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Review
. 2024 Sep 17;134(18):e180076.
doi: 10.1172/JCI180076.

Mechanisms underlying sex differences in autoimmunity

DeLisa Fairweather  1   2   3 , Danielle J Beetler  1   2 , Elizabeth J McCabe  1 , Scott M Lieberman  4
Affiliations
Review

Mechanisms underlying sex differences in autoimmunity

DeLisa Fairweather et al. J Clin Invest. .

Abstract

Autoimmune diseases are a leading cause of disability worldwide. Most autoimmune diseases occur more often in women than men, with rheumatic autoimmune diseases being among those most highly expressed in women. Several key factors, identified mainly in animal models and cell culture experiments, are important in increasing autoimmune disease in females. These include sex hormones, immune genes including those found on the X chromosome, sex-specific epigenetic effects on genes by estrogen and the environment, and regulation of genes and messenger RNA by microRNAs found in extracellular vesicles. Evidence is also emerging that viruses as well as drugs or toxins that damage mitochondria may contribute to increased levels of autoantibodies against nuclear and mitochondrial antigens, which are common in many autoimmune diseases. The purpose of this Review is to summarize our current understanding of mechanisms that may determine sex differences in autoimmune disease.

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Conflict of interest statement

Conflict of interest: DF receives funding and serves as a consultant for Cytokinetics.

Figures

Figure 1
Figure 1. Mechanisms contributing to the development of autoimmune disease.
A combination of genetic predisposition (Genes) and environmental factors (Environment) contributes to the development of autoimmune diseases. Genetic factors (red) include genes on the X chromosome that are not inactivated, such as FOXP3, which may lead to dysregulation of Tregs in females. HLA type is another example of a genetic factor that can increase susceptibility to developing an autoimmune disease. Environmental factors (blue) include chemicals and infections. Some genetic factors can be influenced by environmental factors (purple); for example, the autoimmune regulator gene (AIRE) can be decreased by viral infections or endocrine-disrupting chemicals may alter sex hormone signaling.
Figure 2
Figure 2. Sex differences in autoimmune disease.
Most autoimmune diseases occur more often in women than men. Sex ratios comparing women with men for a number of autoimmune diseases are illustrated, including systemic lupus erythematosus (8.8:1) (12), Takayasu arteritis (6.8:1) (13), primary Sjögren’s disease (6.1:1) (15), thyroiditis (5.8:1) (16), systemic sclerosis (4:1) (167), Graves’ disease (3.9:1) (16), rheumatoid arthritis (2.1:1) (18), multiple sclerosis (1.7:1) (168), celiac disease (1.4:1) (169), type 1 diabetes (1:1.8) (170), Crohn’s disease (1:2) (171), ankylosing spondylitis (1:2.6) (172), myocarditis (1:3.5) (21), and primary biliary cholangitis (1:3.9) (20).
Figure 3
Figure 3. Potential mechanisms increasing the risk for autoimmune disease in women.
Key factors that may increase the risk of developing autoimmune disease in females include genes on the X chromosome, sex hormones such as 17β-estradiol (E2), endocrine disruptors such as bisphenol A (BPA), and infections such as viruses. AIRE, autoimmune regulator gene; EVs, extracellular vesicles; FoxP3, forkhead box P3; mIR, microRNA; mito, mitochondria; XIST, X-inactive specific transcript.
See this image and copyright information in PMC

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