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 individual's 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 individual's 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 person's 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.     

Psychology of fragrance use: perception of individual odor and perfume blends reveals a mechanism for idiosyncratic effects on fragrance choice

Cross-culturally, fragrances are used to modulate body odor, but the psychology of fragrance choice has been largely overlooked. The prevalent view is that fragrances mask an individual's body odor and improve its pleasantness. In two experiments, we found positive effects of perfume on body odor perception. Importantly, however, this was modulated by significant interactions with individual odor donors. Fragrances thus appear to interact with body odor, creating an individually-specific odor mixture. In a third experiment, the odor mixture of an individual's body odor and their preferred perfume was perceived as more pleasant than a blend of the same body odor with a randomly-allocated perfume, even when there was no difference in pleasantness between the perfumes. This indicates that fragrance use extends beyond simple masking effects and that people choose perfumes that interact well with their own odor. Our results provide an explanation for the highly individual nature of perfume choice.     

The significance of mother's perfume for infants in the first weeks of their life

Newborn babies are able, like the young of many animal species, to recognize their mothers' body odors and to orient towards them. The question arises whether infants can also use artificial odors applied to their mothers' bodies in the same way as animals can. In experiments, breast-feeding mothers perfumed their breasts for two weeks and their infants were tested in a choice test situation. At the age of one week the infants oriented their heads significantly more often to that side where they smelled their mothers' perfumes than to the side where they smelled a control odor. At the age of four weeks (mothers had stopped perfuming at two weeks) the infants did not prefer their mothers' perfumes any more.All the infants showed the “tonic neck reflex,” i.e., they significantly preferred one side, mostly the right, for their head turning. Consequently, these two preferences sometimes caused a conflict of response for the infants in our experiments. The interplay of the preference for turning to the side of mother's perfume and turning to a special side, as well as the biological meaning of both, is discussed and compared with the findings of other authors.     

Transporter associated with antigen processing preselection of peptides binding to the MHC: a bioinformatic evaluation

TAP is responsible for the transit of peptides from the cytosol to the lumen of the endoplasmic reticulum. In an immunological context, this event is followed by the binding of peptides to MHC molecules before export to the cell surface and recognition by T cells. Because TAP transport precedes MHC binding, TAP preferences may make a significant contribution to epitope selection. To assess the impact of this preselection, we have developed a scoring function for TAP affinity prediction using the additive method, have used it to analyze and extend the TAP binding motif, and have evaluated how well this model acts as a preselection step in predicting MHC binding peptides. To distinguish between MHC alleles that are exclusively dependent on TAP and those exhibiting only a partial dependence on TAP, two sets of MHC binding peptides were examined: HLA-A*0201 was selected as a representative of partially TAP-dependent HLA alleles, and HLA-A*0301 represented fully TAP-dependent HLA alleles. TAP preselection has a greater impact on TAP-dependent alleles than on TAP-independent alleles. The reduction in the number of nonbinders varied from 10% (TAP-independent) to 33% (TAP-dependent), suggesting that TAP preselection is an important component in the successful in silico prediction of T cell epitopes.     

Discriminating self from nonself with short peptides from large proteomes

We studied whether the peptides of nine amino acids (9-mers) that are typically used in MHC class I presentation are sufficiently unique for self:nonself discrimination. The human proteome contains 28,783 proteins, comprising 10⁷ distinct 9-mers. Enumerating distinct 9-mers for a variety of microorganisms we found that the average overlap, i.e., the probability that a foreign peptide also occurs in the human self, is about 0.2%. This self:nonself overlap increased when shorter peptides were used, e.g., was 30% for 6-mers and 3% for 7-mers. Predicting all 9-mers that are expected to be cleaved by the immunoproteasome and to be translocated by TAP, we find that about 25% of the self and the nonself 9-mers are processed successfully. For the HLA-A*0201 and HLA-A*0204 alleles, we predicted which of the processed 9-mers from each proteome are expected to be presented on the MHC. Both alleles prefer to present processed 9-mers to nonprocessed 9-mers, and both have small preference to present foreign peptides. Because a number of amino acids from each 9-mer bind the MHC, and are therefore not exposed to the TCR, antigen presentation seems to involve a significant loss of information. Our results show that this is not the case because the HLA molecules are fairly specific. Removing the two anchor residues from each presented peptide, we find that the self:nonself overlap of these exposed 7-mers resembles that of 9-mers. Summarizing, the 9-mers used in MHC class I presentation tend to carry sufficient information to detect nonself peptides amongst self peptides.     

