THE concept of 鈥渕an flu鈥� 鈥� the idea that men make too big a deal out of a cold 鈥� is an old joke. But when covid-19 arrived, we had to take a serious look at sex differences in how people respond to infections. Being male was a risk factor for experiencing more severe symptoms of the coronavirus: in England during 2020, . Men are also nearly twice as likely to be diagnosed with tuberculosis and slightly more likely to die from flu. So does your sex put you at an advantage or disadvantage when it comes to immunity?
There may be several reasons for immune sex differences. For one thing, we have discovered in recent years that oestrogen, the main female sex hormone, broadly stimulates immune system activity. The main male equivalent, testosterone, weakens it. But there are other forces at work too.
Sex is governed by DNA, which comes packaged up into 23 pairs of chromosomes. Most women have two X chromosomes, while most men have one X and one Y. To make sure that cells in female bodies don鈥檛 have duplicate X chromosome genes in operation, in every cell.
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This article is part of a special series on immunity, in which we explore:
Which X chromosome is inactivated is determined randomly when embryos are a few weeks old. All the tissues in a female body are therefore mosaics, with half their cells using the X chromosome inherited from the mother and the rest using the one from the father. Because many genes involved in the immune system are located on the X chromosome, this means that female bodies have twice the genetic variation to call on when fighting infections. 鈥淲omen have more diversity when it comes to individual genes,鈥� says , a genetic researcher based in New York.
Automimmune diseases
In addition, not all the genes on the inactivated X chromosome are switched off, with some immune system genes remaining functional on both X chromosomes 鈥� including one called toll-like receptor 7 (TLR7), which helps cells detect viruses. This means that most women have double the dose of TLR7 in their immune system.
Having a stronger immune response is a double-edged sword, though: it may explain why women are more susceptible to autoimmune diseases, such as multiple sclerosis and rheumatoid arthritis, where the body starts to recognise its own cells as dangerous and attacks them.
Another contributor to this increased risk of autoimmune conditions, could be that the mechanisms to prevent autoimmunity work less well in female bodies, says Moalem. In the fetus, immune cells should be 鈥渢rained鈥� to recognise the body鈥檚 own cells. Because most women are mosaics of two populations of genetically different cells, this training process may be less efficient.
On the other hand, women鈥檚 greater propensity to autoimmunity helps them out when it comes to cancer, which arises when cells start multiplying out of control. The immune system is thought to destroy many tumours before they get big enough to be noticed. Immune cells that aren鈥檛 as well trained to recognise the body鈥檚 own cells are more likely to attack them when they start looking different to normal, as tumour cells do.
There are also behavioural explanations for why women tend to get fewer cancers than men, such as men smoking and drinking more 鈥� but so much emphasis has been placed on these social factors, we have previously overlooked the immune sex differences, says Moalem. 鈥淭he more we look, the more we find.鈥�
