Sex and autoimmunity: proposed mechanisms of disease onset and severity

ABSTRACT

Introduction: Chronic autoimmune diseases affect 5–10% of the population worldwide and are largely predominant in women. Sex hormone changes have been widely investigated based on changes in the clinical phenotypes observed during pregnancy and menopause.

It is known that females with autoimmune diseases manifest a higher rate of circulating leukocytes with a single X chromosome, and there have been several reports on the role of X chromosome gene dosage through inactivation or duplication in autoimmunity. However, it is also important not to overlook men with autoimmune diseases, who might manifest a more frequent loss of the Y chromosome in circulating leukocytes.

Areas covered: In the present review, we will discuss the current evidence supporting the mechanisms of female predominance in rheumatic diseases, by discussing the role of reproductive history, sex hormones and abnormalities related to them, clinical differences between male and female patients, and epigenetic changes that have been evaluated through twin studies on genetic and environmental changes in rheumatic patients.

Expert opinion: The influence of sex hormones and chromosomes on the function of the innate and adaptive immune systems needs to be clarified, to better understand the risk of autoimmune diseases, early diagnostic tools, and therapeutic response.

KEYWORDS:

• Gender medicine
• sex chromosome
• estrogen
• rheumatic diseases
• twins
• epigenetics

Article highlights

• The sex ratio in autoimmune diseases may reflect both obvious (sex chromosome changes, X chromosome methylation, sex hormones) and less intuitive (physician awareness, economics) determinants.

• Immunological mechanisms of both innate and acquired immunity need to be clarified and studied to understand how they are influenced by sex.

• Therapeutic targets may act differently in men and women, and sex is likely the most overlooked factor in personalized and precision medicine.

• It is crucial to discuss fertility, pregnancy timing, and contraception with patients.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.