The Search for New Amber Ingredients

There is a constant need for developing new fragrance ingredients in the flavor and fragrance industry, as it allows perfumers to create unique and differentiating perfumes for fine as well as functional products. Among all the categories of notes used in perfume creation, amber notes are indispensible and ubiquitous in their presence in all perfumes. Not only amber notes impart high performance and substantivity to fragrances, but they are paramount in the development of classic and legendary fragrances. This article is based on the plenary lecture delivered at the flavor & fragrance 2013 conference of the German Chemical Society in Leipzig, Germany. The strategy, rationale, and the various synthetic approaches that led to the discovery of two new very powerful, woody, amber materials, Amber Xtreme^® ( 1 ) and Trisamber^® ( 2 ), are delineated.     

“Self” to cytotoxic T cells has to be 1 000 or less high affinity nonapeptides per MHC antigen

In order to serve as the effective target of a relevant cytotoxic T-cell receptor, the same peptide fragment has to occupy at least 0.1% of the class I major histocompatibility complex (MHC) antigen sites on the plasma membrane. Because of this need, I contend that the thymic educator cell of self to cytotoxic T cells can suppress autoreactive T-cell clones only with regard to at the most, 1000 self nonapeptides per a given allelic form of class I MHC antigens; e. g., HLA-A2. Each allelic form of class I MHC antigen apparently developed the preferential binding affinity toward a specific set of nonapeptides. The requirement for preferential binding can either be permissive or stringent. In the case of human HLA-A2, those nonapeptides having either Leu or Met at the second position and mainly Val, but occasionally Leu at the ninth position are preferred. Since both Leu and Val are very common residues, the typical somatic cell type readily supplies nearly 3000 high affinity host nonapeptides preferred by HLA-A2. Of those, the tolerance can be induced, at the most, to only 1000 nonapeptides. In view of this, permissive class I MHC antigens such as HLA-A2 carefully avoid high affinity nonapeptides in viral proteins, for their status as to self or nonself is uncertain, and they choose second choice nonapeptides as T epitopes. In sharp contrast to human HLA-A2, mouse H-2D^b represents the stringent class I MHC antigens. In order to show the high binding affinity toward H-2D^b, nonapeptides are required to carry Asn at position 5 and Met or Ile at the equally critical position 9. Inasmuch as Asn and Met are rare residues and Ile, too, is not a common residue, the typical somatic cell type can supply only several hundred host nonapeptides having the high binding affinity toward H-2D^b. Under the circumstance, there is no problem in memorizing the selfness of all of them. Accordingly, T epitopes are almost invariably chosen from the high affinity nonapeptides that are present in their viral proteins.     

MHC and Preferences for Male Odour in the Bank Vole

Highly polymorphic major histocompatibility complex (MHC) genes are thought to play a central role in the choice of genetically compatible sexual partners in some vertebrates, although the evidence is variable across species. Here, we investigate the association between similarity in the MHC region and sexual preferences in the bank vole Myodes ( =Clethrionomys ) glareolus (Arvicollinae) in a laboratory setting. Females in post-partum oestrus were given the choice between the scents of two males in a Y-maze. Both males were unrelated to the female, but differed in their MHC similarity to the female. We found that females spent more time near the scent of MHC dissimilar males than those, with whom they shared MHC alleles. This suggests that bank voles use MHC-related cues to choose compatible mates.     

Genetic dissimilarity,genetic diversity,and mate preferences in humans

It is clear that genes at the major histocompatibility complex (MHC) are involved in mate preferences in a range of species, including humans. However, many questions remain regarding the MHC's exact influence on mate preference in humans. Some research suggests that genetic dissimilarity and individual genetic diversity (heterozygosity) at the MHC influence mate preferences, but the evidence is often inconsistent across studies. In addition, it is not known whether apparent preferences for MHC dissimilarity are specific to the MHC or reflect a more general preference for genome-wide dissimilarity, and whether MHC-related preferences are dependent on the context of mate choice (e.g., when choosing a short-term and long-term partner). Here, we investigated whether preferences for genetic dissimilarity are specific to the MHC and also whether preferences for genetic dissimilarity and diversity are context dependent. Genetic dissimilarity (number of alleles shared) influenced male, but not female, partner preferences, with males showing a preference for the faces of MHC-dissimilar females in both mating contexts. Genetic diversity [heterozygosity (H) and standardized mean (d²)] influenced both male and female preferences, regardless of mating context. Females preferred males with greater diversity at MHC loci (H) and males preferred females with greater diversity at non-MHC loci (d²) in both contexts. Importantly, these findings provide further support for a special role of the MHC in human sexual selection and suggest that male and female mate preferences may work together to potentially enhance both male and female reproductive success by increasing genetic diversity in offspring.     

