HLA-G 3′ untranslated region gene variants are promising prognostic factors for BK polyomavirus replication and acute rejection after living-donor kidney transplant
Introduction
BK polyomavirus (BKPyV), an ubiquitous human virus, has emerged as one of the most challenging infectious pathogens in kidney transplant in the last decade [1], [2], [3]. After primary infection, BKPyV preferentially establishes latency from which it can reactivate during episodes of immunosuppression. BKPyV replication occurs in up to 60% of all kidney-transplant recipients [4]. The most serious clinical syndrome is the BK polyomavirus-associated nephropathy (PyVAN), a severe allograft dysfunction, which shows progressive decline in kidney function potentially resulting in allograft loss [5]. Currently, there is no direct antiviral treatment approved to limit BKPyV replication and treat PyVAN. Thus, the two pillars of PyVAN management are an active surveillance for BKPyV reactivation as well as in case of BKPyV replication a reduction or modification of immunosuppression in order to reestablish sufficient antiviral control by cellular immunity [2]. At present, little is known on the pathogenesis of BKPyV and it is not clear which factors besides level of immunosuppression and donor BKPyV-seropositivity determine the clinical course of the disease. Viruses have developed various strategies to avoid recognition and destruction by immune effectors. In fact, aberrant expression of the non-classical human leukocyte antigen G (HLA-G) has been reported for several virus infections [6], [7], [8], [9], [10]. Accordingly, we showed that HLA-G 3412 SNP facilitates immune evasion of cytomegalovirus infection after kidney transplant [10].
The important checkpoint molecule HLA-G exerts inhibitory signaling on immune effector cells by interacting with the inhibitory receptors immunoglobulin-like transcript (ILT)2, ILT4 or killer-cell immunoglobulin-like receptor (KIR)2DL4. Thus, HLA-G has the capacity to suppress the function of natural killer (NK) cells and T cells, reduce B cell activation and induce expansion of regulatory T cells. In addition, soluble HLA-G triggers the apoptosis of activated CD8+ T and NK cells [11]. Under physiological conditions, HLA-G cell surface expression is restricted to the maternal-fetal interface and to immune privileged adult tissues where it mediates immune tolerance [12], [13]. However, aberrant expression of HLA-G and its soluble forms has been associated with a vast variety of pathological situations such as cancer, autoimmune, and infectious diseases where HLA-G molecules favor escape from immune surveillance. Studies in transplant cohorts have repeatedly associated an up-regulated HLA-G expression with allograft tolerance [13], [14], [15]. Only few studies have elucidated the impact of HLA-G in the combined context of infectious diseases in transplant recipients [10], [16], [17]. Therefore, it seems reasonable that although the presence of the inhibitory HLA-G molecule may be beneficial for allograft tolerance, it may be detrimental for immune surveillance of viral infections as well.
In contrast to classical HLA molecules, HLA-G displays limited allelic variations. However, at least seven distinct HLA-G isoforms are generated as result of alternative splicing [18]. These isoforms comprise membrane-bound (HLA-G1, -G2, -G3 and -G4) and soluble molecules (HLA-G5, -G6, and -G7) [19], [20], [21]. HLA-G is located on chromosome 6p21.3 and is composed of eight exons and seven introns and to date 69 HLA-G allelic variations have been identified [22]. Notably, the regulation of local HLA-G expression and its soluble forms encompasses post-transcriptional processes such as alternative splicing, altered mRNA stability, microRNA-mediated regulation of translation, and impaired protein transport to the cell surface [23]. Especially the polymorphic 3′untranslated region (UTR) shared by the HLA-G1 to HLA-G6 transcripts plays a pivotal role in HLA-G expression by interfering with transcription, splicing, mRNA stability, and translation [24]. Here, 14 single nucleotide polymorphisms (SNP; +3001C/T, +3003C/T, +3010C/G, +3027C/A, +3032C/G, +3035C/T, +3052C/T, +3092G/T, +3111A/G, +3121C/T, +3142C/G, +3187A/G, +3196C/G, and +3227A/G) and the well-studied 14 bp insertion/deletion (INS/DEL) located at position +2961 have been identified in the 3′UTR potentially modifying the affinity of sequence-specific regulators of gene expression for post-transcriptional factors [24], [25]. These polymorphisms arrange as haplotypes, named UTRs (Table S1). Six already identified microRNA (miR), miR-148a, miR-148b, miR-152, miR-133a, miR-628-5p, and miR-548q, have been reported to bind to certain SNPs in the 3′UTR in a sequence-specific manner, leading to downregulation of HLA-G expression [22].
