Autoimmune Diseases: Women’s Business

23. May 2017

The immune systems of women and men are very different. Women have a better chance of surviving severe infections. With regard to autoimmune diseases, however, women are rather more often affected: around 80 percent of such patients are female.

Men are more susceptible to pathogenic viruses, bacteria, fungi and parasites. Statistics demonstrate that women generally have a better chance of surviving serious infections. It is therefore implied that sex hormones have a significant influence on the immune system and ultimately provide for a more effective body defence in the female. It does appear that hormone-signalling is indeed involved in a variety of effects. It’s also however becoming increasingly clear that genes on the X and Y chromosomes play an important role. An article published in the journal PNAS a few weeks ago shows just this.

Different infections

With this in mind, Cory Teuscher and her colleagues from the University of Vermont bred mice whose genetic makeup matched for all chromosomes other than the Y chromosome, and exposed the animals to pathogenic influenza A and Coxsackie B3 viruses. Depending on the origin of the Y chromosome, the immune responses to influenza differed. Certain variants promoted inflammatory processes in the lungs and the activation of the respective lung cytokines such as IL-17. The researchers found a similar segregation with respect to the male sex chromosome in the response to Coxsackie. Previous studies show that autoimmune processes such as the MS model in the EAE (experimental autoimmune encephalomyelitis) mouse are also dependent on genes on the Y chromosome.

Influenza A strain infections have caused about a million deaths over the last hundred years. Women are much more frequently and severely affected than men. The same is true for infections with the HI virus. After infection with the virus, women have about 40 percent less RNA in the blood than men. Despite this, the risk of an AIDS onset is 1.6 times higher.

In the instance of serious sepsis infections, the main pathogenic agents involved differ from one another simply due to the differentiation between the male and female anatomy. In the female, bacteria usually arrive via the urogenital tract and are more likely to be Gram-negative, whereas the predominantly Gram-positive pathogens in men tend to search out a path into the body by going through the airways.

Massive-scale female defence

The genders also differ when it comes to the the body’s immune system itself being attacked. About 80 percent of patients with autoimmune disease are female. Asthma occurs more frequently in women and is more severe. The same also applies to systemic anaphylactic reactions. Cases where the immune system attacks its owner’s digestive tract, as occurs with irritable bowel syndrome, happen in women two to four times more frequently than in men.

Finally, the sexes also differ in their response to protective inoculations. In almost all common vaccinations the antibody response in women is significantly higher than in men. This means, in turn, that girls need a lower vaccine dose for the same titre than do boys. However, the risk of local and systemic reactions is higher.

When taking into consideration all types of pathogenic microorganisms, men are more likely to be the target of an infection than are women; in the female the pathogens mostly strike a massive defence system and this therefore leads to higher survival rates. This rule applies to almost all higher creatures. With respect to humans a higher titre of NK cells is present in men; neutrophils and macrophages in contrast are all the more active in women. Antigen-presenting cells (such as dendritic cells) perform their tasks better in women than in men.

Sex hormones and chromosomes

In addition to the differences in the human body structure, such as the larger mucosal surface in the genital tract, a series of gender-specific factors are involved in the induction of the immune response. An entire arsenal of genes on the X chromosome has an influence on the defence system. From among approximately 1100 genes, many are not affected by the inactivation of the second X-chromosome. In mice this figure is about seven percent, in humans fifteen. Included among the X-chromosomal encoded proteins are important cytokines such as IL-13. IL-4.IL-10 and TLR (toll-like receptor 7, important for innate immune defence) and FoxP3, a transcription factor for regulatory T cells. So far little studied, but apparently no less important, are genes on the Y chromosome, which were more closely scrutinised by the scientists working with Teuscher in Vermont.

Sexual hormones regulate a whole series of metabolic pathways, including the expression of numerous genes in B and T cells, mast cells, dendritic cells, macrophages and NK cells. Studies have also shown that oestrogens influence the methylation patterns of genes in immune cells. These genes thus show a level of activity proportionate to the hormone level. Testosterone weakens the activity of NK cells and like other androgens ensures an anti-inflammatory response. In contrast, there is hormone-independent regulation of these epigenetic modifications by factors encoded on the sex chromosomes X and Y.

Well-filled inflammatory munition depots

Adam Moeser and his colleagues from Michigan State University similarly posed the question as to why women have a stronger response to stress and allergens than do men. With this in mind they got to work dealing with one of the main actors in these reactions: mast cells. In a comparison between the sexes, they found more than 8,000 diversely expressed genes. In a mouse model they simulated both mental stress and IgE mediated anaphylactic shock. The serum histamine level was found to be higher in females and intestinal permeability increased more than in the males. In the examined mast cells, the female mice stored far more inflammatory mediators and also released these factors.


In the female mast cells, the granules are more densely packed and contain more immune mediators. © A. Moeser, Michigan State University

The exact mechanism behind the gender-specific regulation of immune defence is still not largely understood. For a long time the controversial immunocompetence-handicap model was held to be true. It stated that, among other things, testosterone strongly promotes the formation of secondary male sex organs, but this is at the expense of the immune system, which then allows a higher pathogenic load. Many nowadays regard this hypothesis to be obsolete. It appears, however, that the effective immune response protects the woman against serious infections but is conducive to inflammatory and autoimmune diseases.

Female power in clinical trials

More knowledge about the exact mechanisms leading to the differentiated control in men’s and women’s immune systems might lead to better intervention options – and not only for disorders or overreactions to the microbial attacks on humans. In patients with multiple sclerosis for instance, one topical treatment using testosterone slowed down brain atrophy.

Moreover the controlling authorities in the USA and Europe are ever more often demanding a balanced gender ratio with respect to the planning and interpretation of studies – even in animal experiments in the preclinical area. If we want to further personalise our therapies, we cannot afford to overlook gender medicine. Unravelling and undertaking separate studies on the influence of hormones, of the genes of the sex chromosomes, and not least those of our environment, is only the first step.

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