：
文献类型：
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作者：
Elsner, HA;Blasczyk, R
造血干细胞移植是治疗多种血液和非血液疾病的潜在疗法。造血干细胞移植成功的关键是供受者的人类白细胞抗原（HLA）配型。HLA无效等位基因的特征在于缺乏血清学可检测的产物。由于血清学HLA诊断越来越多地被基于DNA的分型方法所取代，仅考虑基因的小区域，无效等位基因可能被误诊为正常表达的变体。在干细胞移植环境中未能将HLA无效等位基因鉴定为非表达变体可能导致HLA错配，其极有可能刺激同种异体T细胞并触发移植物抗宿主病。对于一些HLA无效等位基因，翻译成截短的多肽链似乎是可能的，因此可能作为次要的组织相容性抗原。由于HLA无效等位基因的患病率可能在0.3%左右甚至更高，因此应在临床实验室中实施HLA无效等位基因的筛查策略。它可能包括血清学和标准分子分型技术的组合。由于标准分子技术有时很麻烦，特别是对于表征HLA I类外显子4的5'端的胞嘧啶岛，并且需要不断更新，因此替代方法可以包括对来自基因组DNA的外显子2-3或4（1类）或外显子2（11类）的所有样品进行测序，包括相邻的内含子剪接位点。这种方法将检测到36/40迄今已知的非表达变异，并有可能很容易地发现新的变异，从而基本上最大限度地减少了忽视这些具有挑战性的变异的风险。
The transplantation of haematopoietic stem cells is a potentially curative therapy for a variety of haematological and non-haematological diseases. Matching of donor and recipient for human leucocyte antigens (HLA) is pivotal for the success of blood stem cell transplantation. HLA null alleles are characterized by the lack of a serologically detectable product. Because serological HLA diagnostics are increasingly replaced by DNA-based typing methods considering only small regions of the genes, null alleles may be misdiagnosed as normally expressed variants. The failure to identify an HLA null allele as a non-expressed variant in the stem cell transplantation setting may result in an HLA mismatch that is highly likely to stimulate allogeneic T cells and to trigger graft-vs-host disease. For some HLA null alleles, the translation into a truncated polypeptide chain seems possible, which thus might act as minor histocompatibility antigens. Because the prevalence of HLA null alleles may be around 0.3% or even higher, a screening strategy for HLA null alleles should, therefore be implemented in the clinical laboratory. It may consist of the combination of serology and standard molecular typing techniques. As the standard molecular techniques are sometimes troublesome especially for characterizing the cytosine island at the 5' end of HLA class I exon 4 and need continuously be updated, an alternative approach may consist of sequencing all samples from genomic DNA for exons 2-3 or 4 (class 1) or exon 2 (class 11), including the adjacent intron splicing sites. This approach will detect 36/40 so far known non-expressed variants and has the potential to easily uncover novel variants, thus essentially minimizing the risk of overlooking these challenging variants.