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杀伤细胞免疫球蛋白样受体KIR2DS4等位基因与疾病相关性的研究进展
中华妇幼临床医学杂志（电子版）, 2016,12(1) : 114-117. DOI: 10.3877/cma.j.issn.1673-5250.2016.01.021
摘要

杀伤细胞免疫球蛋白样受体(KIR)主要表达于自然杀伤(NK)细胞及某些T细胞表面，可调节NK细胞功能。KIR编码基因具有高度多态性，可组成不同单倍型。其中KIR2DS4具有多种等位基因，是单倍型A携带的唯一活化性KIR基因，编码功能性KIR2DS4受体，而当其在第5外显子丢失22 bp碱基后即成为KIR1D基因，编码无功能的可溶性受体KIR1D。由于KIR2DS4具有独特的基因特征、单倍型和群体分布特征，以及KIR2DS4受体与配体的关系，使其在KIR与疾病相关性研究中尤为重要。笔者拟就近年来KIR2DS4等位基因与疾病相关性的研究进展进行综述。

引用本文: 蒋鸣燕, 朱易萍, 李强. 杀伤细胞免疫球蛋白样受体KIR2DS4等位基因与疾病相关性的研究进展 [J/OL] . 中华妇幼临床医学杂志（电子版）, 2016, 12(1) : 114-117. DOI: 10.3877/cma.j.issn.1673-5250.2016.01.021.
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自然杀伤(natural killer, NK)细胞是一类不具有T、B淋巴细胞表面标志物和特征的细胞毒性淋巴细胞，该细胞功能与人类多种疾病的发生、发展密切相关[1]。NK细胞的细胞毒作用受到多种活化性受体和抑制性受体的调控，从而维持机体自身免疫耐受和对病原体、肿瘤细胞免疫监视等的动态平衡[2,3]。其中，杀伤细胞免疫球蛋白样受体(killer cell immunoglobulin-like receptor, KIR)是主要表达于NK细胞及某些T淋巴细胞表面的受体之一，可参与调节NK细胞功能[4]。KIR由人类染色体19q13.42位于白细胞受体复合体(leukocyte receptor complex, LRC)中一段长约150 kb的基因区域编码[5,6]。目前已发现16种KIR基因(包括2个假基因KIR2DP1、KIR3DP1)。其中，编码胞质区L型长尾段的为抑制性KIR基因，包括KIR3DL1-3、KIR2DL1-3及KIR2DL5；编码胞质区S型短尾段的为活化性KIR基因，包括KIR2DS1-5、KIR3DS1；KIR2DL4同时具有抑制和活化功能[5,6]。KIR基因具有高度基因多态性，表现为KIR基因组合数量和种类的多态性，以及同一KIR基因座等位基因的多态性[7,8]。KIR基因组合具有一定规律性，从而形成不同的单倍型，分为单倍型A和单倍型B两组。单倍型A结构较为固定，包括9个基因(KIR3DL3、KIR2DL3、KIR2DP1、KIR2DL1、KIR3DP1、KIR2DL4、KIR3DL1、KIR2DS4及KIR3DL2)，可编码多种抑制性KIR和1种活化性KIR基因(KIR2DS4)。除单倍型A的单倍型统称为单倍型B，由多种基因组成(KIR2DS1、KIR2DS2、KIR2DS3、KIR2DS5、KIR2DL2、KIR2DL5和KIR3DS1等)，可编码多种活化性KIR[8,9]。KIR的配体主要是人类白细胞抗原(human leucocyte antigen, HLA)I类分子[10]。多种抑制性和活化性KIR的组合表达，可通过KIR与靶细胞上的配体结合，产生抑制和活化信号，调节NK细胞杀伤活性，参与人类多种疾病的发生、发展[11,12,13]。

