A friend of mine — a thirty-six-year-old woman who ran marathons, ate meticulously, and had never had a serious illness — called me one evening in 2019 to tell me she had been diagnosed with Hashimoto's thyroiditis. Her immune system, the most sophisticated defense mechanism in the animal kingdom, had decided that her thyroid gland was a foreign invader and had begun methodically destroying it. She would need thyroid hormone replacement for the rest of her life. She would likely develop additional autoimmune conditions over time, because autoimmune diseases cluster — having one increases the probability of developing others. And no one could tell her why it had happened.
"The rheumatologist told me my immune system is confused," she said. "That was the clinical explanation. Confused."
She was not alone. Autoimmune diseases — conditions in which the immune system attacks the body's own tissues — collectively affect an estimated 24-50 million Americans, depending on which conditions are included and which prevalence estimates are used (AARDA, 2023). They are the third most common category of disease in the United States, after cardiovascular disease and cancer. They disproportionately affect women, who account for approximately 78% of autoimmune disease cases. And their incidence is increasing — a trend that cannot be explained by improved diagnosis alone and that has generated intense scientific inquiry into the environmental, dietary, microbial, and chemical factors that may be driving immune dysregulation on a population scale.
What autoimmune disease actually is
The immune system's fundamental task is distinguishing self from non-self — identifying and eliminating pathogens (bacteria, viruses, parasites, fungi) while leaving the body's own tissues unharmed. This distinction is maintained through an elaborate system of immune tolerance that develops during fetal life and infancy: immune cells that strongly react to self-antigens are normally eliminated or suppressed through a process called central and peripheral tolerance (Rosenblum et al., 2015).
Autoimmune disease occurs when this tolerance breaks down — when the immune system incorrectly identifies a component of the body as foreign and mounts an immune response against it. The specific tissue targeted determines the specific disease: if the immune system attacks the myelin sheath of nerve fibers, the result is multiple sclerosis. If it attacks the insulin-producing beta cells of the pancreas, the result is Type 1 diabetes. If it attacks the joints, the result is rheumatoid arthritis. If it attacks the thyroid, the result is Hashimoto's thyroiditis or Graves' disease. If it attacks the skin, the result may be psoriasis, vitiligo, or dermatomyositis.
Over 100 distinct autoimmune diseases have been identified, affecting virtually every organ system. Some are common (Hashimoto's thyroiditis affects approximately 14 million Americans). Others are rare (autoimmune hepatitis affects approximately 100,000). Collectively, they represent a failure mode so diverse and so widespread that it suggests something fundamental about the relationship between humans and their immune systems has changed.
The rising incidence
The evidence that autoimmune diseases are genuinely increasing — not merely being detected more frequently — comes from multiple lines of investigation.
A systematic review published in Arthritis & Rheumatology analyzed incidence data for 19 autoimmune diseases across 34 countries and found that the incidence of 17 of 19 conditions increased significantly between 1970 and 2020, with a mean annual increase of approximately 3-9% depending on the condition (Conrad et al., 2023). Type 1 diabetes incidence has increased by approximately 3-5% annually worldwide for the past four decades. Celiac disease prevalence has approximately doubled every 15-20 years in North America and Europe. Multiple sclerosis incidence has increased by approximately 2.5% annually.
These increases cannot be attributed solely to improved diagnostic sensitivity. While better testing has certainly contributed to increased detection — particularly for conditions like celiac disease, where serological screening has expanded dramatically — the magnitude and consistency of the increases across conditions, populations, and countries exceeds what diagnostic artifact alone can explain.
Something in the human environment is changing the way the immune system functions. The question is what.
The hygiene hypothesis and its evolution
The most influential framework for explaining the rise of autoimmune disease is the hygiene hypothesis — proposed by David Strachan in 1989 and subsequently refined by numerous researchers. In its original form, the hypothesis suggested that reduced childhood exposure to infectious agents, due to improved sanitation, vaccination, and antibiotic use, left the immune system inadequately calibrated, increasing susceptibility to both allergic and autoimmune conditions (Strachan, 1989).
The hypothesis has since evolved into the more nuanced "old friends" or "biodiversity" hypothesis, which proposes that it is not infection per se that is protective, but exposure to the diverse microbial ecosystem with which humans co-evolved over millions of years. This ecosystem — encompassing gut bacteria, helminths (parasitic worms), saprophytic mycobacteria, and environmental microorganisms — provided the immunological stimulation necessary for proper immune development and regulation. As modern life has progressively reduced this microbial exposure — through urbanization, Western diets, antibiotic use, Cesarean delivery, formula feeding, and reduced contact with soil, animals, and natural environments — the immune system has lost the regulatory inputs it evolved to expect (Rook, 2013).
