Nonclassical human leukocyte antigen (HLA-G,HLA-E,and HLA-F) in coronary artery disease

AimsSeveral evidences suggest the association between the evolution of coronary artery disease (CAD) and the development of coronary syndrome that is often associated with disrupted plaque and partial or complete thrombosis of the related artery. Because of the inflammatory nature of CAD, we investigated the human leukocyte antigen (HLA)-G, HLA-E, and HLA-F genetic polymorphisms within CAD patients and evaluated their potential association with this disease in Tunisian population.MethodsDifferent polymorphisms in HLA-G (14-bp Insertion/Deletion, +3142C/G), HLA-E (HLA-E*01:01/01:03 A/G), HLA-F (HLA-F*01:02 T/C, 01:03 C/T, 01:04 A/C) genes were typed using different laboratory techniques in a cohort of 89 CAD patients and 84 controls.ResultsA significant association was reported between the HLA-G +3142 G allele (OR = 1.64, 95% CI = 1.05–2.56, p = 0.02) and increased risk of CAD. No association was found for the other studied polymorphisms. When we considered the haplotypes, we found TDELCA and TDELGG haplotypes associated to CAD with p = 0.008 and p = 0.030, respectively, suggesting the potential interaction between HLA-G and HLA-E genes.ConclusionsOur findings indicated that the HLA-G +3142C/G polymorphism and TDELCA and TDELGG haplotypes can harbour a reliable diagnosis value for the risk of CAD development suggesting that HLA-G, -E and -F molecules might be involved in the pathogenesis of the disease. However, further studies are necessary to confirm our results.     

Human leukocyte antigen (HLA)-G during pregnancy part II: Associations between maternal and fetal HLA-G genotypes and soluble HLA-G

Human leukocyte antigen (HLA)-G is a class Ib molecule with restricted tissue distribution expressed on the extra-villous trophoblast and seems to have immunomodulatory functions during pregnancy. Studies have linked HLA-G polymorphisms to pregnancy complications such as preeclampsia and recurrent miscarriage. Levels of soluble HLA-G (sHLA-G) in blood plasma from non-pregnant donors seem to be associated with these polymorphisms. In the current study, we have genotyped 246 mothers and their offspring for HLA-G polymorphisms in the 3′-untranslated region (3′UTR) and measured sHLA-G in maternal blood plasma samples from gestational week 20 and at term, as well as in fetal umbilical cord blood samples. This is the first large study simultaneously performing HLA-G genotyping of mother and offspring and measuring sHLA-G in both maternal and umbilical cord blood. The results showed that increasing numbers of 14 bp ins (rs66554220) alleles in the mother–child genotype combinations were associated with higher maternal sHLA-G levels at term when restricting the analysis to 14 bp ins/del heterozygous mothers (p = 0.015). Furthermore, increasing numbers of 14InsG haplotypes (14 bp ins/del and +3142C/G (rs1063320) polymorphism) in mother–child genotype combinations were associated with higher levels of sHLA-G at term in heterozygous 14DelC/14InsG mothers (p = 0.005). In conclusion, the results indicate that there is an association between combined feto-maternal HLA-G genotypes and sHLA-G levels in maternal blood plasma.     

Non-classical MHC-I human leukocyte antigen (HLA-G) in hepatotropic viral infections and in hepatocellular carcinoma

The human leukocyte antigen (HLA)-G is a “nonclassical” major histocompatibility complex (MHC) class Ib gene, located at chromosome 6, in the 6p21.3 region.     

