Sex and Immunity

If you were to pit a man’s immune system against a woman’s, who would get the edge?  The answer – most likely the woman.  Women’s immune systems are generally stronger and respond better to pathogenic stimuli, including viral, bacterial, fungal, and parasitic diseases, than men’s.  For example, studies show that in surgical patients with severe sepsis (defined as systemic inflammatory response + infection + organ dysfunction), women have a significantly higher survival rate (74%) compared to men (31%).  Additionally, incidence of severe sepsis is significantly lower in female ICU patients than male in nearly all age groups.  Ironically, the same mechanisms that enable women with this immunological survival advantage also increase their susceptibility to autoimmune disorders, such as systemic lupus, multiple sclerosis, and rheumatoid arthritis. 

Sex-based differences in disease and the immune system’s response are attributable to several mechanisms, including anatomy, differential expression of steroid hormones, X-chromosome inactivation, and life and gender-specific experiences.  For instance, estrogens have multiple roles influencing immunocompetence.  Estrogen receptors are expressed on T cells, B cells, dendriditc cells, macrophages, neutrophils, and natural killer cells.  The estrogen ligand/receptor complex on these cells gets translocated to the nucleus where is regulates transcription.  Estrogens have anti-inflammatory effects on monocytes and neutrophils, they increase numbers of Treg cells during the follicular phase of the menstrual cycle, and they affect expression of some chemokine receptors (chemokine receptor 5 is upregulated by estrogens, an interesting connection to our discussion about the mechanism of infection of HIV).  Additionally, estrogens have several affects of B cells, including enhancing polyclonal activation, which leads to higher IgM and IgG serum levels. 

A significant number of genes involved in immunity are located on the X chromosome.    Because of this, women can also gain immunological advantages from X-inactivation.  X-inactivation is the silencing of one X chromosome in females, resulting in female mosaicism – every cell in a female body has either one or the other X chromosome inactivated.  This actually allows females to cope with recessive mutations or other vulnerabilities introduced by one of their X chromosomes.  However, males have only one X chromosome and no saving grace if they end up with an undesirable allele. 

A group from Ghent University in Belgium recently hypothesized that this same phenomenon in X-linked microRNAs involved in immunity could also lead to sex-specific immune responses.  MicroRNAs (miRNA) are important negative regulators of protein expression and function and act by targeting and degrading mRNA transcripts.  There are a number of known miRNAs on the X chromosome directly involved in immune functions; however, there are no miRNAs on the Y chromosome.  MiRNAs are upregulated during chronic inflammation and, interestingly, the deletion of Dicer (the key enzyme for miRNA processing) leads to reduced T cell numbers and a complete arrest in B cell maturation.  Could these X-linked miRNAs also contribute to the immunological advantage of females and/or their predisposition to autoimmune diseases? 

Just some food for thought.  Men vs. Women.  A battle of immune systems.   

Fish EN.  2008.  The X-files in immunity: sex-based differences predispose immune responses.  Nature Reviews Immunology 8: 737-744.

Pinheiro I, Dejager L, Libert C.  2011.  X-xhromosome-located microRNAs in immunity: Might they explain male-female differences?  Bioessays.