To our knowledge, there are no studies on the association between BKPyV replication and HLA-G 3′UTR polymorphisms in kidney transplant donor and recipients. Considering the functional differences between the HLA-G polymorphisms within the 3′UTR, we hypothesized that the genetic background affects the clinical occurrence BKPyV replication and PyVAN as well as rejection after kidney transplantation, and might serve as a predictive parameter to identify patients at risk.
Section snippets
Study population, BKPyV, and PyVAN screening
In total, 251 living-donor kidney transplant recipients and their corresponding donors from the living-kidney donor program at University Hospital Essen, Germany, were enrolled in this retrospective study. Transplantations were performed from 2005 till 2017. Exclusion criteria were CMV disease during follow-up (n = 33) and immunosuppression containing an mTOR inhibitor (n = 10) [26]. Informed consent was obtained from all patients in accordance with the Declaration of Helsinki, and the local
Results
In total, 30 recipients (14.4%) were tested positive for BKPyV viremia. Nine out of these 30 recipients had at least one biopsy proven PyVAN after kidney transplantation.
Discussion
HLA-G is a naturally occurring immune suppressive molecule that plays an important role in the modulation of immunity. Its expression is regulated at transcriptional, co-, and post-transcriptional levels. Co- and post-transcriptional regulation is achieved by alternative splicing or binding of certain miRNAs within the HLA-G 3′UTR [31]. A number of studies highlighted the differential modulation of HLA-G gene expression as a prognostic factor for clinical outcome in a variety of pathological
Conclusion
The present data highlight the complexity of the genetic background of HLA-G affecting the clinical course of kidney transplantation. Improved understanding of HLA-G regulation will contribute to the development of strategies detecting BKPyV or rejection-susceptible recipients prior to kidney transplant, thus helping to improve allograft survival.
Author contributions
HR, PAH, OW, VR: conceived and designed research. HR, ES, RTM, SS: performed the experiments. FMH: contributed reagents. SD, AG, BW, JK: collected and provided clinical data. HR, ES, RTM, VR: interpreted data and HR, ES, AG, VR: performed statistical analysis. HR and VR: wrote the initial draft. HR, ES, RTM, SS, SD, AG, MT, BW, JK, FMH, PAH, AK, OW, VR: read and approved the final article.
Declaration of Competing Interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Acknowledgments
We thank the living-donor and recipient pairs participating in this study.
HR was supported by the “IFORES Research fellowship-program of the University Duisburg-Essen Medical School”. OW is supported by an unrestricted grant of the Rudolf-Ackermann-Stiftung (Stiftung für Klinische Infektiologie).
References (50)
Impact of immune suppressive agents on the BK-Polyomavirus non coding control region
Antiviral Res.
(2018)- et al.
BK polyomavirus in solid organ transplantation
Am J Transplant
(2013) Immunosuppressive HLA-G molecule is upregulated in alveolar epithelial cells after influenza A virus infection
Hum. Immunol.
(2009)The effect of human leukocyte antigen G alleles on human papillomavirus infection and persistence in a cohort of HIV-positive pregnant women from Brazil
Infect. Genet. Evol.
(2015)HLA-G-dependent suppressor cells: diverse by nature, function, and significance
Hum. Immunol.
(2008)Role of HLA-G as a predictive marker of low risk of chronic rejection in lung transplant recipients: a clinical prospective study
Am. J. Transplant.
