The human body has an immune system that acts as a defense shield, always on guard against invaders of the virus or bacterium world, parasitic threats, or even cellular mutations. The reason the defense against different threats isn’t equal for either sex is the new focus of study.
In a study led by the Garvan Institute of Medical Research and UNSW Sydney, a long-held biological conundrum has now been answered: why women have superior immune responses but a higher proportion of autoimmune diseases (at least 80%).
The study found there are now more than a thousand new specific sex ‘genetic’ switches that modify immune functions very differently for both men and women, with the information published today in The American Journal of Human Genetics.
Single-Cell Breakthrough: Beyond Sex Chromosomes It was once believed that immunity ‘deviations between the sexes’, both men and women, must be largely thanks to the effects of hormones and/or their chromosomes (X and Y). Prior studies were on more general and combined cellular material from blood samples that did not go ‘inside the cells’.
A single-cell RNA sequencing study analyzed the expression of thousands of genes for over one million individual human immune cells, revealing immune variation between males and females is a much deeper phenomenon than just hormone or chromosome influence: Genetic Control on the Autosomes.
More than just on the sex chromosomes (X and Y, which everyone has, but men one ‘X’ and women two), most new ‘genetic’ switches reside on autosomes (the other non-sex chromosomes that all individuals possess an equal balance of).
Gene Expression “Volume Controls”: These genetic switches act like molecular ‘volume controls’ for genes – either turning them on/up, or off/down, specific to a particular sex, or even a particular type of cell (scientifically calledexpression quantitative trait loci, or eQTLs).
An evolutionary trade-off in viral defense and risk of autoimmune disease: As the scientific research into the immune variations in both sexes revealed distinct cellular identities, it’s evident how a healthier immunity in females contrasts to male’s overall lower prevalence of autoimmune diseases:
The Female Immune Profile: High Alert!
High B Cells & Tregs
Inflammatory Pathways Primed
Better Viral Defence
More Autoimmune Risk (e.g. Lupus)
* Advantages: A fast and robust immune response means you ‘fight off infections faster and have greater efficacy when vaccinated’… as your immune system is ‘primed to kick off the inflammatory process quickly’.
* The Trade-Offs: You keep these defences on high alert so you may end up ‘accidentally target[ing] healthy tissues, leading to autoimmune disease’. For instance ‘9 women have lupus for every1 man who does’.
The Male Immune Profile: Focused on Normalisation
High Monocytes (First responders)
Basline Cellular Maintenance Active
Lower Autoimmune Risk
More Infection & Cancer Vulnerability
* Advantages: ‘Lower levels of chronic inflammatory markers and the risk factors that drive autoimmune disease’.
* Trade-Offs: ‘We’ve given more latitude for acute responses such as infections like the COVID-19’ and ‘infections as a cause for non-reproductive cancers’.
Future ‘Precision Medicine’: Now that sex-specific immune profiles are being defined, our health treatments could ‘tailored not just to an individual’s disease but also their specific sex- and age- and ethnicity-related’ immune, and hence overall biological and genetic make-up as well.
‘In the past, for decades drug trials were mainly run on men – on white, middle-class, working men’ on the assumption that the cells were fundamentally similar ‘regardless of whether one was born male or female.’
The ‘key and exciting insight’ of this study is the finding of ‘specific genetic and cell-based factors… that can inform targeted new therapeutic strategies’ based not only on who has cancer (which most clinical trials are based), but how an immune cell behaves depending on whether the patient is male or female.
What This Means for the Future of Precision Medicine: Historically, clinical trials and medical research relied heavily on male-biased cohorts, assuming baseline cellular mechanics were uniform across sexes.
These findings emphasize that male and female autoimmune conditions may operate through distinct biological pathways. Tailoring treatments, diagnostic metrics, and drug dosages to reflect an individual’s underlying genetic immune profile marks a crucial step toward true precision medicine.