1　KIR2DS4等位基因

KIR2DS4是单倍型A携带的唯一活化性KIR基因，具有12种等位基因，其中，9种等位基因存在编码区核苷酸改变：2DS4*00101、*00102和*00103编码完整的细胞表面受体KIR2DS4，而2DS4*003、004、006、007、008和009等位基因则在第5外显子缺失22 bp碱基，导致读码框移位，形成截短的KIR2DS4受体，而该受体由于失去跨膜区和胞质区结构域，无法锚定于细胞膜上，从而产生可溶性无功能变异体KIR1D[14,15,16]。不同人种KIR2DS4等位基因频率不同。黄种人(包括中国汉族人、日本人和韩国人)KIR2DS4与KIR1D基因频率比例约为2：1[17,18,19]，白种人以KIR1D基因为主[20,21]。KIR2DS4受体在胞质区无免疫受体酪氨酸抑制基序(immunoreceptor tyrosine-based inhibitory motif, ITIM)，但在跨膜区含有带正电荷的赖氨酸残基，可以与其他含有免疫受体酪氨酸活化基序(immunoreceptor tyrosine-based activation motif, ITAM)的分子如DNAX相关蛋白(DNAX-associated protein, DAP)12，或杀伤细胞活化受体相关蛋白(killer cell activating receptor-associated protein, KARAP)非共价结合，使DAP12、Sky酪氨酸激酶、磷脂酶C等发生磷酸化，激活丝裂原活化蛋白激酶(mitogen activated protein kinase, MAPK)级联反应，引起NK细胞活化[22]。

目前，KIR2DS4的生理作用及其功能性配体仍尚未完全明确。有研究结果显示，KIR2DS4可能与某些HLA-Ⅰ类分子[10,23,24,25,26]及其他未知配体[如主要组织相容性复合体(major histocompatibility complex，MHC)-Ⅰ类分子]结合[27]，例如KIR2DS4与部分HLA-C的亲和力弱于KIR2DS1，而KIR2DS4可与HLA-A*11结合[25]。Katz等[24]研究结果显示，KIR2DS4可与表达HLA-Cw4的细胞低亲和力结合，还可识别黑色素瘤细胞上表达的非HLA-Ⅰ类配体，增强NK细胞活性，杀伤靶细胞[27]。

2　KIR2DS4与相关疾病
2.1　KIR2DS4与感染性疾病

KIR2DS4和KIR1D与感染性疾病的相关性日益成为研究热点之一。携带KIR2DS4的血清人类免疫缺陷病毒(human immun-odeficiency virus，HIV)呈阳性患者更易将HIV-1传递给血清HIV呈阴性的伴侣[26]。一项关于母婴传播HIV的研究结果显示，胎儿宫内感染组KIR1D基因频率较非感染组显著升高[28]。对于母亲KIR2DS4－而胎儿KIR2DS＋者，分娩期发生母婴传播HIV的婴儿携带KIR1D基因比例较未发生母婴传播HIV的婴儿显著升高[28]。Zhuang等[29]研究结果显示，中国汉族梅毒患者KIR1D纯合子(KIR1D/KIR1D)的基因频率较正常对照组显著增高，提示KIR1D纯合子可能与中国汉族人群的梅毒易感性相关。疟原虫阳性患者杂合子(KIR3DL1/KIR3DS1)联合KIR2DS4纯合子(KIR2DS4/KIR2DS4)的基因频率也较疟原虫阴性患者显著升高[30]。在KIR基因簇中，KIR3DL1和KIR2DS4(包括KIR2DS4及其变异体KIR1D)均位于端粒侧，并且二者存在明显连锁不平衡(linkage disequilibrium, LD)[31]。基于上述结构关系，KIR3DL1可能作为KIR2DS4活化的抑制体，提示二者活化和抑制信号的平衡关系可能参与个体免疫功能的平衡。这种调节机制可能是上游KIR3DL1的表达调节KIR2DS4的转录[30]。KIR等位基因的多态性可能产生不同的KIR表达水平，从而具有不同的配体特异性[32]。Paladino等[33]研究结果显示，丙型肝炎病毒(hepatitis C virus，HCV)感染者KIR2DS4基因频率降低，提示特定KIR基因对一种疾病有益的同时，可能对另一种疾病有害。

2.2　KIR2DS4与肿瘤性疾病

目前，KIR2DS4与肿瘤性疾病关系的研究较多。Pan等[34]研究结果显示，肝细胞性肝癌组患者KIR2DS4基因频率较非肝细胞性肝癌组患者增高，但二者比较，差异无统计学意义，并且KIR2DS4是否可与乙型肝炎病毒(hepatitis B virus，HBV)感染细胞上的蛋白结合仍需进一步研究。De Re等[35]研究结果显示，KIR2DS4－转移性结直肠癌患者治疗后完全缓解率较KIR2DS4＋患者显著增高。

