Is there a role played by HLA-E, if any, in HPV immune evasion?

Cervical cancer incidence worldwide exceeds half a million new cases per year. The human papillomavirus (HPV) being the major causative agent of CC uses a variety of strategies to evade immune surveillance, where the immune status varies amongst individuals. This immune evasion altered by HPV is reflected in persistent infections, causing the evolution of cervical neoplasia. The role of the immune system in viral recognition and elimination is of extreme relevance in the development of CC. The interactions of the HLA-E ligand in the target cell along with CD94/NKG2 receptors, which are expressed predominantly, but not exclusively, on NK cells' surface, are responsible for activating or inhibiting cytotoxic activity according to their function. The engagement between HLA-E and CD94/NKG2 molecules is one of the fundamental surveillance mechanisms in patients with CIN I, II and III, where HLA-E expression increases significantly, especially in HPV 16 and 18 infections. Higher HLA-E expression was observed in most histopathological types of CC, and at the same time was correlated to best survival of the patient. This review aims to summarize and discuss the immunological role of HLA-E in the context of HPV infection and immune system evasion, and the oncogenic process of cervical cancer.

MICA-129 A/G dimorphism, its relation to soluble mica plasma level and spontaneous preterm birth: A case-control study.

The aim of this case- control study was to investigate the association between preterm birth (PTB), MICA-129 A/G dimorphism and sMICA levels. Fifty pregnant women with singleton pregnancy and previous PTB, or clinic diagnostic of threatened preterm labor in the actual pregnancy, or cervical length less than 25 mm and 50 healthy pregnant women were enrolled. DNA was extracted for genotyping for MICA-129 A/G by real-time PCR and sMICA plasma level was quantified by sandwich ELISA assay. Clinical and socioeconomic characteristics, results of TaqMan® genotyping and ELISA quantification were compared between the groups using qui-square, Fisher´s exact or Mann-Whitney test. A binary logistic regression model was used to predict PTB. The correlation between MICA-129 A/G genotypes and sMICA levels was investigated. There were not statistically significant differences between MICA-129 A/G polymorphism and sMICA plasma level.There was found a correlation between MICA-129 val/val genotype and higher levels of sMICA (ρ: -0.342; p:0.001). The presence of MICA-129  val/val genotype may be influencing sMICA expression.

MICA diversity and linkage disequilibrium with HLA-B alleles in renal-transplant candidates in southern Brazil.

The major histocompatibility complex (MHC) class I chain-related gene A (MICA) is located centromerically to the human leukocyte antigen (HLA)-B. The short distance between these loci in the MHC indicates the presence of linkage disequilibrium (LD). Similarly to the HLA, the MICA is highly polymorphic, and this polymorphism has not been well documented in different populations. In this study, we estimated the allelic frequencies of MICA and the linkage disequilibrium with HLA-B alleles in 346 renal-transplant candidates in southern Brazil. MICA and HLA were typed using the polymerase chain reaction-sequence-specific primer method (PCR-SSO), combined with the Luminex technology. A total of 19 MICA allele groups were identified. The most frequent allele groups were MICA*008 (21.6%), MICA*002 (17.0%) and MICA*004 (14.8%). The most common haplotypes were MICA*009-B*51 (7.8%), MICA*004-B*44 (6.06%) and MICA*002-B*35 (5.63%). As expected from the proximity of the MICA and HLA-B loci, most haplotypes showed strong LD. Renal patients and healthy subjects in the same region of Brazil showed statistically significant differences in their MICA polymorphisms. The MICA*027 allele group was more frequent in renal patients (Pc = 0.018, OR: 3.421, 95% CI: 1.516-7.722), while the MICA*019 allele group was more frequent in healthy subjects (Pc = 0.001, OR: 0.027, 95% CI: 0.002-0.469). This study provided information on the distribution of MICA polymorphisms and linkage disequilibrium with HLA-B alleles in Brazilian renal-transplant candidates. This information should help to determine the mechanisms of susceptibility to different diseases in patients with chronic kidney disease, and to elucidate the mechanisms involved in allograft rejection associated with MICA polymorphisms in a Brazilian population.

Is HLA-E a possible genetic marker relevant for natural conception?

BACKGROUND: HLA-E products, class Ib human leukocyte antigens, act in the immunology of human reproduction as modulators of the maternal immune system during pregnancy. AIMS: To evaluate HLA-E role in the establishment of a viable pregnancy. MATERIALS & METHODS: HLA-E was genotyped by sequence-based typing (SBT) and analyzed for specific polymorphisms, comparing couples who underwent assisted reproduction treatment (ART) and fertile control couples. RESULTS: There was a significant difference in HLA-E allele and genotype distributions between ART couples and control couples. The allele HLA-E*01:03 was observed in 63.2% of ART men and in 35.1% of fertile men (P = 0.0032). CONCLUSION: These results suggest that HLA-E allelic variants may play a role in the modulation of immune responses in the context of the inability of natural conception and establishment of a viable pregnancy.

HLA-G profile of infertile couples who underwent assisted reproduction treatment.

