Autoimmune diseases encompass a diverse group of disorders in which the immune system mistakenly attacks the body’s own tissues, leading to chronic inflammation and tissue damage.1 These conditions affect approximately 5–8% of the global population, with a striking gender disparity: women account for about 78–80% of those affected. Diseases such as lupus, rheumatoid arthritis, and Hashimoto’s thyroiditis often peak in the fifth decade of life, particularly in the case of rheumatoid arthritis.2 However, many autoimmune diseases begin during the reproductive years, typically between ages 15 and 44, posing significant health challenges during a critical period of personal and professional development.3

While the mortality rate for systemic autoimmune diseases is relatively low, it remains significant, with approximately 14.6 deaths per million attributed to these conditions. Beyond mortality, autoimmune diseases can cause substantial morbidity, affecting quality of life, productivity, and mental health. Despite their prevalence and severity, the exact causes of autoimmune diseases remain unclear. Current research suggests a complex interplay of genetic predisposition, hormonal influences, environmental exposures, and immune system dysregulation.4

Engraved in Our Biology

Genetic susceptibility plays a pivotal role in autoimmune diseases. Specific genes, such as PTPN22 and CD40, are associated with increased risk for conditions like rheumatoid arthritis and lupus. Autoimmune diseases also exhibit chromosomal influences, particularly linked to the X chromosome, which carries numerous immune-related genes.5,6

To balance gene expression, one X chromosome in females undergoes X-chromosome inactivation (XCI), but some genes escape this process, leading to higher expression levels that may contribute to autoimmunity. In contrast, Y-linked genes are largely pseudogenized or deleted, creating unequal gene content between males and females. Interestingly, X-inactivation mechanisms differ across species, evolving alongside placental development. In humans, about 30% of genes on the inactive X escape silencing, with variability between individuals, tissues, and cells—potentially contributing to differences in disease phenotypes.7,8

Beyond genetics, evolutionary theories offer additional insights. The Pregnancy Compensation Hypothesis proposes that sex-specific immune modulation evolved to counteract the immunological challenges posed by an invasive placenta. This adaptation, while beneficial for reproduction, may inadvertently increase autoimmune disease risk in women. Moreover, modern industrialized environments, with their altered diets, lower pathogen exposure, and increased stress, may amplify these sex-based disparities in disease prevalence.9

Autoimmune Diseases Flare with Hormonal Shifts

Autoimmune diseases frequently flare during significant hormonal changes, such as menstruation, pregnancy, or menopause. Estrogen, in particular, plays a key role in modulating immune responses, with fluctuations potentially exacerbating symptoms. Pregnancy and breastfeeding can have protective effects, whereas irregular menstrual cycles and early menopause may increase the risk of autoimmunity. These hormonal influences highlight the need to better understand fluctuations in hormone levels to effectively manage disease flares.10

Emerging Theories

Recent studies have shed light on the roles of gut microbiota, chronic stress, and environmental toxins in the pathogenesis of autoimmune diseases. The gut microbiome, a vast community of microorganisms, plays a crucial role in immune system development and regulation. Dysbiosis, or microbial imbalance, has been linked to several autoimmune conditions.11

Chronic stress is another key factor that can alter immune function, potentially triggering or exacerbating autoimmune responses. Environmental exposures, such as certain chemicals or infections, may also act as catalysts in individuals with a genetic predisposition to autoimmunity. For instance, infections like COVID-19 have been associated with the onset of autoimmune conditions such as type 1 diabetes.12

Like Many Women’s Diseases, Still Overlooked

Despite the significantly higher prevalence of autoimmune diseases among women, much of the research in this field has historically focused on male subjects. This disparity has contributed to a limited understanding of why women are disproportionately affected and how best to develop effective treatments. Addressing this research gap is crucial for advancing gender-specific approaches to autoimmune disease management.13


References:

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  2. Elena Ortona. (2016). Sex-based differences in autoimmune diseases

  3. Capital women’s care. (2021). Women and Autoimmune Diseases.

  4. Mitratza M, Klijs B, Hak AE, Kardaun JWPF, Kunst AE. Systemic autoimmune disease as a cause of death: mortality burden and comorbidities. Rheumatology (Oxford). 2021 Mar 2;60(3):1321-1330. doi: 10.1093/rheumatology/keaa537. PMID: 32944773; PMCID: PMC7937014.

  5. Gregersen PK, Olsson LM. Recent advances in the genetics of autoimmune disease. Annu Rev Immunol. 2009;27:363-91. doi: 10.1146/annurev.immunol.021908.132653. PMID: 19302045; PMCID: PMC2992886.

  6. Gregersen PK, Olsson LM. Recent advances in the genetics of autoimmune disease. Annu Rev Immunol. 2009;27:363-91. doi: 10.1146/annurev.immunol.021908.132653. PMID: 19302045; PMCID: PMC2992886.

  7. Natri, H., Garcia, A. R., Buetow, K. H., Trumble, B. C., & Wilson, M. A. (2019). The Pregnancy Pickle: Evolved Immune Compensation Due to Pregnancy Underlies Sex Differences in Human Diseases. Trends in genetics : TIG, 35(7), 478–488. https://doi.org/10.1016/j.tig.2019.04.008

  8. Tukiainen T et al. (2017) Landscape of X chromosome inactivation across human tissues. Nature 550, 244–248

  9. Khramtsova EA et al. (2019) The role of sex in the genomics of human complex traits. Nat. Rev. Genet 20, 173–190

  10. Desai MK, Brinton RD. Autoimmune Disease in Women: Endocrine Transition and Risk Across the Lifespan. Front Endocrinol (Lausanne). 2019 Apr 29;10:265. doi: 10.3389/fendo.2019.00265. PMID: 31110493; PMCID: PMC6501433.

  11. Wang X, Yuan W, Yang C, Wang Z, Zhang J, Xu D, Sun X, Sun W. Emerging role of gut microbiota in autoimmune diseases. Front Immunol. 2024 May 3;15:1365554. doi: 10.3389/fimmu.2024.1365554. PMID: 38765017; PMCID: PMC11099291.

  12. Hileman, C. O., Malakooti, S. K., Patil, N., Singer, N. G., & McComsey, G. A. (2024). New-onset autoimmune disease after COVID-19. Frontiers in immunology, 15, 1337406. https://doi.org/10.3389/fimmu.2024.1337406

  13. (2024). Stanford Medicine-led study shows why women are at greater risk of autoimmune disease