Wow, your immune system smells good…

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For the second instalment of the new baby science category, we’ll look at an early event in the baby making process. At choosing a mate. Scientific evidence suggests that we choose our mates, at least in part, based on scent, including the odour of their immune system. The idea is that we aim to choose a mate, who carries immune receptors, called MHCs, different to our own. A diverse immune receptor repertoire will give offspring better chances at fighting pathogens.

What are MHCs?

Major histocompatibility complexes (MHCs) are receptors on the cell surface that can present parts of pathogens (called epitopes or antigens) and thereby activate the adaptive immune system.

MHC class I molecules are expressed on all cells in our body except red blood cells. They present antigens from intracellular pathogens (like viruses) and trigger CD8+ cytotoxic T lymphocytes. So when a cell gets infected with a virus, it can process parts of the virus, present it on its cell surface, thereby alerting the immune system to the thread. The activated T cells, carrying a T cell receptor matching the antigen presented by the cell, then kills the cell. This mechanism limits the spread of intracellular infections. In addition, the expression of MHC I also tells the immune system that a given cells is from the body and not an intruder. MHCs therefore also help the immune system to distinguish between self and non-self.

The expression of MHC class II molecules is limited to specialized antigen presenting cells such as macrophages, DCs and B cells. These cells have developed mechanisms that allow the uptake (phagocytosis), processing and presentation of extracellular pathogens such as most bacteria. Epitope plus MHC II molecule activate CD4+ T cells, which depending on the local environment differentiate into effector cells fighting the infection.

In humans MHC molecules are called Human Leukocyte Antigens (HLAs), the genes for which are encoded on chromosome 6. The MHC I locus comprises three major (HLA-A, -B and -C) and three minor (HLA-E, -F, -G) genes, while class II includes three major and two minor genes.  HLA-DP, -DQ and -DR form the cell surface receptor for MHC class II molecules, while HLA-DM and -DOB help process and load the antigens onto the receptor.

The genes encoding for the different HLAs are among the most diverse in the body. Between 3 500- 4 700 different gene versions (alleles) are known for HLA-A, -B and -C. The class II receptors are even more diverse as two genes form one receptor, making more than 30 000 variations of HLA-DQ possible. Not all variants  mount functionally different molecules, meaning that some variants bind the same antigens and are therefore functionally identical. In general, however, the genetic diversity equals diversity in the antigen-binding site of the HLA molecules. This means that different HLA molecules bind and present different antigens from the same pathogen.

Every person carries two alleles of each HLA gene. One from their mother and one from their father. Both alleles are expressed, they are co-dominate. As the different HLA alleles bind different antigens, having a diverse mix improves ones immune response. The idea that one can smell the MHC types of the potential mate would therefore make great evolutionary sense as it ensures the expression of different HLAs in their offspring.

Evidence on mating choice depending on immune markers

In 1995, a study by Wedekind and colleagues found that women that aren’t on the contraceptive pill prefer the smell of t-shirts from men with dissimilar HLA types in a double-blinded study. Female and male students were typed for their HLA-A, -B and -DR status. The female students were then asked to rate the smell of t-shirts worn for two nights by the male students. Not only did the women score the smell of the HLA- dissimilar males as more pleasing but they also thought that they reminded them of former partners. A similar study with male and female “smellers” found that men showed the same tendency to prefer the smell of HLA-dissimilar mates.

Looking at genome-wide genotype data, European American couples tend to be significantly more dissimilar than randomly paired individuals, suggesting that our mate choices are influenced by HLA-type. Surprisingly, this finding could not be repeated in African couples. The authors explain this by socio-demographic processes, in which mate-choice is more limited by the family and community than biological attraction in the African cohort.

In an interesting approach Milinski and Wedekind have tested whether people judge perfume ingredients such as rose, jasmine or patchouli differently depending on which HLA type they carry. They asked 137 subjects if they would like to smell like 36 scents themselves. Indeed, people sharing the same HLA-subtype preferred the same perfume ingredients. The authors speculate that we use perfumes to enhance our individual MHC- related smell. Scoring 18 scents on whether your partner should smell like them, did not mount any correlations. This lack of a preference may be explained by the fact that we randomly prefer HLA types different to our own. We therefore prefer smells different to ours, but none specifically. Bad news for the perfume industry I guess, as there is no scientific proof for a mate-attracting scent.

How can the MHC molecules affect our body odour?

The exact molecular mechanisms behind the findings above remain unknown. However, several attempts at an explanation have been made, a few are listed here:

Genes encoding for olfactory receptors have been found in the MHC locus. Polymorphisms (difference in these genes) are linked to certain HLA-alleles and it may be that our sense of smell is thereby linked to the HLA-alleles we carry.

The peptide-microflora hypothesis, which could not be proven so far, proposes that the peptides bound by MHC molecules could be metabolized or broken down by commensal bacteria inducing a MHC molecule-specific smell in urine or sweat. The antigen presenting capacity of different MHC types may also shape the kind of commensal bacteria we carry with us and thereby shape our smell.

Lastly, it has been suggested that the antigens presented by MHC molecules to activate the adaptive immune system – these small protein fragments – can be smelled themselves. In mice, specialized sensory neurons have been identified that can bind peptides in an MHC-like fashion.

What ever the mechanism is – keep sniffing 🙂

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