HLA-G codes for a non-classical class I (Ib) protein which is mainly expressed in trophoblast cells. Many pieces of evidence pointed out its essential role conferring immunological tolerance to the fetus. Some HLA-G alleles have been linked to enhanced or reduced HLA-G protein levels expression, which have been associated with reproductive failure. In this study 33 couples undergoing ART (assisted reproduction treatment; n=66) and 120 couples who conceived naturally (controls; n=240) were enrolled in the study. Genotyping was performed by SBT and tagged an 1837bp at 5'URR as well as exons 2, 3 and4 of HLA-G. Alleles, genotypes and haplotypes were compared between infertile and control groups using Fisher Exact Test. The haplotype HLA-G∗010101b/HLA-G∗01:01:01 showed statistically significant higher frequency in control groups. The immunogenetics of infertility is complex and might be dependent on different genes involved in the establishment of a successful pregnancy. A better understanding of HLA-G alleles and haplotypes structure and how the genetic diversity at their regulatory sites could impact on their level of expression and build up the susceptibility or protection conditions may shed light on the comprehension of immunogenetics mechanisms acting at the fetus-maternal interface.

HLA-E polymorphisms in an Afro-descendant Southern Brazilian population.

HLA-E is a non-classical I (Ib) gene which has limited polymorphism and low levels of tissue expression. Currently, 11 alleles are described in the literature with only three protein products. In the present study we investigated HLA-E gene variations at exons 2 and 3 and calculated allele, genotype and haplotype frequencies in a sample of 152 individuals who reported themselves as being Afro-descendants and who are voluntary bone marrow donors living in the state of Paraná, Brazil. The most frequent allele in the sample analyzed was the E(∗)01:01 (59.21%). The presence of the E(∗)01:04 allele was not detected suggesting that it has a very low worldwide frequency or that this allele may be an artifact of sequencing. We reported the most frequent alleles found as well as genotypes and haplotypes and compared our results with the few other studies found in the literature. This study is the first to investigate Afro-descendants from the South of Brazil.

Analysis of HLA-G polymorphisms in couples with implantation failure.

PROBLEM: HLA-G expression is related as an immune modulator of fetal-maternal tolerance, and its levels was correlated with pregnancy outcome. In a case-control study, we investigate the association between the genetic variability of the HLA-G gene and serum levels of soluble HLA-G in cases of embryo implantation failure. METHOD OF STUDY: Forty couples with at least two unsuccessful fresh embryo transfers (implantation failure; IF) and 83 fertile couples with at least two successful pregnancies was genotyped by sequencing-based typing. HLA-G alleles were defined by nucleotide sequence variations at exon 2, 3, and 4, and the quantification of soluble HLA-G (sHLA-G) was performed by ELISA. RESULTS: There was a significant difference between the HLA-G allelic distributions between IF couples and the control couples. The HLA-G*01:03:01 allele was increased in the IF couples. There were no significant differences in the serum levels of sHLA-G in the IF and control groups. CONCLUSION: The results suggest that the distribution of HLA-G products may play a significant role in the modulation of maternal-fetal immune response.

HLA-G regulatory haplotypes and implantation outcome in couples who underwent assisted reproduction treatment.

The role of HLA-G in several clinical conditions related to reproduction has been investigated. Important polymorphisms have been found within the 5'URR and 3'UTR regions of the HLA-G promoter. The aim of the present study was to investigate 16 SNPs in the 5'URR and 14-bp insertion/deletion (ins/del) polymorphism located in the 3'UTR region of the HLA-G gene and its possible association with the implantation outcome in couples who underwent assisted reproduction treatments (ART). The case group was composed of 25 ART couples. Ninety-four couples with two or more term pregnancies composed the control group. Polymorphism haplotype frequencies of the HLA-G were determined for both groups. The Haplotype 5, Haplotype 8 and Haplotype 11 were absolute absence in ART couples. The HLA-G*01:01:02a, HLA-G*01:01:02b alleles and the 14-bp ins polymorphism, Haplotype 2, showed an increased frequency in case women and similar distribution between case and control men. However, this susceptibility haplotype is significantly presented in case women and in couple with failure implantation after treatment, which led us to suggest a maternal effect, associated with this haplotype, once their presence in women is related to a higher number of couples who underwent ART.

HLA-G e reprodução humana / HLA-G and human reproduction

O gene HLA-G tem sido investigado em várias condições clínicas relacionadas à reprodução. Casais com abortamento espontâneo de repetição, mulheres com pré-eclâmpsia ou que se submetem a tratamentos de reprodução assistida têm participado de estudos caso-controle com o objetivo principal de obter informações que possam esclarecer a participação de HLA-G nessas ocorrências clínicas. Este trabalho traz uma revisão bibliográfica com os estudos principais e mais recentes que descrevem o gene HLA-G e suas isoformas proteicas, bem como a variação genética e polimorfismos que possam influenciar etapas importantes do processo reprodutivo humano. Considerando-se a gestação como uma característica multifatorial, com influência de fatores genéticos e ambientais, não existe um consenso sobre o papel desempenhado pelo gene HLA-G nesse processo. No entanto, variantes alélicas de HLA-G e suas correspondentes isoformas solúveis ou de membrana, têm sido associadas a níveis plasmáticos dos HLA-G e consideradas prognóstico favorável do processo implantacional.

The HLA-G has been investigated in several clinic conditions related to reproduction. Couples with spontaneous recurrent miscarriage, women with preeclampsia or who were submitted assisted reproduction treatments have participated in case-control studies whose main objective was to obtain information that could shed light on the involvement of HLA-G in such clinic conditions. This paper presents a bibliographic revision with the most recent major studies describing HLA-G gene and its protein isoforms, genetic variation and polymorphisms that may influence important stages of the human reproductive process. Considering pregnancy as a multifactorial feature, with the influence of genetic and environmental factors, there is no consensus about the role of HLA-G gene in pregnancy. However, allelic variants of HLA-G and their corresponding soluble or membrane bound isoforms, have been associated with plasma levels sHLA-G and considered a favorable prognosis of the implantation process.