Biological processes are susceptible to outside influence
Biological processes in humans are vulnerable to influence from a variety of different factors. It is well documented that genetic, environmental, and socio-economic factors can have different positive or negative impacts on any given process. Immunity and specifically the process of inflammation is notoriously fickle.
Within the field of Immunology, several of these factors are well documented and understood except for sex. While sex is well studied to have an impact on different areas of the immune response, Immunology is reportedly the lowest of 10 biological disciplines for reporting sex-based differences in both animals and humans with fewer than 10% of articles discussing data by sex.
Sex within this article is referring to the genetic combination of chromosomes wherein XX denotes female and XY denotes male, and the usual sex-linked variation observed is a result of these chromosome combinations. This is separate from gender, which includes behaviors relating to human culture that can also affect the immune response with respect to access to healthcare and exposure to pathogens, among other variables.
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Why is the immune response different?
Generally, females are observed to have a stronger innate and adaptive immune response than males, which is thought to contribute to the disparity in autoimmune conditions of which 80% of patients are women.
Alternatively, males show a twofold higher risk of death from cancer, and responses to seasonal influenza vaccines are consistently twice as strong in females than males. The apparent pattern observed is that females tend to experience chronic inflammatory conditions with lower mortality whereas males experience more susceptibility to viral infections and acute and severe inflammatory conditions.
This difference is seen in many species, the theory posited is that male immune responses are weaker as a tradeoff for selection for positive traits prioritizing reproductive success.
An example of this is seen within some species of birds where females exhibit higher antibody and cell-mediated immune responses than males, which is particularly pronounced during mating seasons when male testosterone levels are at their highest.
Similarly, female reproduction involves trans-generational immune priming, wherein there is a non-genetic transfer of passive immunity from mother to offspring. It is hypothesized that a stronger immune response in females is a preparatory measure for this process.
Sex-linked hormone levels can strongly influence immune cells
Generally, estrogen is immunostimulatory while testosterone is immunosuppressive. Estrogen has been shown to regulate the immune response by modulating B-cell function and leading to a T-helper type 2 (Th2) response. Th2 response activation is implicated in symptom exacerbation in some cases of systemic lupus erythematosus, conversely in females with other autoimmune conditions, such as multiple sclerosis, symptoms show improvement with higher estrogen levels (such as during pregnancy) because of Th2 activation.
Immune regulation by androgens such as testosterone augment the T-helper type 1 (Th1) response, activate CD8 cells, and increase production of anti-inflammatory interleukin-10 (IL-10) production, while down-regulating natural killer (NK) cell response and tumor necrosis factor-alpha (TNFα).
Sex-specific responses were observed using a humanized mouse model of inflammation where exogenous estradiol and castration led to an increase in autoimmunity. This was achieved by increasing major histocompatibility complex II expression and modulating B-cell function.
B-cells particularly are therapeutic targets in a variety of autoimmune diseases; depletion of B-cells in arthritic female mice showed higher efficacy than in males this is like observations in arthritic patients treated with rituximab where females achieved higher remission rates than males.
The X chromosome is strongly involved in mediating the immune response
Genetic responses such as X-chromosome inactivation (XCI) are vital mechanisms in females due to the dosage-sensitive nature of many X-linked genes. XCI is the process causing one X chromosome to be silenced to equalize dosage between XX and XY cells. This is generally a protective mechanism that gives females a protective advantage over males.
Where males are haploid for aberrant X-linked genes, heterozygous females have cell populations that express both the wild-type and mutant genes, this is a well-recognized compensatory mechanism wherein the penetrance of the mutant allele is nullified or lessened. Dysregulation results in severe developmental or health-related consequences.
In chromosomal disorders such as Klinefelter syndrome (XXY) or Turner syndrome (X0, one X-chromosome), XCI is observed and as a result, causes hormonal and immune imbalances in patients. Immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) is a rare inflammatory disease that affects males. In IPEX the gene that encodes FOXP3 is mutated, and thus regulatory T-cells do not develop normally, in females the healthy X chromosome encodes enough healthy FOXP3 protein to compensate and maintain a healthy level of regulatory T-cells.
COVID-19 data may show a sex-linked disparity
Throughout the coronavirus disease 2019 (COVID-19) pandemic, a large amount of data was generated allowing insights into a variety of different areas in healthcare and disease research.
One factor that has been increasingly reported is the large sex disparity in infected patient outcomes, with males making up around 60% of all COVID-19 related deaths globally. Consistently, males experience greater susceptibility to infections such as hepatitis C and HIV and a higher viral load than females, but females with COVID-19 have a higher viral load and better outcome.
One study observed a significantly more robust T-cell activation in females during SARS-CoV-2 infection which is sustained in old age. Furthermore, in male patients poor T-cell response negatively correlated with patients’ age and was associated with worse disease outcomes, this was not seen in female patients.
Another study proposes androgen-mediated sensitivity to SARS-CoV-2 where androgens receptors are transcription promoters for transmembrane protease serine 2 (TMPRSS2) which the SARS-CoV-2 spike proteins rely on for entry to host cells.
Sex Differences Found in Immune Responses to Coronavirus
Should immunology have a stronger consideration for sex-linked differences?
Sex is a highly influential factor that is considered in most immunological disorders due to its strong influence on immune homeostasis and function. Evidence indicates that immunology may need a stronger grasp on the sex-based disparity in disease outcomes as evidenced by the COVID-19 pandemic.
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