The evidence supporting this framework is substantial if indirect:
Geographic gradients. Autoimmune diseases are most prevalent in industrialized, urbanized, high-income countries and least prevalent in rural, agrarian, low-income countries — the inverse of the pattern for infectious diseases. Within countries, autoimmune disease prevalence is higher in urban areas than rural areas. The gradient correlates with indices of modernization and inversely correlates with microbial exposure (Bach, 2002).
Migration studies. When individuals migrate from low-prevalence to high-prevalence countries, their autoimmune disease risk increases within one to two generations — suggesting that environmental rather than genetic factors are primarily responsible for the prevalence differential. First-generation immigrants from South Asia, for example, have lower MS rates than native-born populations in the UK, but their UK-born children have rates comparable to the native population (Dean & Elian, 1997).
Microbiome differences. Individuals with autoimmune diseases consistently show altered gut microbiome composition compared to healthy controls — typically characterized by reduced microbial diversity and reduced abundance of regulatory species. Whether these changes are cause or consequence remains debated, but experimental evidence in animal models demonstrates that specific microbial alterations can directly promote or suppress autoimmune disease development (Vatanen et al., 2016).
The environmental triggers
Beyond the broad microbial hypothesis, specific environmental factors have been implicated in autoimmune disease onset:
Viral infections. The Epstein-Barr virus (EBV), which infects approximately 95% of adults worldwide, has been identified as a major risk factor for multiple sclerosis. A landmark study published in Science analyzed military health records for 10 million active-duty personnel over 20 years and found that EBV infection increased MS risk 32-fold — the strongest risk factor identified for any autoimmune disease (Bjornevik et al., 2022). The mechanism may involve molecular mimicry, in which viral proteins structurally resemble self-antigens, triggering cross-reactive immune responses that attack the body's own tissues.
Vitamin D insufficiency. Multiple autoimmune diseases show higher prevalence at higher latitudes and during winter months, suggesting that vitamin D — synthesized in the skin through UV exposure — plays a regulatory role in immune function. In vitro and animal studies have demonstrated that vitamin D promotes immune tolerance by enhancing regulatory T cell function and suppressing inflammatory cytokine production (Aranow, 2011). Whether vitamin D supplementation can prevent or modify autoimmune diseases in humans remains under active investigation.
Dietary factors. The Western diet — high in ultra-processed foods, refined sugars, saturated fats, and additives, and low in fiber, fermented foods, and micronutrient diversity — has been associated with increased autoimmune disease risk through multiple mechanisms: altered gut microbiome composition, increased intestinal permeability, enhanced inflammatory signaling, and impaired regulatory immune function (Manzel et al., 2014). Specific dietary components have been implicated: gluten (in genetically susceptible individuals), excessive sodium (which promotes Th17 inflammatory responses), and dietary emulsifiers (which disrupt the intestinal mucus barrier and promote bacterial translocation).
Chemical exposures. Endocrine-disrupting chemicals, organic solvents, heavy metals, and pesticides have all been associated with increased autoimmune disease risk in epidemiological studies. Silica exposure is a well-established risk factor for systemic lupus erythematosus and rheumatoid arthritis. Trichloroethylene (a common industrial solvent and groundwater contaminant) has been associated with autoimmune liver disease and systemic sclerosis. The immunotoxic effects of these chemicals may operate through disruption of immune cell signaling, alteration of epigenetic programming, or direct modification of self-antigens in ways that trigger autoimmune recognition (Parks et al., 2014).
The gender gap
The striking female predominance of autoimmune diseases — women account for 78% of cases overall, and over 90% for conditions like Sjögren's syndrome, systemic lupus erythematosus, and autoimmune thyroid disease — has driven extensive research into the role of sex hormones and sex chromosomes in immune regulation.
Estrogen is generally immunostimulatory — it enhances antibody production, promotes inflammatory cytokine secretion, and increases the activity of autoreactive B cells. This is likely an evolutionary adaptation: enhanced immune surveillance during reproductive years protects both the mother and developing offspring from infection. But this enhanced immune activity comes at a cost — a higher baseline probability of autoimmune recognition (Ngo et al., 2014).
The X chromosome hypothesis offers an additional explanation. The X chromosome contains a disproportionate number of immune-related genes. While one X chromosome is normally inactivated in female cells (to equalize gene dosage between XX females and XY males), X-inactivation is often incomplete — a phenomenon called "escape from X-inactivation." The result is that female cells may express higher levels of X-linked immune genes than male cells, potentially increasing the threshold of immune activity and the probability of autoimmune cross-reactivity (Syrett & Anguera, 2019).