A sweetmeat plant,a perfume plant and their weedy relatives: A chapter in the history ofCyperus esculentus L. andC. rotundus L.

Tubers ofCyperus esculentus (tiger nuts) andC. rotundus were used in the ancient eastern Mediterranean as food, perfume and medicine. Tiger nuts that were consumed in Egypt, either boiled in beer, roasted or as sweets made of ground tubers with honey, were found in tombs from the 4th millenniumb.c. to the 5th centurya.d. C. rotundus tubers, a dietary staple in a Stone Age Egyptian community, were used much later in perfumes and medicine by the Egyptians, Mycenaeans and Greeks, and recorded by Theophrastus, Pliny and Dioscorides. An Egyptian preparation made ofCyperus tubers, other plant ingredients, honey and wine, described by Dioscorides, is similar to one in the Ebers papyri, demonstrating its continuity over 1600 years.Cyperus perfumes are mentioned in Mycenaean documents and by classical authors. Classical authors’ views on weeds, and whetherC. rotundus is described as a weed by Dioscorides, are reviewed. The domestication ofC. esculentus, and the evolution of both nutsedges towards weeds are discussed.     

The Association Between HLA-A Alleles and Young Alu Dimorphisms Near the HLA-J, -H,and -F Genes in Workshop Cell Lines and Japanese and Australian Populations

At least two polymorphic Alu insertions have been previously identified and characterized within the class I region of the major histocompatibility complex (MHC). We have identified another two new polymorphic Alu insertions, AluyHJ and AluyHF, located near HLA-J and HLA-F, respectively, within the a block of the MHC. Here we report on (1) the haplotypic relationships between the Alu dimorphisms and the HLA-A locus within a panel of 51 IHW homozygous cell lines representing at least 36 HLA class I haplotypes, (2) the Alu genotype, allele, and haplotype frequencies present in the Australian Caucasians and Japanese populations, and (3) the frequency of association between the different Alu dimorphisms and the HLA-A alleles in 109 Australian Caucasians and 99 Japanese. PCR was used to detect the presence or absence of insertion for AluyHJ, AluyHG, and AluyHF within the DNA samples prepared from the cell lines and the two population groups that had been previously typed for HLA-A. In the homozygous cell lines, all three Alu insertions were found in only one HLA class I haplotype (HLA-A1, -B57, -Cw6), no Alu insertions were detected in six HLA class I haplotypes and one or more of the Alu insertions were found in 29 HLA class I haplotypes. At least one of the Alu insertions was found in about 86% of the Japanese and Australian individuals, with the AluyHJ generally related inversely to AluyHG and/or AluyHF. The gene frequency of the AluyHJ and AluyHF insertions was significantly different (p <0.05) BETWEEN JAPANESE AND AUSTRALIANS, WHEREAS THERE WAS NO DIFFERENCE (P > 0.05) between the frequencies of AluyHG in the two populations. The Alu haplotype frequencies were also significantly different between the Japanese and the Australians. In the cell lines and the population groups, the AluyHJ insertion was most frequently found associated with HLA-A1 or A24, AluyHG with HLA-A2, and AluyHF with HLA-A2, -A10, or -A26. This study suggests that the three polymorphic Alu elements have been inserted into the a block of the MHC in different progenitor groups and therefore will be useful lineage and linkage markers in human population studies and for elucidating the evolution of HLA class I haplotypes.     

Plasticity in the Contribution of T Cell Receptor Variable Region Residues to Binding of Peptide–HLA-A2 Complexes