HLA-G and vertical mother-to-child transmission of human papillomavirus infection

Role of host factors in transmission of human papillomavirus (HPV)-infection from mother to her offspring is not known. Our aim was to study whether human leukocyte antigen (HLA)-G allele concordance among the mother–child pairs could facilitate vertical transmission of HPV, because HLA-G may contribute to immune tolerance in pregnancy. Altogether, 310 mother-child pairs were included from the Finnish Family HPV study. Overall, nine different HLA-G alleles were identified. The HLA-G genotype concordance of G¹01:01:01/01:04:01 increased the risk of high risk (HR)-HPV genotype positivity in cord blood and infant’s oral mucosa. The mother-child concordance of G¹01:01:02/01:01:02 increased the risk of oral HPV positivity with HR-HPV genotypes both in the mother and offspring; OR 2.45 (95%CI 1.24–4.85). Discordant HLA-G allele for G¹01:04:01 and for G¹01:06 was significantly associated with infant’s oral low risk (LR)-HPV at birth, OR 3.07 (95%CI 1.01–9.36) and OR 5.19 (95%CI 1.22–22.03), respectively. HLA-G had no association with HPV genotype-specific concordance between the mother and child at birth nor influence on perinatal HPV status of the child. Taken together, our results show that HLA-G molecules have a role in predicting the newborn’s likelihood for oral HPV infection at birth.     

The association between human leukocyte antigen (HLA)-G polymorphisms and human papillomavirus (HPV) infection in Inuit women of northern Quebec

Background

The human leukocyte antigen (HLA)-G molecules act as negative regulators of the immune response. We analyzed the associations between HLA G polymorphisms and human papillomavirus (HPV) infection and squamous intraepithelial lesions (SIL) in Inuit women from Nunavik, northern Quebec.

Methods

Cervical specimens from a cohort study of 548 Inuit women were tested for HPV DNA. HPV genotypes were classified according to tissue-tropism groupings of alpha-papillomavirus species: alpha group 1 includes low risk (LR) cervical species, group 2 includes high risk (HR) cervical species, and group 3 includes LR vaginal species. HLA-G alleles were typed using direct DNA sequencing.

Results

HLA-G^∗01:01:01 was associated with an increased risk of period prevalent alpha groups 1 (OR = 2.23, 95% CI:1.08–4.59) and 3 (OR = 1.70, 95% CI:1.09–2.65). The homozygous HLA-G^∗01:04:01 genotype was associated with a decreased risk of alpha group 3 infection period prevalence (OR = 1.69 95% CI = 1.07–2.67). No HLA-G alleles were significantly associated with HPV persistence. HLA-G^∗01:01:02, G^∗01:04:01 and G^∗01:06 were associated with high grade (HG)SIL, but the association did not reach statistical significance.

Conclusions

These results suggest that HLA-G polymorphisms play a role in the natural history of HPV infection, likely at the stage of host immune recognition. HLA-G polymorphisms interacted differently with the three alpha papillomavirus groups.     

Human leukocyte antigen (HLA)-G during pregnancy part I: Correlations between maternal soluble HLA-G at midterm,at term,and umbilical cord blood soluble HLA-G at term

Human leukocyte antigen (HLA)-G is a class Ib molecule with restricted tissue distribution expressed on trophoblast cells and has been proposed to have immunomodulatory functions during pregnancy. Soluble HLA-G1 (sHLA-G1) can be generated by the shedding of membrane-bound HLA-G molecules; however, three soluble isoforms also exist (HLA-G5 to -G6). During pregnancy, it is unknown whether there is a correlation between sHLA-G levels in maternal and fetal blood. In 246 pregnancies, we have measured the levels of sHLA-G1/-G5 in maternal blood plasma samples from gestational week 20 (GW20) and at term, as well as in umbilical cord blood samples. Soluble HLA-G levels declined by 38.4% in maternal blood from GW20 to term, and sHLA-G levels were significantly lower in maternal blood at term than in GW20 (P < 0.001). At term, the sHLA-G levels were significantly higher in maternal blood than in umbilical blood (P < 0.001). HLA-G levels in maternal blood in GW20 and at term, and in maternal blood at term and umbilical cord blood, were correlated (P < 0.001 and P < 0.01, respectively). This is the first large study simultaneously measuring sHLA-G in both maternal and umbilical cord blood. The finding that sHLA-G levels are significantly lower in fetal compared with maternal blood at term documents for the first time that sHLA-G is not freely transferred over the placental barrier. Soluble HLA-G levels in maternal and fetal blood were found to be correlated, which may be due to shared genetic factors of importance for production of sHLA-G in the mother and child, or it may support the theory that sHLA-G in the pregnant woman and the fetus is partly derived from a “shared organ”, the placenta.     