Living with autoimmunity
The clinical experience of autoimmune disease is characterized by features that distinguish it from most other medical conditions and that create particular challenges for patients:
Diagnostic odyssey. The average time from symptom onset to autoimmune disease diagnosis is 4.6 years, during which patients see an average of four physicians (AARDA, 2021). Many patients report being dismissed, told their symptoms are psychosomatic, or diagnosed with anxiety or depression before receiving a correct diagnosis. The diagnostic delay reflects both the nonspecific early symptoms of many autoimmune conditions (fatigue, joint pain, brain fog, malaise) and the fragmented specialty structure of medicine, which distributes autoimmune conditions across rheumatology, endocrinology, gastroenterology, neurology, and dermatology without a unifying framework.
Chronicity and unpredictability. Autoimmune diseases are chronic and typically characterized by a relapsing-remitting course — periods of relative stability punctuated by flares of disease activity that are often unpredictable and may be triggered by infection, stress, hormonal changes, or environmental exposures. This unpredictability creates a particular form of psychological burden: the inability to plan, the constant vigilance for symptoms, and the erosion of trust in the body.
Treatment limitations. Current treatments for most autoimmune diseases are immunosuppressive — they dampen the immune system broadly rather than correcting the specific defect in immune tolerance. This approach reduces autoimmune damage but increases susceptibility to infection, disrupts normal immune surveillance, and often produces significant side effects. The holy grail of autoimmune therapy — restoring immune tolerance to specific self-antigens without broadly suppressing immune function — remains largely aspirational, though emerging approaches including tolerogenic dendritic cell therapy, regulatory T cell therapy, and antigen-specific immunotherapy show promise in early-phase clinical trials (Serra & Santamaria, 2019).
The rise of autoimmune disease is telling us something important about the relationship between human biology and the modern environment. Our immune systems evolved in a microbial, dietary, and chemical context that no longer exists. The result is a growing population of people whose most sophisticated defense system has turned against them — and a medical system that can manage the consequences but cannot yet reverse the cause.
References
- AARDA. (2021). Autoimmune Disease Diagnostic Delay. American Autoimmune Related Diseases Association.
- AARDA. (2023). Autoimmune Disease Statistics. American Autoimmune Related Diseases Association.
- Aranow, C. (2011). Vitamin D and the immune system. Journal of Investigative Medicine, 59(6), 881–886.
- Bach, J. F. (2002). The effect of infections on susceptibility to autoimmune and allergic diseases. NEJM, 347(12), 911–920.
- Bjornevik, K., et al. (2022). Longitudinal analysis reveals high prevalence of Epstein-Barr virus associated with multiple sclerosis. Science, 375(6578), 296–301.
- Conrad, N., et al. (2023). Incidence, prevalence, and co-occurrence of autoimmune disorders over time and by age, sex, and socioeconomic status. The Lancet, 401(10391), 1878–1890.
- Dean, G., & Elian, M. (1997). Age at immigration to England of Asian and Caribbean immigrants and the risk of developing MS. Journal of Neurology, Neurosurgery & Psychiatry, 63(5), 565–568.
- Manzel, A., et al. (2014). Role of 'Western diet' in inflammatory autoimmune diseases. Current Allergy and Asthma Reports, 14(1), 404.
- Ngo, S. T., et al. (2014). Gender differences in autoimmune disease. Frontiers in Neuroendocrinology, 35(3), 347–369.
- Parks, C. G., et al. (2014). Environmental exposures and autoimmunity. Arthritis & Rheumatology, 66(11), 2925–2938.
- Rook, G. A. (2013). Regulation of the immune system by biodiversity. PNAS, 110(46), 18360–18367.
- Rosenblum, M. D., et al. (2015). Mechanisms of human autoimmunity. Journal of Clinical Investigation, 125(6), 2228–2233.
- Serra, P., & Santamaria, P. (2019). Antigen-specific therapeutic approaches for autoimmunity. Nature Biotechnology, 37(3), 238–251.
- Strachan, D. P. (1989). Hay fever, hygiene, and household size. BMJ, 299(6710), 1259–1260.
- Syrett, C. M., & Anguera, M. C. (2019). When the balance is broken: X-linked gene dosage from two X chromosomes and female-biased autoimmunity. Journal of Leukocyte Biology, 106(4), 919–932.
- Vatanen, T., et al. (2016). Variation in microbiome LPS immunogenicity contributes to autoimmunity in humans. Cell, 165(4), 842–853.