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.

Immunomodulatory Potential of Non-Classical HLA-G in Infections including COVID-19 and Parasitic Diseases

“…HLA-G plays a major role in the down-regulation of the functions of the innate and adaptive immune system cells through interaction with multiple inhibitory receptors such as Leukocyte Immunoglobin-Like Receptors (LILRs) and in the presentation of non-peptidic antigens to non-classical T cells, leading to unique and fast immune responses upon infections [ 2 ]. The origin, structure, and functions of this molecule have been recently published.…”

Placental Immune Tolerance and Organ Transplantation: Underlying Interconnections and Clinical Implications

“…The sHLA-G level can predict the renal allograft outcome for high expression in patients with renal allograft (31.6 ± 20.2 vs. 17.7 ± 8.5, P =0.003). These studies suggest that HLA-G and its polymorphisms might play a potential protective role in organ transplantation ( 53 ). However, another study did not support the protective effect of HLA-G in liver transplantation since sHLA-G levels were higher in recipients with acute rejection than nonrejectors ( 54 ).…”

COVID-19: Integrating the Complexity of Systemic and Pulmonary Immunopathology to Identify Biomarkers for Different Outcomes

“…Human leukocyte antigens (HLA) are involved in several important functions of the immune system, starting from antigen presentation to lymphocytes, performed by the classical class I (HLA-A/B/C) and class II (HLA-DR/DQ/DP) histocompatibility molecules), and extending until the control of the immune response, primarily performed by the non-classical class I molecules (HLA-E/F/G) (179). Among these molecules, HLA-G is the most studied, and its major function is the downregulation of the function of the innate and adaptive immune system cells, by means of the interaction with inhibitory receptors (180). Accordingly, HLA-G may inhibit the proliferation of T and B lymphocytes, the activity of antigenpresenting cells (APC) and the cytotoxicity of CD8 + T cells and NK cells (181,182).…”