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Immune Responses In Females And Males Can Be Different And Now We Know Why


Dr. Katie Spalding

Katie has a PhD in maths, specializing in the intersection of dynamical systems and number theory.

Freelance Writer


It turns out it actually *might* just be that time of the month. Image: LightField Studios/Shutterstock

There’s an old saying: “What doesn’t kill you makes you stronger.” It sounds good, but it’s not true – there are plenty of things out there that can leave you alive but weaker, like COVID-19, or 40,000 ecstasy pills.

According to a new paper published in the journal Frontiers in Immunology, there’s something else that can leave us weaker – and by “us,” we mean approximately 50 percent of the population. It turns out anemia, the condition where a person lacks enough healthy red blood cells to adequately oxygenate their body, generates a different immune response in female bodies than in males – and thanks to a combination of some weird enzymes and a tendency to be actively losing blood for 10 to 25 percent of the time, it turns out simply being female might be enough to significantly impact your immune system. This, the authors say, adds to the idea that we need to stop treating both sexes with the same strategies.


“Red blood cells are obviously crucial in transporting oxygen to our tissues,” immunologist and study lead Shokrollah Elahi told IFLScience. “[Especially] when we face COVID and hypoxia and all those complications. But we haven’t paid attention to immature red blood cells in the past.”

Immature blood cells – that is, blood cells newly generated by the bone marrow – aren’t really supposed to be in circulation, explained Elahi. Under normal circumstances, they would mature in the marrow before entering the blood stream. “Immature red blood cells outside of the bone marrow,” he told IFLScience, indicates “something unusual.”

Now, “unusual” doesn’t necessarily mean “bad”: it’s perfectly normal to find lots of immature red blood cells in pregnant people or newborns, Elahi explained. But they also increase in bodies with cancer, or HIV – even COVID-19.

“We didn’t know that they had an immunological function,” Elahi told IFLScience. “Basically, they suppress the immune system … [and] females in general have significantly more immature red blood cells in their blood circulation than males.”


Drawing on multiple studies on mice and humans, Elahi described the double whammy suffered by female immune systems: not only do females have more immature red blood cells in their system than males, but those cells are also “more potent,” he explained, with special immunosuppressive enzymes that are “more abundant … in females versus males.”

“The question is why – we don’t know that,” he said. But they do have an idea: immature red blood cells can often turn up in the blood when a person is suffering from anemia or blood loss. When that happens, the body tries to compensate: it sets the bone marrow to work generating new, immature, blood cells, Elahi explained – and some of them leak out into the bloodstream.

“We have been thinking that anemia is a physiological issue – you are anemic, OK, don’t worry about it,” he told IFLScience. “But we have demonstrated that … anemia should be taken into consideration as an immune related disorder.”

Further bolstering the idea that anemia and blood loss can impact the immune system, Elahi pointed to research showing that inducing anemia in mice resulted in a massive increase of immature red blood cells. More than that, they became much more susceptible to infection than their non-anemic peers – and female anemic mice were hit worst of all. But even stranger was the effect of these immature cells in otherwise healthy blood: when immature red blood cells were transfused into mice without anemia, their susceptibility to infection went up.


So much for mice, but what about humans? Elahi’s team collected blood from healthy individuals and measured the presence of immature red blood cells in male and female subjects. The results, Elahi told IFLScience, were the same “regardless of species.” In humans, though, there’s one obvious reason why a female might be experiencing blood loss: their period. Working on this idea, the team decided to compare blood from pre- and post-menstrual subjects to see if there was any increase in immature red blood cells.

“We did see [that] yes there was,” Elahi told IFLScience. “The same individual looking pre and post cycle … we did see a significant difference.”

“Obviously in humans we couldn’t infect them and do further investigation,” he continued. “But … based on the animal studies, we [concluded] that women’s immune systems will be compromised, will be suppressed post their menstrual cycle – because of the expansion of these immunosuppressive cells.”

The study has important real-world implications, Elahi notes, as it provides important context to diagnoses that could pave the way for so-called "precision" medicine.


"The basis for personalized medicine is that males and females have different biology and immune responses. Sex influences the immune system resulting in sex-specific outcomes from autoimmune and infectious diseases, cancers and even response to immunization," he explained in a statement. "Understanding such mechanisms will define important new strategies for effective prevention and treatment of immune-related conditions."

There is much about these results that is still unknown: the exact mechanism behind the different levels of immature red blood cells in males and females, for example, is “obviously hormonal” – but not necessarily just hormonal. Another potential factor the team have hypothesized is that females have what's known as erythropoiesis islands in their spleens – a kind of “second source … of red blood cells” says Elahi, to compensate for the amount lost through menstruation.

“We did show that in mice,” Elahi told IFLScience. “But in humans … it’s impossible to collect the spleen from healthy individuals.”

Another unknown is how these findings translate onto females who don’t menstruate, such as post-menopausal women or trans men. It’s “a very good question,” says Elahi – but not one he knows the answer to yet.


“This is a very new field,” he told IFLScience. “It would be very interesting to look at the menopause effect [or] transgender [people] … I think that would be very, very informative.”


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