Maria da Graça Bicalho

New evidence that the MHC influences odor perception in humans: a study with 58 Southern Brazilian students

Increasing evidence suggests a correlation between mate choice, odor preference, and genetic similarity at the Major Histocompatibility Complex (MHC) in a variety of animals, including our species. The MHC is a highly polymorphic group of genes that play an important role in the immunological self/nonself recognition. Its products have been reported to take part on the variety of compounds and reactions that together build an individuals body odor. It has been suggested, therefore, that animals use body odor as a guide to identify possible mates as MHC-similar or MHC-dissimilar from their own genotype. Preference for a MHC-dissimilar partner enhances MHC heterozygosity of an individuals offspring. The possible adaptive advantages are clear: it is a mechanism of avoiding inbreeding and MHC-heterozygous offspring may have enhanced immunocompetence. The aim of this study was to search, in our species, new evidence on the correlation between specificities at HLA-A and HLA-B and assessments of pleasantness regarding specific body odors. HLA is the name for the human MHC. Four olfactory sessions were performed with 58 young Southern Brazilian students, in order to investigate whether assessments of pleasantness of body odors from individuals correlate to a persons HLA phenotype. Body odors were collected via sweat and urine from all participants. Women smelled and scored all male odor samples and men did the same with all female samples. We found a significant correlation only when female smellers evaluated male sweat odors.

A Case–Control Study in IL6 and TGFB1 Gene Polymorphisms and Recurrent Spontaneous Abortion in Southern Brazilian Patients

Problem:  A high proportion of recurrent spontaneous abortions (RSA) remains unexplained. Cytokine genotyping has been investigated. We studied the relationship between unexplained RSA, IL6 (−174 G→C) and TGFB1 (+869, T→C; +915, G→C) gene polymorphisms.

Major histocompatibility complex class I chain-related gene A polymorphism and linkage disequilibrium with HLA-B alleles in Euro-Brazilians

Major histocompatibility complex class I chain-related gene A (MICA) was identified within the human leukocyte antigen (HLA) class I region and was located 46 kb centromeric from HLA-B locus. It functions as a ligand for human gammadelta T, CD8 T and natural killer (NK) cells by binding the NKG2D receptor. The aims of the present study were to determine the distribution of MICA alleles and MICA-HLA-B haplotypes in a sample of Euro-Brazilians. Through the combination of three typing methods, polymerase chain reaction (PCR)-sequence-specific oligonucleotide probe, PCR-sequence-specific primer and PCR-restriction fragment length polymorphism, 19 alleles were detected besides a MICA gene deletion in a sample composed by 204 unrelated Euro-Brazilians. The most commonly observed alleles were: MICA*00801 (25.3%), MICA*00201 (17.7%) and MICA*00901 (13.7%). The GCT repeat polymorphism variant A6 was the most commonly found. The most frequent haplotype found in this study was MICA*00901-B*51 (8.1%), followed by haplotypes MICA*00201-B*35 (6.1%) and MICA*00801-B*07 (6.1%). MICA*00801 truncated product, and its low affinity for NKG2D receptor may work as an inhibitor in its putative soluble form. It may also be that selective forces may favor MICA*00801 heterozygosity with NKG2D high affinity MICA alleles enabling activation and inhibition of cytotoxic activity of cells expressing the NKG2D receptor. The possibility of selective neutrality or of balancing selection still provides no explanation for MICA gene polymorphisms. Is it maintained by genetic drift or by the influence of migratory waves? Are there favored alleles while others present the same adaptive value?

A study of HLA-G polymorphism and linkage disequilibrium in renal transplant patients and their donors

The role of the Major Histocompatibility Complex (MHC) in transplantation immunology is widely known. Incompatibilities associated with Human Leukocyte Antigens (HLA) between donors and recipients are related to poorer prognosis in allograft acceptance and survival, often resulting in rejection episodes. HLA-A, HLA-B, HLA-DR and HLA-DQ compatibility are widely studied in clinical transplants but few studies investigated the influence of non-classical HLA loci, such as HLA-G, a non-classical class I HLA gene located at 6p21.31 in the MHC region, i.e. 300 kb telomeric to HLA-A. MHC region genes are characterized by extreme polymorphism as well as strong positive linkage disequilibrium (LD) between HLA loci (alleles). LD studies related to MHC region provide investigators with a tool to assess candidate genes with an at-risk HLA haplotype, with implications for allograft transplants, human reproduction and disease susceptibility. Many studies reported striking LD between HLA-G and HLAA alleles and also between HLA-G and HLA Class II alleles, but the biologicalimplications for these findings are not clear yet. DNA sequencing methodology was used to determine HLA-G (exons 2 and 3) polymorphisms from 52 patients who underwent kidney transplantation and their donors. It is the purpose of this study to investigate the influence of HLA-G polymorphism in a set of kidney transplants and the occurrence of rejection episodes. It was observed that pairs with 2 HLA-G matches presented a lower risk of rejection occurrence than those pairs with 0 or 1 match. It was also observed that subjects whose genotype presented one synonymous substitution (S) in one HLA-G allele in the HLA-G0101 group of alleles and another allele with a non-synonymous substitution (N/S) on HLA-G0103, HLA-G010401, HLA-G010403 or HLA-G0105N alleles, apparently had a greater chance of rejection episodes. Additionally, HLA-G, as well as HLA-A, -B e -DR, compatibility may also be important for allograft acceptance (rejection probability lower than 0.09%). Besides, heterozygous S/NS patients had a five times greater chance of rejection than S/S and NS/NS patients. Some haplotypes found in the present study were already described in literature: A01-G01B (010102 or 0106), A03-G0101A, A23-G010401, A26-G01B, A31-G0103, A02-G0101A, A24-G0101A, A33-G0103, A68-G01B. We have also described LD between HLA-G alleles and HLA class II DRB1 allelic groups and found significant LD between DRB104-G01B, DRB113-G010401, DRB114-G010108, DRB115-G0103, DRB103-G0101A and DRB103-G01B.

