Sex & Gender The Role of Sex in Autoimmune Diseases

The Role of Sex in Autoimmune Diseases

By Miloni Shah on behalf of the SAEM Sex and Gender in Emergency Medicine Interest Group

Autoimmune (AI) disease is a result of the inability of the body’s immune system to protect itself from selfantigens. Among the multiple factors that contribute, such as environmental triggers and human leukocyte antigens, the role of biological sex is crucial in the development of autoimmunity.

Females have a more robust immune system than males in both humoral and cellular immunity. Additionally, sex hormones influence the propensity of AI conditions, with estrogen and progesterone stimulating immune effects and androgens largely suppressing them through autoimmune regulator (AIRE) expression that prevents autoreactive T cells. For this reason, females are more at risk of developing AI conditions, and currently, 80% of individuals with AI diseases are female. Sex chromosomes also play a large role in the sex bias of autoimmunity, as the X chromosome contains many immune-related genes, including CD40 ligand, tyrosine-protein kinase BTK,

“...it is vital to understand the current therapies used to treat both acute and chronic manifestations of AI conditions and whether these treatments have been studied based on sex differences.” and chemokine CXCR3, among others. Lastly, immunity in the gut microbiota is influenced in a sex-specific manner, as seen by many animal models for type 1 diabetes, where male microbiota seems to play a protective role.

Three AI conditions where sex differences are prominent include systemic lupus erythematosus (SLE), Sjogren syndrome, and rheumatoid arthritis. A combination of hormonal and genetic factors contributes to the varying disease incidence, severity, and response to treatment.

Sjogren’s syndrome consists of the AI destruction of exocrine glands, including lacrimal and salivary. It has the highest female-to-male ratio for the incidence of all AI diseases (16:1). Many females are at the highest risk during their childbearing years, as an increase in estrogen and prolactin levels are linked to disease incidence. The highest disease prevalence is seen in ages 40-60. Estrogen and prolactin both increase the anti-Ro and anti-La autoantibodies. Studies have also shown an increase in CD40L expression in the lip biopsies of patients with Sjogren syndrome.

SLE is a multifactorial inflammatory condition targeting multiple organ systems through auto-antibody complexes that cause tissue injury. Pre-menopausal women have the highest rates compared to men (7:1). Like Sjogren’s, lupus is also seen as a “woman’s disease” for this reason. The ratio of female to male is reduced in pre-adolescents and post-menopausal women when the difference in estrogen levels is reduced. E2 influences immune function and production is accelerated through the estrogen receptor ERα, which converts androgens to ER. Moreover, estrogen activates the CD40L on CD4+ cells on the inactivated X chromosome, which increases the interaction between B and T cells. These hormonal and genetic factors contribute to the predominance of Raynaud’s phenomenon, malar rash, and arthritis in females. Conversely, SLE in males presents later in life, and genetic factors play a significant role in disease formation, as many males have concomitant Klinefelter syndrome. There is not as much evidence to suggest the role of hormonal regulation and activation in males.

While SLE incidences are highest in pre-menopausal women, cases of rheumatoid arthritis peak in middle-aged women (3:1 prevalence over males). In contrast to SLE, there is not a clear relationship between increased E2 and progesterone and the development of RA. Studies do not show an increased incidence of RA with hormonal contraception or hormone replacement therapy, and pregnancy seems to decrease the incidence risk. Research suggests that androgens have a protective role in the development of the severity of RA. Moreover, a polymorphism in the CYB5A gene for androgen synthesis in females was associated with an increased risk of RA. Males usually have less severe symptoms of RA and respond better to androgen replacement therapy as an adjuvant treatment than females.

These three AI conditions encompass a few examples of a strong female bias within autoimmunity due to genetics, hormones, and environmental factors. For this reason, it is essential to continue to further research sex-specific therapies that can reduce the complications of these conditions. Furthermore, it is vital to understand the severity of acute manifestations of AI conditions that often present in the ED, including pericarditis and acute glomerulonephritis in SLE, atlantoaxial dislocation and vasculitis in RA, and interstitial pneumonia in Sjogren’s syndrome. In the future, it is vital to understand the current therapies used to treat both acute and chronic manifestations of AI conditions and whether these treatments have been studied based on sex differences.

ABOUT THE AUTHOR

Miloni Shah is a fourth-year medical student at Wayne State University School of Medicine applying for internal medicine residency and has an interest in sex and genderbased medicine within rheumatology. @milshah27