Biological sex is a significant variable in how the immune system functions. Males and females exhibit distinct immunological responses to internal and external threats, which contributes to different patterns in disease susceptibility and severity between the sexes. These inherent differences are rooted in hormones and genetics.
Hormonal Influences on Immunity
The hormonal environments in males and females play a large part in shaping their immune responses. Sex hormones, primarily estrogens in females and androgens like testosterone in males, interact directly with immune cells. These hormones influence the development, lifespan, and function of these cells, which explains why many immune differences become most apparent after puberty.
Estrogens, particularly estradiol, are immunoenhancing, promoting more vigorous responses from various immune cells. For example, estrogens can stimulate antibody production by B cells and influence the activity of T cells, which are part of the adaptive immune system. This heightened response is advantageous in fighting off infections.
In contrast, testosterone often has an immunomodulatory or suppressive effect. Higher levels of testosterone are linked with a tempered immune response, reducing the production of certain inflammatory signaling molecules. This balance between estrogens and androgens creates a more reactive immune system in females and a more regulated one in males.
The Genetic Component
Beyond hormones, genetics determined by sex chromosomes explain immune disparities. Females have two X chromosomes (XX), while males have one X and one Y (XY). The X chromosome contains a large number of genes related to immune function, far more than the Y chromosome, giving females a greater reservoir of immune-related genetic instructions.
This “double dose” of X-linked immune genes, like those for signaling protein Toll-like receptor 7 (TLR7), can lead to more robust immune reactions. While a process called X-chromosome inactivation (XCI) silences one X chromosome in each female cell, the process is not always complete. Some immune genes escape this silencing, resulting in higher expression levels in female immune cells compared to male cells.
This incomplete inactivation creates a mosaic of gene expression in females, as different cells may express genes from either the maternal or paternal X chromosome. This variability contributes to a more diverse immune arsenal. For example, genes on the X chromosome include FOXP3, which is for regulatory T cells, and CD40LG, for T-cell activation.
Impact on Autoimmune Conditions
The features of the female immune system that provide strong defense against pathogens can also be a liability. This heightened reactivity makes females more susceptible to autoimmune diseases, where the immune system mistakenly attacks the body’s own tissues. Approximately 80 percent of individuals diagnosed with an autoimmune condition are female.
Examples of this disparity include systemic lupus erythematosus (SLE) and Sjögren’s syndrome, where women are affected at a rate as high as nine to one compared to men. Other conditions like rheumatoid arthritis and multiple sclerosis also show a significant female bias.
The enhanced ability to produce antibodies and mount strong T-cell responses can lead to the creation of autoantibodies that target self-antigens. This process turns a protective advantage into a mechanism of self-damage. In effect, the immune system loses its ability to distinguish between foreign invaders and the body itself.
Responses to Infections and Vaccines
Sex-based immune differences are evident when responding to infections. Females often mount faster and more powerful immune responses to pathogens, including the viruses that cause influenza and COVID-19. This can result in more rapid clearance of the infection and less severe disease.
This robust response extends to vaccinations. Following vaccination for diseases like influenza, hepatitis, and measles, females develop higher antibody levels than males. These stronger responses suggest a more effective and potentially longer-lasting immunity from the vaccine.
However, this powerful response has downsides. The same vigorous reaction can lead to more pronounced side effects from vaccines, such as fever, aches, and local inflammation. During an active infection, a highly inflammatory response can sometimes contribute to greater tissue damage, even while being protective.
Changes Across the Lifespan
Immunological differences between males and females evolve across the lifespan. These distinctions are minimal before puberty when sex hormone production is low. They become most pronounced during the reproductive years when hormonal differences are at their peak.
During pregnancy, the female immune system undergoes complex modulation to tolerate the fetus. After menopause, as estrogen levels decline, the female immune advantage wanes, and some immunological differences between the sexes become less distinct.
Advancing age brings changes to the immune system in both sexes, a process known as immunosenescence. After age 65, the immune systems of men and women can age differently. Women often retain more robust adaptive immune function for a longer period.