Why Do Males Get More Infectious Diseases and Females More Autoimmune Disorders? Israeli Researchers Found the Answer

And Hashem created man in His image, in the image of Hashem He created him; male and female He created them. Genesis 1:27

Many illnesses affect men and women to the same degree. But it has been noticed by physicians and researchers over the years that males are more likely to contract infectious diseases – including more severe cases – than females and that females are at higher risk of suffering from a large variety of autoimmune diseases, in which the body’s immune system mistakenly recognizes tissues and organs as foreign and attacks them. 

But these doctors and scientists have not been able to provide a reason for this gender difference. Sex hormones and genetics (XY or XX chromosomes) have been given an explanation, but they are not the whole story. 

A new study by researchers at Ben-Gurion University of the Negev (BGU) in Beersheba looks at this question researchers by comparing the transcriptome of the immune system of female and male mice. The transcriptome is the set of all RNA molecules in one cell or a population of cells. Unlike the genome, which is roughly fixed for a given cell line (not including mutations), the transcriptome can vary with external environmental conditions. 

Dr. Tal Shay of BGU’s department of life sciences and her student Shani Talia Gal-Oz profiled female mice.as part of the global Immunological Genome Project (ImmGen) and published their research in a recent edition of Nature Communications

Additional researchers from Harvard Medical School, Icahn School of Medicine at Mount Sinai Hospital, the University of Chicago, Northwestern University, Hebrew University of Jerusalem, and RIKEN Center for Integrative Medical Sciences of Japan participated in the study.

It recently came to ImmGen’s notice that all of their studies focused on male mice. They and their colleagues discovered some significant differences, not all tied to XX vs XY chromosomes.

When the researchers compared the female and male immune systems, in one cell type called macrophages, a few genes were expressed at higher levels in female mice. Stimulating the mice with interferon increased the difference between the macrophages of the males and females. This difference might contribute to the stronger female reaction that helps them fight off infectious diseases and physical trauma more quickly and efficiently than their male counterparts. However, this is also likely to make females more prone to develop autoimmune disorders, perhaps because of this fierce response to infection.

One of the most striking sex differences in autoimmune diseases is of systemic lupus erythematosus (SLE), in which nine out of 10 patients are female. SLE is characterized by a wide profile of autoantibodies, causing inflammation and irreversible organ damage. Overproduction of interferons – a group of signaling proteins in the immune system – is highly correlated with autoimmunity. They authors suggest that sex-based differential activation of interferon pathways may contribute to sexual dimorphism in SLE and other autoimmune disorders.

The mammalian immune system displays widespread sexual dimorphism – differences between males and females. In general, females are healthier than males, and they have better outcomes for illnesses caused by infectious diseases, sepsis, trauma or injury. Males experience infectious diseases more frequently and with increased severity, but females are more prone to the majority of autoimmune diseases, they continued. “In addition, there is a sex bias in the frequency and survival for various types of cancer, and males and females respond differently to viral vaccines and transplantations. Sexual dimorphism of the immune system is not limited to mammals but extends to birds, but death rates from infectious diseases are higher in the males.

 “Females might have an innate enhanced potential to withstand immune challenges due to more highly activated innate immune pathways prior to pathogen invasion,” the BGU team wrote. “This female immune alertness, which makes females less vulnerable to infectious diseases, comes at the price of females being more prone to autoimmune diseases,” they concluded.