The association of HLA-G polymorphisms and the synergistic effect of sMICA and sHLA-G with chronic kidney disease and allograft acceptance

• Published in: PloS one Vol. 14; no. 2; p. e0212750
• Main Authors: Hauer, Vanessa, Risti, Matilde, Miranda, Bruna L M, da Silva, José S, Cidral, Ana L, Pozzi, Carolina M, Contieri, Fabiana L de C, Sadissou, Ibrahim A, Donadi, Eduardo A, Augusto, Danillo G, Bicalho, Maria da G
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 22.02.2019; Public Library of Science (PLoS)
• Subjects: Adult; Allografts; Analysis; Antigens; Biology and Life Sciences; Case-Control Studies; Chronic kidney failure; Cytotoxicity; Disease susceptibility; DNA sequencing; EDTA; Enzyme-linked immunosorbent assay; Female; Gene expression; Gene polymorphism; Genes; Genetic analysis; Genetic factors; Genetic polymorphisms; Genetics; Genomics; Genotypes; Genotyping; Graft rejection; Graft Rejection - genetics; Graft Rejection - immunology; Graft Rejection - pathology; Haplotypes; Health aspects; Histocompatibility antigen HLA; Histocompatibility Antigens Class I - genetics; Histocompatibility Antigens Class I - immunology; HLA antigens; HLA-G Antigens - genetics; HLA-G Antigens - immunology; Humans; Immunomodulation; Immunoregulation; Inflammation; Inflammatory response; Integrated software; Kidney diseases; Kidney Transplantation; Kidneys; Lymphocytes; Male; Medicine and Health Sciences; Middle Aged; Miscarriage; Mycophenolate sodium; NK Cell Lectin-Like Receptor Subfamily K - genetics; NK Cell Lectin-Like Receptor Subfamily K - immunology; Oligonucleotides; Organ transplantation; Patients; Polymerase chain reaction; Polymorphism; Polymorphism, Genetic; Prostate cancer; Rejection; Renal Insufficiency, Chronic - genetics; Renal Insufficiency, Chronic - immunology; Renal Insufficiency, Chronic - pathology; Renal Insufficiency, Chronic - surgery; Risk Factors; Surgery; Synergistic effect; Transplantation; Transplants & implants; Brazil
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0212750

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.