One hypothesis accounting for major histocompatibility complex (MHC) restriction by T cell receptors (TCRs) holds that there are several evolutionary conserved residues in TCR variable regions that contact MHC. While this “germline codon” hypothesis is supported by various lines of evidence, it has been difficult to test. The difficulty stems in part from the fact that TCRs exhibit low affinities for pep/MHC, thus limiting the range of binding energies that can be assigned to these key interactions using mutational analyses. To measure the magnitude of binding energies involved, here we used high-affinity TCRs engineered by mutagenesis of CDR3. The TCRs included a high-affinity, MART-1/HLA-A2-specific single-chain TCR and two other high-affinity TCRs that all contain the same Vα region and recognize the same MHC allele (HLA-A2), with different peptides and Vβ regions. Mutational analysis of residues in CDR1 and CDR2 of the three Vα2 regions showed the importance of the key germline codon residue Y51. However, two other proposed key residues showed significant differences among the TCRs in their relative contributions to binding. With the use of single-position, yeast-display libraries in two of the key residues, MART-1/HLA-A2 selections also revealed strong preferences for wild-type germline codon residues, but several alternative residues could also accommodate binding and, hence, MHC restriction. Thus, although a single residue (Y51) could account for a proportion of the energy associated with positive selection (i.e., MHC restriction), there is significant plasticity in requirements for particular side chains in CDR1 and CDR2 and in their relative binding contributions among different TCRs.     

Making scents of sex underwater

Sex and scents have long been associated. Musk, for example, is a sexual scent that has been used for many years in the perfume industry. In humans, the debate on the existence of sex pheromones continues, whereas in insects their role is well known. Through recent research, we are discovering that such chemicals are equally important in conveying sexual signals between aquatic animals.     

MHC binding peptides for designing of vaccines against Japanese encephalitis virus: A computational approach

Japanese encephalitis (JE), a viral disease has seen a drastic and fatal enlargement in the northern states of India in the current decade. The better and exact cure for the disease is still in waiting. For the cause an in silico strategy in the development of the peptide vaccine has been taken here for the study. A computational approach to find out the Major Histocompatibility Complex (MHC) binding peptide has been implemented. The prediction analysis identified MHC class I (using propred I) and MHC class II (using propred) binding peptides at an expectable percent predicted IC (50) threshold values. These predicted Human leukocyte antigen [HLA] allele binding peptides were further analyzed for potential conserved region using an Immune Epitope Database and Analysis Resource (IEDB). This analysis shows that HLA-DRB1*0101, HLA-DRB3*0101, HLA-DRB1*0401, HLA-DRB1*0102 and HLA-DRB1*07:01% of class II (in genotype 2) and HLA-A*0101, HLA-A*02, HLA-A*0301, HLA-A*2402, HLA-B*0702 and HLA-B*4402% of HLA I (in genotype 3) bound peptides are conserved. The predicted peptides MHC class I are ILDSNGDIIGLY, FVMDEAHFTDPA, KTRKILPQIIK, RLMSPNRVPNYNLF, APTRVVAAEMAEAL, YENVFHTLW and MHC class II molecule are TTGVYRIMARGILGT, NYNLFVMDEAHFTDP, AAAIFMTATPPGTTD, GDTTTGVYRIMARGI and FGEVGAVSL found to be top ranking with potential super antigenic property by binding to all HLA. Out of these the predicted peptide FVMDEAHFTDPA for allele HLA-A*02:01 in MHC class I and NYNLFVMDEAHFTDP for allele HLA-DRB3*01:01 in MHC class II was observed to be most potent and can be further proposed as a significant vaccine in the process. The reported results revealed that the immune-informatics techniques implemented in the development of small size peptide is useful in the development of vaccines against the Japanese encephalitis virus (JEV).     

Major histocompatibility complex class II compatibility,but not class I,predicts mate choice in a bird with highly developed olfaction

Mate choice for major histocompatibility complex (MHC) compatibility has been found in several taxa, although rarely in birds. MHC is a crucial component in adaptive immunity and by choosing an MHC-dissimilar partner, heterozygosity and potentially broad pathogen resistance is maximized in the offspring. The MHC genotype influences odour cues and preferences in mammals and fish and hence olfactory-based mate choice can occur. We tested whether blue petrels, Halobaena caerulea, choose partners based on MHC compatibility. This bird is long-lived, monogamous and can discriminate between individual odours using olfaction, which makes it exceptionally well suited for this analysis. We screened MHC class I and II B alleles in blue petrels using 454-pyrosequencing and quantified the phylogenetic, functional and allele-sharing similarity between individuals. Partners were functionally more dissimilar at the MHC class II B loci than expected from random mating (p = 0.033), whereas there was no such difference at the MHC class I loci. Phylogenetic and non-sequence-based MHC allele-sharing measures detected no MHC dissimilarity between partners for either MHC class I or II B. Our study provides evidence of mate choice for MHC compatibility in a bird with a high dependency on odour cues, suggesting that MHC odour-mediated mate choice occurs in birds.     