ORIGINAL ARTICLE: Activating Killer Cell Immunoglobulin-Like Receptor Genes’ Association with Recurrent Miscarriage

Problem  Natural killer (NK) cells are regulated through NK cell receptors such as killer cell immunoglobulin‐like receptors (KIRs). KIRs are suspected of being involved in the causes of recurrent miscarriage (RM) as a higher proportion of activated NK cells were observed in women with RM when compared with that in controls. The aim of this study was to investigate if KIR genes coding for receptors known to have as ligands HLA class I molecules are correlated with RM.

Analysis of HLA-G Polymorphisms in Couples with Implantation Failure

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.

Variation and linkage disequilibrium within odorant receptor gene clusters linked to the human major histocompatibility complex

Odorant receptors (OR) are G-protein-coupled receptors that are predominantly expressed in the membrane of olfactory neurons. Members of the two OR gene clusters on the short arm of human chromosome 6 could be involved in major histocompatibility complex (MHC)-associated behavioral traits, such as olfaction-influenced mate selection and cryptic female choice. In this context, OR gene polymorphisms and haplotypes are likely to play an important role. Here we report an investigation of polymorphisms within 12 MHC-linked OR genes in 10 human cell lines. Eight of these OR loci belong to the telomeric, smaller OR gene cluster, whereas four are located centromeric, between the first cluster and the MHC. We also assessed part of this genomic region using sequence data from eight additional cell lines that had previously been sequenced. Thirteen novel OR variants were found through direct DNA sequencing and cloning, in addition to the detection of OR polymorphisms already known, and the number of OR cluster haplotypes could be increased to 21. Two loci belonging to the telomeric cluster (OR2B8P and OR1F12) were found to exhibit nonfunctional and potentially functional alleles and should therefore be considered as segregating pseudogenes. The results provide a detailed picture regarding polymorphisms and phenotypic variation in an ethnically diverse sample of major histocompatibility complex-linked OR clusters and identify a subregion of unusually pronounced genetic variability. We expand these data by analyzing linkage disequilibrium both within these OR clusters as well as between them and the HLA complex in 11 unrelated HapMap populations. The sequence data described in this paper have been submitted to the GenBank database under the accession numbers GU251059, GU251060, GU251061, GU251062, GU251063, GU251064, GU251065, GU251066, GU251067, GU251068, GU251069, GU251070, GU251071, and GU251072.

Haplótipos HLA mais freqüentes em doadores voluntários de medula óssea de Curitiba, Paraná

Bone Marrow Transplant (BMT) is a therapy used to treat patients with hematological diseases. The success of the transplant relies on a HLA match between host and donor. The HLA is located in the Major Histocompatibility Complex in the 6p12.3 region of the chromosome 6. The HLA gene products are involved in the immunomodulation of the immune response due to their function of presenting peptides to the T cells. The HLA genes are the most polymorphic in humans and the most relevant genetic marker for clinical transplants and are largely used in population studies. The knowledge of the HLA-A, HLA-B and HLA-DR haplotype frequencies of bone marrow donors is an important tool when a patient needs an identical HLA donor, and there are few population studies similar to this in Brazil. The HLA typing was performed in the LIGH of the UFPR by the PCR-SSP technique. The most common haplotypes among the population studied were HLA-A*01B*08DR*03, HLA-A*29B*44DR*07 and HLA-A*03B*07DR*15. The search of a Brazilian patient for an identical HLA donor is usually hopeless and the understanding of the HLA frequencies permits a real foreknowledge of the success of this search. Success depends on the eventual registration of the perfect donor in the national centers of bone marrow donation. Aiming to increase the perspectives of patients who need a BMT, the evaluation of the HLA frequencies and the enhancement of the national registrations of bone marrow donors are crucial for the accomplishment of this objective.

HLA class II polymorphisms and recurrent spontaneous abortion in a Southern Brazilian cohort

A high proportion of human recurrent spontaneous abortions (RSA) remain unexplained. The possible association between RSA and different genetic polymorphisms within the human leucocyte antigen system (HLA system, the human major histocompatibility complex) has been investigated with conflicting results since many decades. Here, we describe a case–control study with 136 Southern Brazilian women of predominantly European ancestry (75 control and 61 cases with unexplained RSA). We investigated the relationship between unexplained RSA and alleles and genotypes from two classical loci of the HLA: HLA‐DRB1 and HLA‐DQB1, as well as three loci related to cytokine production and their serum levels: TNFA (−308G>A), IL10 (−1082G>A, −819T>C, −592A>C) and IFNG (+874A>T). Genotyping was performed by an allele‐specific PCR method. While all results concerning cytokine‐related genes turned out to be negative, we found the genotype HLA‐DQB1*02:02, 03:01 to be significantly decreased and the allele HLA‐DRB1*11:04 to be significantly increased among patients.

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.