Laboratório de Imunogenética e Histocompatibilidade, Departamento de Genética, Universidade Federal do Paraná, Curitiba, Paraná, Brazil.
Setor de Transplante Renal, Hospital Universitário Evangélico de Curitiba, Alameda Augusto Stellfeld, Curitiba, Brazil.
PLoS One. 2019 Feb 22;14(2):e0212750. doi: 10.1371/journal.pone.0212750. eCollection 2019.
The HLA-G and MICA genes are stimulated under inflammatory conditions and code for soluble (sMICA and sHLA-G) or membrane-bound molecules that exhibit immunomodulatory properties. It is still unclear whether they would have a synergistic or antagonistic effect on the immunomodulation of the inflammatory response, such as in chronic kidney disease (CKD), contributing to a better prognosis after the kidney transplantation. In this study, we went from genetic to plasma analysis, first evaluating the polymorphism of MICA, NKG2D and HLA-G in a cohort from Southern Brazil, subdivided in a control group of individuals (n = 75), patients with CKD (n = 94), and kidney-transplant (KT) patients (n = 64). MICA, NKG2D and HLA-G genotyping was performed by polymerase chain reaction with specific oligonucleotide probes, Taqman and Sanger sequencing, respectively. Levels of soluble forms of MICA and HLA-G were measured in plasma with ELISA. Case-control analysis showed that the individuals with haplotype HLA-G*01:01/UTR-4 have a lower susceptibility to develop chronic kidney disease (OR = 0.480; p = 0.032). Concerning the group of kidney-transplant patients, the HLA-G genotypes +3010 GC (rs1710) and +3142 GC (rs1063320) were associated with higher risk for allograft rejection (OR = 5.357; p = 0.013 and OR = 5.357, p = 0.013, respectively). Nevertheless, the genotype +3010 GG (OR = 0.136; p = 0.041) was associated with kidney allograft acceptance, suggesting that it is a protection factor for rejection. In addition, the phenotypic analysis revealed higher levels of sHLA-G (p = 0.003) and sMICA (p < 0.001) in plasma were associated with the development of CKD. For patients who were already under chronic pathological stress and underwent a kidney transplant, a high sMICA (p = 0.001) in pre-transplant proved to favor immunomodulation and allograft acceptance. Even so, the association of genetic factors with differential levels of soluble molecules were not evidenced, we displayed a synergistic effect of sMICA and sHLA-G in response to inflammation. This increase was observed in CKD patients, that when undergo transplantation, had this previous amount of immunoregulatory molecules as a positive factor for the allograft acceptance.
HLA-G 和 MICA 基因在炎症条件下受到刺激，编码可溶性（sMICA 和 sHLA-G）或膜结合分子，具有免疫调节特性。目前尚不清楚它们在炎症反应的免疫调节中是协同作用还是拮抗作用，例如在慢性肾脏病 (CKD) 中，这是否有助于肾移植后的更好预后。在这项研究中，我们从遗传分析到血浆分析，首先评估了来自巴西南部队列的 MICA、NKG2D 和 HLA-G 的多态性，将其分为对照组个体（n=75）、CKD 患者（n=94）和肾移植（KT）患者（n=64）。MICA、NKG2D 和 HLA-G 基因分型通过聚合酶链反应与特异性寡核苷酸探针、Taqman 和 Sanger 测序分别进行。用 ELISA 测量血浆中可溶性 MICA 和 HLA-G 形式的水平。病例对照分析显示，具有 HLA-G*01:01/UTR-4 单倍型的个体发生慢性肾脏病的易感性较低（OR=0.480；p=0.032）。关于肾移植患者，HLA-G 基因型+3010 GC（rs1710）和+3142 GC（rs1063320）与同种异体移植物排斥的风险增加相关（OR=5.357；p=0.013 和 OR=5.357，p=0.013，分别）。然而，基因型+3010 GG（OR=0.136；p=0.041）与肾同种异体移植接受相关，表明其是排斥反应的保护因素。此外，表型分析显示，血浆中 sHLA-G（p=0.003）和 sMICA（p<0.001）水平升高与 CKD 的发生有关。对于已经处于慢性病理应激并接受肾移植的患者，移植前高 sMICA（p=0.001）证明有利于免疫调节和同种异体移植接受。即便如此，尚未证明遗传因素与可溶性分子的差异水平之间存在关联，我们显示了 sMICA 和 sHLA-G 对炎症的协同反应。在 CKD 患者中观察到这种增加，当他们接受移植时，这些先前的免疫调节分子数量是同种异体移植接受的一个积极因素。
