The immune system responds to sex hormones

So, what are the physiological drivers behind these differences in immunity between males and females? The fundamental factors responsible for the differentiation of the sexes are the sex hormones. Previous molecular and physiological studies have uncovered the effects that these hormones have on both the differentiation and function of immune cells. Androgens, such as testosterone (which exists in high levels in males), prinicpally act as immunosuppressants, while oestrogens have been shown to enhance the immune system. Since females produce much higher levels of oestrogens, this is thought to be key to their higher immune-competency. ‘This suggestion is corroborated by the fact that postmenopausal women, in parallel to the decline of oestrogen levels, also lose their immunological advantage against infections, but at the same time suffer less from autoimmune diseases.’ Professor Segner explains. ‘In addition, immunity and disease expression of women correlates with their reproductive status (i.e., oestrogen levels), for instance, SLE can undergo remission during pregnancy.’

Evolution of the immune system

Professor Segner and his colleagues want to find out if these immune actions of sex hormones are relevant in fish as well as mammals. They are also interested in understanding what lies behind this immune cell response to sex hormones. He asks the question: ‘What is the evolutionary sense of this?’ One hypothesis is that the sex hormones have immunomodulating activity because the organism has to deal with resource limitations for both the immune and reproductive systems – two highly valuable fitness components of animals. ‘Life history theory proposes that organisms are not selected for optimisation of either reproduction or immunity, but that evolution selects for the optimal allocation of the limited resources among fitness-associated traits,’ Professor Segner explains. ‘Nutrient and energy resources are limited and cannot sustain all life history traits at maximum levels. This implies that organisms have to make compromises in the allocation of resources among competing traits, and this implicates that they correlate negatively or “trade-off”.’

Life history theory also explains why the effects of sex hormones may differ between males and females. ‘As proposed in Bateman’s principle, females gain fitness through increased survival and longevity, while males gain fitness by mating with many females,’ Professor Segner explains. ‘As a consequence, males invest less in immune defence and thus have lower life expectancy.’ Additionally, males of most vertebrate species are less invested in parenting their young to increase the offspring’s chance of survival. Instead, they devote their time to courting females and competing with other males to increase their mating success. In contrast, females cannot increase their reproductive success by mating with more than one male. ‘They are choosy in mating and invest heavily in their offspring and, thus, future reproduction. In line with this, females show higher investment in the immune system in order to support survival and longevity and to increase the lifetime reproductive success,’ says Professor Segner.

Understanding the effect of oestrogens on fish immunity

When embarking on their initial investigations, Professor Segner and his team found that very little was known about the effect of oestrogens on the immune systems of fish. First, the team needed to determine if fish immune cells are indeed influenced by oestrogens. To do this, they analysed the cells of rainbow trout to see if oestrogen receptors are present using Reverse Transcription Polymerase Chain Reaction (RT-PCR). Since this technique is used to detect RNA expression, the team used it to find RNA sequences that code for the creation of oestrogen receptors. Remarkably, all four nuclear oestrogen receptors (ERa1, ERa2, ERß1 and ERß2) were discovered in the studied immune cell populations. The presence of nuclear oestrogen receptors in other fish species has now also been identified, as have membrane-bound oestrogen receptors.

The team then investigated how exposure to oestrogens can modulate immune gene expression and immune functions in fish. This was done both in isolation and in the presence of pathogens. Professor Segner tells us about the importance of performing these experiments in the presence of a pathogen: ‘It is often the case that an immunomodulatory effect becomes evident only when the immune system is activated, and not in the resting immune system.’ They exposed rainbow trout either to oestrogens alone, or to a combination of oestrogens and a pathogenic parasite. Using a microarray approach, they discovered that when exposed to both stressors, parasite and high oestrogen levels, the fish response differed to then exposed to a single stressor alone. For example, some genes were downregulated (less expressed) when exposed to oestrogens, but in the presence of the pathogen they were upregulated (more expressed), while others remained downregulated.