Giebel等[36]研究结果显示，波兰接受造血干细胞移植(hematopoietic stem cell transplantation，HSCT)的慢性粒细胞白血病(chronic myeloid leukemia，CML)患者携带KIR2DS4－KIR1D＋基因频率较供者显著增高，但未发现接受HSCT的急性髓细胞白血病(acute myelocytic leukemia，AML)和急性淋巴细胞白血病(acute lymphoblastic leukemia，ALL)患者和供者中KIR2DS4－KIR1D＋基因频率有类似差异。该研究结果提示，CML细胞可能是KIR2DS4受体介导杀伤作用的靶细胞，而由于无功能的KIR1D替代KIR2DS4，可能降低NK细胞对CML细胞的杀伤作用。张艳等[37]研究结果显示，中国汉族白血病患者KIR2DS4基因频率较正常对照组显著升高，而进一步比较发现CML组患儿KIR2DS4基因频率较急性非淋巴细胞白血病(acute nonlymphocytic leukemia，NALL)组，ALL组及对照组患儿均显著升高，该结果提示活化性KIR2DS4可能是CML发病的危险因素。但由于该研究未区分KIR2DS4及其等位基因KIR1D，可能影响针对KIR2DS4与白血病发病相关性研究的结果[38]。Almalte等[39]研究结果显示，法裔加拿大B-ALL患儿活化性KIR基因(包括KIR2DS4，不包括KIR1D)基因频率较正常对照组显著降低，提示活化性KIR基因对儿童B-ALL具有保护作用。但随后德国一项研究结果显示，白种人活化性KIR基因与儿童B-ALL的发病无类似相关性，但该研究未区分KIR2DS4与KIR1D[40]。

目前，对KIR2DS4相应配体的认知较为有限。有研究结果显示，KIR2DS4配体主要为HLA-A*11、部分HLA-C1和HLA-C2及未识别的黑色素瘤抗原[10,23,25]。由于KIR1D编码可溶性分子，因此KIR1D可屏蔽KIR2DS4或某些细胞(如T细胞、NK细胞)上其他受体的配体[41]，或作为清除可溶性HLA的诱导物，干扰NK细胞功能[15,36]。Pan等[34]研究结果亦显示，KIR1D分子可能通过与KIR2DS4的配体相互作用发挥功能。KIR1D蛋白在表达其配体的细胞上可能发挥旁分泌功能，或者在表达交叉重叠配体上发挥膜受体竞争功能[15,36]。上述猜测与Gomez-Lozano等[42]研究的KIR3DP1v功能类似。此外，由于抑制性受体的配体HLA-Ⅰ表达水平降低，削弱抑制信号，从而可能增强NK细胞对白血病细胞的溶解作用[43,44]。

2.3　KIR2DS4与其他疾病

HSCT后巨细胞病毒(cytomegalovirus，CMV)再活化的患者KIR2DS2和KIR2DS4蛋白表达增加[45]。此外，由于供者活化性KIR是发生急性移植物抗宿主病(acute graft-versus-host disease，aGVHD)的潜在高危标志物[46]。Bao等[47]发现KIR2DS4作为AA基因型供者体内唯一的活化性KIR基因，KIR2DS4的表达增加异基因造血干细胞移植(allogeneic hematopoietic stem cell transplantation, allo-HSCT)后aGVHD的发生风险。Chen等[48]研究结果显示，含有更多活化性KIR受体的NK细胞可产生更多γ-干扰素，进而产生强烈的细胞溶解效应。而γ-干扰素已被证实与aGVHD的发生有关[49]。对于因肾小球肾炎进入终末期肾病而接受肾脏移植的患者，其KIR2DS4和KIR1D基因增加急性排斥反应的发生风险[41]。进行肝脏移植的供者与受者KIR基因错配影响移植物存活率。例如，对于接受HLA-C1－(HLA-C2＋/HLA-C2＋)供者移植的KIR2DS4＋受者，其移植物存活率显著低于接受HLA-C1＋/HLA-C1＋供者移植的受者[50]。全身型幼年特发性关节炎(juvenile idiopathic arthritis，JIA)患儿KIR2DS4基因频率明显低于多关节型JIA、少关节型JIA患儿及健康儿童[51]。此外，携带单倍型A KIR1D基因的孕妇分娩成功率较低[52]。

KIR2DS4作为单倍型A的唯一活化性KIR基因，其基因多态性与疾病的相关性日益引起人们关注[24,36,37]。由于样本量、分组标准及研究人种等因素不同，上述研究可能得出不一致结果。因而，KIR2DS4和KIR1D基因、蛋白及其配体的功能仍有待于进一步探索，明确其参与疾病发生发展的具体机制，以指导临床诊疗。

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1　KIR2DS4等位基因
2　KIR2DS4与相关疾病
2.1　KIR2DS4与感染性疾病
2.2　KIR2DS4与肿瘤性疾病
2.3　KIR2DS4与其他疾病
参考文献
　
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