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

Date Published: February 22, 2019

Publisher: Public Library of Science

Author(s): 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, Wisit Cheungpasitporn.


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.

Partial Text

Previous studies on the major histocompatibility complex (MHC) genomic region identified genes that are important for immune regulation [1–3]. Among these genes are HLA-G (human leukocyte antigen-G) and MICA (major histocompatibility complex class I chain-related gene A). The few studies that concomitantly evaluated those genes left questions to be clarified about their functions [4,5]. HLA-G and MICA are highlighted, because they are produced in inflammatory and pathological conditions [5,6], can be expressed on cell membranes and reach distant immunological targets when in the form of soluble isoforms (sHLA-G and sMICA) [7,8].

Case-control analysis included HLA-G, MICA and NKG2D genotype data and quantification of soluble molecules (sHLA-G and sMICA) involved in immunomodulation of inflammatory response. Regarding the association tests performed for chronic kidney disease patients, the HLA-G*01:01/UTR-4 was found to be a protective factor for the development of chronic kidney disease (FET analysis). In particular, UTR-4 has previously been related to higher stability of HLA-G transcripts and immunoregulation in successful pregnancies [43]. This suggest the HLA-G*01:01/UTR-4 could be a protection against inflammatory conditions and pathological states, not just found in women with secondary recurrent miscarriage, but also in CKD patients.

The increased production of immunoregulatory molecules, such as sMICA and sHLA-G, was associated with chronic kidney disease. Still, a higher sMICA production in the pre-transplant period was found to be associated with a better kidney allograft outcome.