Epidemiology and persistence of cervical human papillomavirus infection among outpatient women in Heilongjiang province: A retrospective cohort study

As persistent carcinogenic human papillomavirus (HPV) infection is a prominent driver of cervical cancer, it is essential to explore HPV persistence and its associated factors for cancer screening and prevention. A retrospective cohort study was performed in outpatient women between March 2010 and 2019 in Heilongjiang, northeast China. HPV genotyping was performed by polymerase chain reaction-membrane hybridization. An unconditional logistic regression model was used to analyze the association of factors with persistence. The overall prevalence of HPV at baseline was 27.1%, with a downward trend from 2010 to 2019 (P < .0001). The most commonly observed high- and low-risk HPVs were HPV16 (N = 1094, 5.9%) and HPV11 (N = 596, 3.2%), respectively. The probabilities of 6-month persistence were high for women infected with HPV16 (P = .0001), HPV58 (P = .018), and HPV53 (P = .014), as well as for women with multiple infections (P = .009), and those who were 51 to 60 years old (P = .004) or more than 60 years old (P = .007). The probabilities of 12-month persistence were high for women infected with HPV53 (P = .017) and 51- to 60-year-old women (P = .044). HPV16 is the dominant HPV type in Heilongjiang. An age in the range of 51 to 60 years and infection with HPV53 is associated with HPV infection persistence in the Heilongjiang population.     

Human leukocyte antigen class I polymorphisms influence the mild clinical manifestation of Plasmodium falciparum infection in Ghanaian children

A prospective study that included 429 children for active detection of mild malaria was conducted in a coastal region of Ghana to reveal whether the incidence of malaria is affected by human leukocyte antigen (HLA) polymorphism. During 12 months of follow-up, 85 episodes of mild clinical malaria in 74 individuals were observed, and 34 episodes among them were accompanied with significant parasitemia at >5000 infected red blood cells per cubic millimeter. Attributable and relative risks conferred by genetic factors in the HLA region were evaluated by comparison of the incidence in children, stratified by carrier status, of a given allele of HLA-A, -B, -DRB1 and TNFA promoter polymorphism. HLA-B*35:01 reduced the incidence by 0.178 events per person per year (0.060 versus 0.239 for B*35:01-positive and -negative subpopulations, respectively), and a relative risk of 0.25, which remained statistically significant after Bonferroni's correction for multiple testing (p(c) = 8.2 × 10(-5)). Further, HLA-B*35:01 and -B*53:01 exhibited opposite effects on the incidence of malaria with significant parasitemia. When parasite densities in different HLA carriers status were compared, HLA-A*01 conferred an increase in parasite load (p = 6.0 × 10(-7)). In addition, we found a novel DRB1 allele that appears to have emerged from DRB1*03:02 by single nucleotide substitution.     

Role of human leukocyte antigen, killer-cell immunoglobulin-like receptors, and cytokine gene polymorphisms in leptospirosis

Leptospirosis is an emerging zoonotic disease caused by pathogenic species of the genus Leptospira. It has a broad range of clinical presentations in humans. Although progress has been made in the characterization of the host immune system factors that may affect disease progression and outcome, to date few reports have addressed the role of genetic polymorphisms in the susceptibility to leptospirosis. In this work a group of patients with a history of leptospiral infection and a control group were compared for polymorphisms in the human leukocyte antigen (HLA), in killer-cell immunoglobulin-like receptors (KIR), and in cytokine genes. Alleles in the HLA-A and -B loci were associated with susceptibility, as were the class I haplotype A*01-B*08-Cw*07 and the 8.1 ancestral haplotype (A*01-B*08-Cw*07-DRB1*03-DQB1*02). Single nucleotide polymorphisms in the interleukin (IL)-4 and IL-4Rα genes also had significantly higher frequencies in the patient group. No association was reported between KIR gene profile and leptospirosis. This work highlights the importance of using genetic polymorphisms to better understand the mechanisms involved in the immune response to leptospirosis.     

