MICA/MICB细胞外结构域的突变热点

A. Yu. Stolbovaya, I. V. Smirnov
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引用次数: 0

摘要

MICA和MICB是非典型的MHC分子,表明细胞应激。它们作为NK细胞上发现的NKG2D受体的配体,从而引发对受损、感染或转化细胞的细胞毒性反应。MICA/MICB的可溶性形式是通过细胞外结构域(ECDs)的分裂产生的。MICA/MICB分子在肿瘤切片中的表达或其在血液中可溶形式的水平具有作为癌症诊断工具的潜力。它们可以预测癌症患者的重要临床结果,如总生存率和无复发生存率。然而,它们广泛的分子多态性使单克隆抗体(mab)用于诊断的发展复杂化。因此,基于单克隆抗体的检测方法的诊断价值可能因当地人群中等位基因变异的频率而异。我们检测了超过280个MICA和50个MICB等位基因变异的ECD氨基酸序列。此外,我们鉴定了172和58个单核苷酸多态性(snp)位于各自基因的编码区,导致氨基酸替换。最常见的氨基酸替换(>10%)分别发生在MICA和MICB的11个和4个位点。我们发现,在不同的人群中,尽管等位基因变异频率存在多样性,但在确定的热点中snp的频率彼此之间具有很强的相关性。只有一个位点的功能作用是已知的。用蛋氨酸取代152号位置的缬氨酸增强了MICA对NKG2D受体的亲和力。由于热点分布在整个ECD序列中,它们可能除了调节与NKG2D受体相互作用的亲和力外,还发挥其他作用。我们建议用于验证抗mica /MICB单克隆抗体的Ag集满足两个标准。首先,它们应该包括MICA和MICB等位基因,因为这些基因具有高度相似的序列。其次,等位基因应覆盖在鉴定的热点地区观察到的变异性。
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Mutation hot spots in MICA/MICB extracellular domains
MICA and MICB are non-classical MHC molecules that indicate cellular stress. They act as ligands for NKG2D receptors found on NK cells, thereby triggering a cytotoxic response against damaged, infected, or transformed cells. The production of soluble forms of MICA/MICB occurs via the cleavage of their extracellular domains (ECDs). The expression of MICA/MICB molecules in tumor sections or the levels of their soluble forms in blood have potential as diagnostic tools for cancer. They can predict important clinical outcomes for cancer patients, such as overall and recurrence-free survival. However, their extensive molecular polymorphism complicates the development of monoclonal antibodies (mAbs) for diagnostic use. Therefore, the diagnostic value of mAb-based assays may vary depending on the frequencies of allelic variants in local human populations. We examined the ECD amino acid sequences of more than 280 MICA and 50 MICB allelic variants. Additionally, we identified 172 and 58 single nucleotide polymorphisms (SNPs) located in the coding regions of the respective genes and resulting in amino acid replacements. The most frequent amino acid replacements (> 10%) in the ECD occur at 11 and 4 sites of MICA and MICB, respectively. We found that the frequencies of SNPs in the identified hot spots strongly correlate with each other in different human populations, despite the diversity of allelic variant frequencies. The functional role of only one site is known. The replacement of valine with methionine at position 152 enhances the affinity of MICA to NKG2D receptor. As the hot spots are dispersed throughout the entire ECD sequences, they may play a role other than modulating affinity with the NKG2D receptor interaction. We recommend that Ag sets used to validate anti-MICA/MICB mAbs meet two criteria. First, they should include both MICA and MICB alleles, as these genes have highly similar sequences. Second, the alleles should cover the variability observed in the identified hot spots.
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来源期刊
Medical Immunology (Russia)
Medical Immunology (Russia) Medicine-Immunology and Allergy
CiteScore
0.70
自引率
0.00%
发文量
88
审稿时长
12 weeks
期刊介绍: The journal mission is to promote scientific achievements in fundamental and applied immunology to various medical fields, the publication of reviews, lectures, essays by leading domestic and foreign experts in the field of fundamental and experimental immunology, clinical immunology, allergology, immunodiagnostics and immunotherapy of infectious, allergy, autoimmune diseases and cancer.
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