Seasonal Changes in Scents and Responses to them in Meadow Voles: Evidence for the Co-evolution of Signals and Response Mechanisms

Relatively little is known about the mechanisms of communication during the non-breeding season in species that are seasonal breeders. Previous work with meadow voles, Microtus pennsylvanicus, housed under long photoperiods, has shown that they prefer the odors of opposite-sex conspecifics. In this paper, we investigated the effects of short photoperiod on preferences for sex-specific odors and the production of such odors. Short-photoperiod females preferred anogenital and fecal scents of other short-photoperiod females over those of males, but did not show sexual preferences for three other scents. Short-photoperiod males did not exhibit sexual preferences for any of the odors. Furthermore, scents from short-photoperiod voles did not elicit sex-specific preferences in long-photoperiod voles, and scents from long-photoperiod voles did not elicit preferences from short-photoperiod voles. These and previous results indicate that both the odors and responses to odors change seasonally and that long-photoperiod voles respond selectively to scents from long-photoperiod voles and short-photoperiod voles respond selectively to scents from short-photoperiod voles. Taken together, these results suggest the co-evolution of seasonal changes in scents and in perceptual or other response mechanisms.     

Psi-screen, an in vitro toxicity test system: applications in the bioassay of perfumes and fragrance chemicals

The effects of 65 perfume formulations (perfume oils, perfumes, eau de parfum, eau de toilette) on mitochondrial membrane potential (Psim) and mitochondrial respiration have been investigated using a mitochondria-based assay for (Psim, termed Psi-Screen. All the perfume formulations tested are highly active in the Psi-Screen assay, and the major site of inhibition in all cases is NADH-ubiquinone reductase (Complex I). This is confirmed in studies on the inhibition of NADH oxidase and NADH-ubiquinone reductase. Some formulations also inhibit succinate oxidation at either Complex II or Complex III. Evidence for the inhibition of mitochondrial ATPase is presented, as well as for the induction of reactive oxygen species production by perfume inhibition of Complex I. Thus, perfume formulations are multiple inhibitor mixtures which inhibit multiple bioenergetic functions at high dilutions. The implications of these findings are discussed with respect to cell toxicity via necrosis and/or apoptosis. Twenty candidate fragrance chemicals were investigated and all inhibited Complex I (5 at <35 microM). Mass screening strategies and high-throughput screening assays are discussed.     

Early evolution of MHC polymorphism

There is unwarranted satisfaction with the view that MHC polymorphism evolved because there was a selective advantage in having a variety of MHC proteins to bind a variety of peptide subsets for presentation to T cells. While this may, in part, explain its maintainance, polymorphism may have evolved initially to reject foreign virus "grafts". The possession of similar membranes promotes aggregation between "like" cells, but it also promotes aggregation between the cells and viruses which retain membrane components of their previous host. The selection pressure afforded by hostile virus "grafts" would favour cells which developed polymorphic membrane components (since "like" will not aggregate with "not-like"). This polymorphism would have evolved before the appearance of multicellular organisms. Thus, the evolution of modern immune systems would have been imposed upon pre-existing polymorphic systems. A path this evolution may have taken involves the development of mechanisms for intracellular distinction between self and not-self.     

MATE CHOICE FOR NONADDITIVE GENETIC BENEFITS CORRELATE WITH MHC DISSIMILARITY IN THE ROSE BITTERLING (RHODEUS OCELLATUS)

Good genes models of mate choice predict additive genetic benefits of choice whereas the compatibility hypothesis predicts nonadditive fitness benefits. Here the Chinese rose bitterling, Rhodeus ocellatus, a freshwater fish with a resource‐based mating system, was used to separate additive and nonadditive genetic benefits of female mate choice. A sequential blocked mating design was used to test female mate preferences, and a cross‐classified breeding design coupled with in vitro fertilizations for fitness benefits of mate choice. In addition, the offspring produced by the pairing of preferred and nonpreferred males were reared to maturity and their fitness traits were compared. Finally, the MHC DAB1 gene was typed and male MHC genotypes were correlated with female mate choice. Females showed significant mate preferences but preferences were not congruent among females. There was a significant interaction of male and female genotype on offspring survival, rate of development, growth rate, and body size. No significant male additive effects on offspring fitness were observed. Female mate preferences corresponded with male genetic compatibility, which correlated with MHC dissimilarity. It is proposed that in the rose bitterling genetic compatibility is the mechanism by which females obtain a fitness benefit through mate choice and that male MHC dissimilarity, likely mediated by odor cues, indicates genetic compatibility.