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

Abstract

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.

• Authors: Vanessa Hauer, Matilde Risti, Bruna L M Miranda, José S da Silva, Ana L Cidral, Carolina M Pozzi, Fabiana L de C Contieri, Ibrahim A Sadissou, Eduardo A Donadi, Danillo G Augusto, Maria da G Bicalho
• Journal: PloS one (PLoS One) Vol. 14 Issue 2 Pg. e0212750 ( 2019) ISSN: 1932-6203 [Electronic] United States
• PMID: 30794652 (Publication Type: Clinical Trial, Journal Article, Multicenter Study, Research Support, Non-U.S. Gov't)

Chemical References

• HLA-G Antigens
• Histocompatibility Antigens Class I
• KLRK1 protein, human
• MHC class I-related chain A
• NK Cell Lectin-Like Receptor Subfamily K

Topics

• Adult
• Allografts
• Case-Control Studies
• Female
• Graft Rejection (genetics, immunology, pathology)
• HLA-G Antigens (genetics, immunology)
• Histocompatibility Antigens Class I (genetics, immunology)
• Humans
• Kidney Transplantation
• Male
• Middle Aged
• NK Cell Lectin-Like Receptor Subfamily K (genetics, immunology)
• Polymorphism, Genetic
• Renal Insufficiency, Chronic (genetics, immunology, pathology, surgery)
• Risk Factors