Sex: it is one of the most patent differentiating features of humans, yet until recently it has usually been an overlooked or even ignored factor in the scientific and clinical study of gender-neutral diseases. However, thanks to new research maleness and femaleness, along with all of the accompanying anatomical, physiological, and genetic differences, are taking on a new importance, one which may change the way we approach the treatment of infectious diseases, such as influenza and HIV/AIDS.
Differences between the sexes are observed not only in the prevalence of diseases but also in the associated symptoms, immune system responses, and responses to vaccination. For example, females mount a larger and more severe immune system attack against the flu than males. Twice as many men than women are diagnosed with late Lyme arthritis despite equal infection rates with Lyme disease. Females have been shown to acquire HIV at a younger age and progress faster to AIDS than males. Because of the clear relationship between sex and disease, understanding what causes one sex to respond differently to a particular disease from the other would allow therapeutic treatments to be specialized accordingly.
One disease in particular that suggests the potential for sex-based treatments is genital herpes. “There is a huge gender bias [in virally transmitted sexual infections],” says Dr. Akiko Iwasaki, Associate Professor of Immunobiology and of Molecular, Cellular, and Developmental Biology at the Yale School of Medicine. Iwasaki has embraced the sex-based biology perspective in her research as she seeks to better understand how a host immune system detects a virus and initiates a response, in particular to herpes simplex virus type 2, or HSV-2, which causes genital herpes.
Though HSV-2 can infect both men and women, more women carry the virus and suffer symptoms of recurrent genital sores, while the disease is less common and more likely to be asymptomatic in men, Iwasaki explains. One reason for this discrepancy is anatomical: the mucosal vagina, with its thin epithelial tissue, is highly susceptible to HSV-2, whereas the penis, particularly when circumcised, has much less of this tissue and therefore has less risk of infection.
Hormonal changes, too, may play a role in women’s susceptibility to genital herpes, though Iwasaki cautions that there is no clear clinical evidence for this in humans yet. In her studies of mice, however, Iwasaki has discovered a clear difference in the immune system in different stages of the estrous cycle, the primary reproductive cycle of most female mammals. Notably, mice are susceptible to herpes only during the phase in which progesterone levels are high. During this stage, when progesterone dramatically thins the vaginal epithelium, many more antigen-presenting cells are present in an HSV-2-infected mouse. This thinning of the epithelium in response to progesterone is not seen to the same extent in humans, though as Iwasaki says, the effect of sex hormones on the immune system remains an important question that has not been fully addressed.
Taking Physiology and Genetics into Account
Nevertheless, Iwasaki explains it is well established that in humans, females generally mount a more robust immune response to infection than males, including responses to many autoimmune diseases. Studies show that women have higher basal levels of immunoglobulins, or antibodies, than men. In response to infection, men demonstrate lower CD3+ and CD4+ T cell counts and smaller responses by type 1 T helper cells ; these three cell types are all lymphocytes, white blood cells important for the function of the cell-mediated immune system. Differences between males and females have also been demonstrated in the production of interferons and interleukins, two types of cytokines, or signaling molecules, which are responsible for promoting inflammation. A “cytokine storm” is initiated by the host in response to infection by such highly pathogenic strains of the influenza virus as avian H5N1.
But where do these differences come from? It is clear that there is more to maleness and femaleness than mere anatomy. In fact, sex-based biologists contend that “every cell has a sex,” and that it is important to take sexual genotype — specifically chromosomal differences — into account when investigating a disease. Females inherit two X chromosomes, one from each parent, whereas males inherit an X chromosome from their mothers and a Y chromosome from their fathers. In order to have comparable expression of X-linked genes, one X chromosome in each cell is randomly inactivated in females, resulting in a “mosaic expression” of maternal and paternal copies. As a result, X-linked mutations will be expressed in approximately half of a female’s cells but in all of a male’s cells. Because several immunological protein genes are found on the X chromosome, this results in a greater rate of immunodeficiencies in males. Genomic imprinting, which causes only a particular copy of a gene, either maternal or paternal, to be expressed, may also influence the relationship between sex and disease.
Though not yet shown to have a role in the sex differences observed with HSV-2, sex steroids, namely testosterone, estrogen, and progesterone, may also play a role in influencing differences in immune system responses in males and females. Their impact is especially evident during pregnancy, when a woman’s immune system adapts to prevent rejection of the fetus, depending more on anti-inflammatory type 2 T helper cells and less on inflammatory type 1 T helper cells. Consequently, this change, mediated by hormones such as progesterone, also decreases the immune system’s antiviral response. Combined with increased stress on the heart and lungs caused by carrying a fetus, hormonal changes may help explain the increased rate of severe influenza cases seen in pregnant women.
The elevated immune response seen in non-pregnant women may not be fully beneficial either. While helping to combat viral infections, the magnitude of the inflammatory response may itself be harmful, potentially resulting in tissue damage or death. Female mice have been shown to respond to influenza virus with an inflammatory response 100 times greater than that of male mice. Possible consequences may include excessive production of proteins and movement of immune cells into the lungs.
Consequences for Vaccination
This increased antibody response may also explain the higher incidence of side effects suffered by women in response to the influenza vaccine. Research has shown that women produce the same number of antibodies in response to a half dose of the trivalent inactivated virus (TIV) seasonal flu vaccine as men do to a full dose. Similar responses have likewise been observed with vaccines for yellow fever virus; measles, mumps, and rubella; hepatitis A and B viruses; and herpes simplex virus.
It is not yet known whether these vaccines work differently in males and females. Adult and elderly women have been shown to have higher hemagglutination inhibition (HAI) titers — a measure of virus concentration based on the clumping of red blood cells in the presence of antibodies — following influenza vaccination than men. Because an HAI is a strong correlate of protection against the flu, higher HAIs may indicate greater efficiency of the vaccine in females.
The Need for a New Approach
Despite the evidence that not all infectious diseases affect men and women equally, recognition of these differences is not apparent in the body of scientific research. In fact, published papers often lump together data from male and female subjects. In order to avoid the complexities that a female’s hormonal cycles introduce, researchers sometimes go so far as to use only male mice in their studies. Yet, as Iwasaki contends, “there’s a huge difference in the type of disease that a virus causes, in susceptibilities, in child bearing … we cannot possibly use males for all these models. We cannot start treating women with drugs tested in men. People should be thinking about gender differences.”
In other words, an acknowledgement of what studies have uncovered — that males and females do not suffer from infectious diseases equally; that immunological responses are influenced by sex chromosomes, and possibly, by sex hormones; and that vaccinations may work differently depending on one’s sex — may dramatically improve not only the treatment of infectious diseases, but also the way in which research itself is conducted.