Low-level persistence of human papillomavirus 16 DNA in a cohort of closely followed adolescent women

Most human papillomavirus (HPV) infections in young women become undetectable by standard assays after a few months. It is possible that many HPV infections do not actually clear, but persist at very low levels for years, becoming detected again later in life. The purpose of this study is to describe HPV 16 clearance, reappearance, and low‐level persistence in a cohort of adolescent women. Adolescent women (N = 66), not vaccinated against HPV, were recruited from 1998 to 2008 into a longitudinal study. Self‐collected vaginal samples were obtained quarterly and tested for HPV by Linear Array HPV Genotyping Test (LA‐HPV). To explore low‐level persistence, a type‐specific nested PCR for HPV 16 (TSN‐PCR‐16) was developed. Women with HPV 16 detected by LA‐HPV had their negative swabs retested with TSN‐PCR‐16. Forty‐two participants with HPV 16, followed for a mean of 6.3 years, were analyzed. Using LA‐HPV, the median duration of HPV 16 detection was 428 days (SD 852.5 days). TSN‐PCR‐16 detected HPV 16 during periods of LA‐HPV non‐detection in samples from many women. Using a combination of LA‐HPV and TSN‐PCR‐16 results, the median duration of HPV 16 detection was 1,022.5 days (SD 943.7 days). The durations of detection differed significantly between the two methods (P = 0.0042) with a mean difference of 434.5 days. In adolescent females, duration of HPV 16 detection was significantly longer when TSN‐PCR‐16 was combined with LA‐HPV. Some apparently cleared HPV 16 could be shown to persist at low levels using nested PCR. J. Med. Virol. 83:1362–1369, 2011. © 2011 Wiley‐Liss, Inc.     

Cutaneous squamous cell cancer (cSCC) risk and the human leukocyte antigen (HLA) system

Cutaneous squamous cell carcinoma (cSCC) is the second most common cancer among Caucasians in the United States, with rising incidence over the past decade. Treatment for non-melanoma skin cancer, including cSCC, in the United States was estimated to cost $4.8 billion in 2014. Thus, an understanding of cSCC pathogenesis could have important public health implications. Immune function impacts cSCC risk, given that cSCC incidence rates are substantially higher in patients with compromised immune systems. We report a systematic review of published associations between cSCC risk and the human leukocyte antigen (HLA) system. This review includes studies that analyze germline class I and class II HLA allelic variation as well as HLA cell-surface protein expression levels associated with cSCC risk. We propose biological mechanisms for these HLA-cSCC associations based on known mechanisms of HLA involvement in other diseases. The review suggests that immunity regulates the development of cSCC and that HLA-cSCC associations differ between immunocompetent and immunosuppressed patients. This difference may reflect the presence of viral co-factors that affect tumorigenesis in immunosuppressed patients. Finally, we highlight limitations in the literature on HLA-cSCC associations, and suggest directions for future research aimed at understanding, preventing and treating cSCC.     

Correlation of high-risk human papillomavirus genotypes persistence and risk of residual or recurrent cervical disease after surgical treatment

The evidence on genotype-specific risk in women infected with human papillomavirus (HPV) with normal cytology and the importance of the distinction of high-risk (HR)-HPV genotypes in the management of low-grade lesions suggest that the distinction of HR-HPV genotypes has the potential to improve the follow-up of patients treated for high-grade cervical lesions. The aims of this study were to define the persistence of the different HR-HPV in the follow-up of surgical treated women, to detect the changes of genotypes from the pre- to the post-operative status, and to evaluate whether genotype-specific persistence can predict the development of residual or recurrent disease during the follow-up. HR-HPV detection and genotyping was carried out by the Linear Array HPV Genotyping Test on cervical cytological samples from 72 women treated by surgery. The 6-month post-operative HPV status was correlated with the pre-operative HPV genotype and with the residual or recurrent disease within 24 months. It was observed that the residual or recurrent disease in women with persistence of HPV 16 and/or HPV 18 was higher (82.4%) than in women with persistence of at least one HR-HPV type of group 2 (HPV 31, 33, 35, 45, 52, and 58) (66.7%) and at least one type of group 3 (HPV 39, 51, 56, 59, 68, 26, 53, 66, 73, and 82) (14.3%). These data defined HR-HPV groups for the risk of progression of disease and suggested that the identification of persistent infection with different HR-HPV genotypes has the potential to improve the management of these patients.     