(2015)Impact of HLA-G 14-bp polymorphism on acute rejection and cytomegalovirus infection in kidney transplant recipients from northwestern China
Transpl. Immunol.
(2012)14-bp ins/del polymorphism and +3142C>G SNP of the HLA-G gene have a significant impact on acute rejection after liver transplantation
Hum. Immunol.
(2016)Identification of HLA-G7 as a new splice variant of the HLA-G mRNA and expression of soluble HLA-G5, -G6, and -G7 transcripts in human transfected cells
Hum. Immunol.
(2000)HLA-G and HLA-E: fundamental and pathophysiological aspects
Immunol. Today
(2000)
The prognostic impact of soluble and vesicular HLA-G and its relationship to circulating tumor cells in neoadjuvant treated breast cancer patients
Hum. Immunol.
HLA-G 3'UTR polymorphisms in high grade and invasive cervico-vaginal cancer
Hum. Immunol.
BK polyomavirus replication in renal tubular epithelial cells is inhibited by sirolimus, but activated by tacrolimus through a pathway involving FKBP-12
Am. J. Transplant.
A new statistical method for haplotype reconstruction from population data
Am. J. Hum. Genet.
HLA-G: from biology to clinical benefits
Trends Immunol.
Implication of HLA-G 5' upstream regulatory region polymorphisms in idiopathic recurrent spontaneous abortions
Reprod. Biomed. Online
Implication of HLA-G molecule in heart-graft acceptance
Lancet
Soluble HLA-G in heart transplantation: their relationship to rejection episodes and immunosuppressive therapy
Hum. Immunol.
HLA-G gene expression influenced at allelic level in association with end stage renal disease and acute allograft rejection
Hum. Immunol.
Infection in organ transplantation
Am. J. Transplant.
The relationship between HLA-G and viral loads in non-responder HCV-infected patients after combined therapy with IFN-alpha2alpha and ribavirin
Hum. Immunol.
Lower frequency of the HLA-G UTR-4 haplotype in women with unexplained recurrent miscarriage
J. Reprod. Immunol.
Tolerance versus immune response – microRNAs as important elements in the regulation of the HLA-G gene expression
Transpl. Immunol.
The 14-bp deletion in the HLA-G gene indicates a low risk for acute cellular rejection in heart transplant recipients
J. Heart Lung Transplant.
HLA-G 3' UTR-2 haplotype is associated with human African trypanosomiasis susceptibility
Infect Genet. Evol.
Cited by (10)
Donor and recipient human leukocyte antigen-G polymorphisms modulate the risk of adverse immunologic events following lung transplantation
2023, American Journal of TransplantationHuman genetic polymorphisms and risk of viral infection after solid organ transplantation.
2022, Transplantation ReviewsCitation Excerpt :The presence of the haplotype UTR-4 was significantly associated with BKPyV replication and nephropathy, both in recipients (OR: 2.260; 95% CI: 1.01 8–5.018; P-value = 0.041) and donors (OR: 3.33; 95% CI: 1.493–7.448; P-value = 0.0023). On the other hand, the presence of +3003C SNP in UTR-4 in recipients had a protective role for antibody-mediated acute rejection, whereas UTR-2 in donors was associated with both cell-mediated and antibody-mediated rejection [58]. The role of non-classical HLA is further supported by the protective effect against BKPyVAN reported for recipient HLA-E*01:01 homozygous state [59].
Examining extended human leukocyte antigen-G and HLA-F haplotypes: the HLA-G UTR-4 haplotype is associated with shorter time to pregnancy in an infertility treatment setting when both female and male partners are carriers
2020, Fertility and SterilityCitation Excerpt :The functional impact of UTR-4 is not very well understood. A recently published study found that kidney transplant recipients carrying UTR-4 were less likely to experience antibody-mediated rejection of their transplant (41). That study also found an association between donor and recipient UTR-4 and replication of the BK polyomavirus, a virus often challenging kidney transplantations.
Biological Characteristics of HLA-G and Its Role in Solid Organ Transplantation
2022, Frontiers in Immunology