The ILT2(LIR1) and CD94/NKG2A NK cell receptors respectively recognize HLA-G1 and HLA-E molecules co-expressed on target cells

Previous studies on NK recognition of HLA-G1 employed as targets 721.221 transfectants (.221-G1) that unknowingly co-expressed the HLA-E molecule, subsequently found to be a major ligand for the CD94/NKG2 receptors. In the present study we re-evaluated the relative role played by CD94/NKG2 and ILT2(LIR1) molecules in recognition of HLA-G1 by NK clones. We employed as targets .221-G1 cells and a surface HLA-E-negative transfectant, .221-G1(E_neg), generated by site-directed mutagenesis of the HLA-G1 leader sequence. The antagonistic effects of receptor- (i.e. CD94/NKG2A, ILT2) and ligand-specific mAb (i.e. HLA-G, HLA-E) were assessed. In addition, binding of an ILT2-Ig fusion protein to the .221-AEH, expressing only HLA-E, and the .221-G1(E_neg) transfectants was analyzed. Our data demonstrate that NK recognition of cells expressing HLA-G1 involves at least two non-overlapping receptor-ligand systems: the CD94/NKG2 interaction with HLA-E, and the engagement of the ILT2(LIR1) receptor by HLA-G1 molecules.     

Genomic diversity of human papillomavirus (HPV) Genotype 38

Human papillomavirus (HPV) genotype HPV 38 is a HPV genotype associated with skin cancer and is classified taxonomically in the beta‐PV genus–species 2. At least six genomic variants of HPV 38, including prototype isolate and its subtype FA125, have been characterized so far. In order to investigate further the genomic diversity of HPV 38, a total of 39 HPV 38 positive samples obtained from hairs plucked from pubic, scrotal, perianal or eyebrow regions from 31 immunocompetent healthy male individuals were analyzed. The characterization of genomic variants was based on analysis of L1, E6, and E7 genomic regions. Sequence analysis revealed the presence of a single genomic variant in 35 samples and the presence of at least two different HPV 38 genomic sequences in four samples. A total of nine, nine, and five L1, E6, and E7 genomic variants were identified among 35 isolates, respectively. After combining nucleotide variations in all three genomic regions for a particular isolate, 13 different variants were identified, of which 6 and 7 corresponded to HPV 38 and FA125, respectively. In addition to 5 genomic variants identified previously (prototype isolate, subtype FA125, putative subtype AF091444, isolates U21875 and AF091443), 12 novel genomic variants were characterized. A sixth genomic variant described previously (L38917) was found to be identical with prototype HPV 38 isolate. Taking into account the results of this and previous studies, at least seventeen HPV 38 genomic variants exist today, 12 of which are described for the first time in this study. J. Med. Virol. 81:288–295, 2009. © 2008 Wiley‐Liss, Inc.     

Human papillomavirus (HPV) infection and genotype frequency in the oral mucosa of newborns in Milan,Italy

Human papillomavirus (HPV) causes cutaneous and mucosal infections in both adults and children. In order to evaluate HPV prevalence and the spectrum of genotypes in the oral cavity of paediatric subjects, a retrospective study was carried out on oral-pharyngeal swabs collected from 177 newborns aged 0–6 months. HPV-DNA was detected by a nested-PCR; the viral typing was made through DNA sequencing. HPV infection was identified in 25 subjects (14.1%) and the sequence analysis showed eight distinct genotypes. These data confirm HPV detection in newborn oral mucosa. Further investigations are needed to clarify the methods of HPV acquisition.