What causes autoimmune disorders?

The immune system is designed to be our body’s most vigilant protector, an intricate army whose sole purpose is to distinguish between “self”—the body’s own healthy cells—and “non-self,” such as invading bacteria, viruses, or abnormal cells. ^[1][9] When this defense mechanism malfunctions, the result is an autoimmune disorder, a category encompassing over 100 distinct health conditions. ^[4][6] In these states, the immune system misidentifies parts of the body as foreign and launches an inappropriate attack, leading to chronic inflammation and resulting tissue damage in organs ranging from the joints and skin to the endocrine glands and nervous system. ^[1][4] Understanding what causes this fundamental breakdown in self-recognition is a primary focus of medical research, but the answer is rarely singular; it is instead a confluence of inherited tendencies and external forces. ^[2][4]

# Immune Misdirection

At its basic level, an autoimmune condition is the consequence of this self-targeting immune response. ^[8] The body creates autoantibodies or autoreactive T cells specifically designed to attack its own components. ^[2][9] This process is chronic, meaning that once established, the condition typically lasts for decades, even if symptoms come and go in episodes known as flares. ^[4][6] The resulting pathology can be localized to a specific organ, like the thyroid in Hashimoto’s thyroiditis, or systemic, affecting the body broadly, as seen in systemic lupus erythematosus (SLE). ^[6][10]

Researchers note that the mechanism is often driven by the adaptive immune system—the targeted defense involving B and T cells—but increasingly, the innate immune system—the body's rapid, non-specific defense—is also understood to play a prerequisite role in initiating the adaptive attack. ^[9] In fact, the distinction between purely autoimmune and autoinflammatory conditions, where innate cells dominate, is becoming blurred, suggesting a continuous spectrum where both systems contribute to inflammation and tissue damage. ^[9] The presence of autoantibodies often precedes clinical diagnosis by years, serving as an early immunological clue that the system has lost tolerance. ^[2]

# Genetic Blueprint

The role of genetics in autoimmunity is undeniable, often conferring a baseline level of risk known as predisposition or genetic susceptibility. ^[2] Autoimmune diseases frequently exhibit familial aggregation, meaning they tend to run in families. ^[2] For instance, having a specific immune system gene, such as HLA-DR4, is associated with an increased chance of developing rheumatoid arthritis. ^[1]

However, genetics alone are rarely the full story. Studies involving identical twins—who share the exact same genetic makeup—show that if one twin develops an autoimmune disease, the other does not always follow suit; the concordance rate is typically only between 25% and 50%. ^[1][2] This strongly suggests that non-genetic, or environmental, factors are necessary to switch the disease process on. ^[1]

There is no single, universally shared “autoimmune disease gene” responsible for the majority of cases; rather, these conditions are overwhelmingly considered polygenic or multifactorial. ^[2] Numerous genes across the entire genome contribute, but the individual impact of each one is small, usually conferring only a slight increase in odds. ^[2] Among the identified genes, those within the MHC locus (known as HLA in humans) show the strongest links to most autoimmune diseases. ^[2]

In a rare subset of cases, a condition may be monogenic, caused by a defect in a single gene. Conditions like Autoimmune Polyendocrinopathy-Candidiasis-Ectodermal Dystrophy (APS-1), linked to the AIRE gene defect, have provided significant insight into tolerance failure because the effect of one broken component is clearly traceable. ^[2] For the vast majority of patients, their inherited blueprint contains the susceptibility, but it requires an external catalyst to become active. ^[10]

# Inherited Susceptibility Meets Lifestyle Trigger

When considering the interaction between an inherited genetic tendency and environmental influence, the concept of epigenetics becomes particularly relevant. ^[3][10] Epigenetics refers to alterations in gene expression—what the DNA actually produces—without changing the underlying DNA sequence itself. ^[7] Environmental inputs, whether from toxins, diet, stress, or infection, can interact with this epigenetic layer, effectively placing chemical tags on the DNA that can activate a previously dormant gene or silence a necessary one. ^[3][10] This means that while one may inherit the genetic blueprint for autoimmunity (e.g., certain HLA types), the disease may only manifest when a specific environmental stressor interacts with the epigenome to flip the necessary genetic switches, effectively "turning on" the autoimmune process. ^[10] The body, therefore, is reacting to an external challenge that has altered its internal controls, overriding genetic safeguards. ^[10]

# Environmental Prompts

If genetics provide the predisposition, environmental factors are thought to deliver the triggers that make the disease clinically apparent. ^[2] This area is scientifically challenging to study because triggers often confer only a small increase in risk and must be present years before diagnosis. ^[2]

# Infections and Mimicry

Certain infectious agents have been heavily scrutinized for their role in initiating autoimmunity. ^[1][3] A notable example is the Epstein-Barr virus (EBV), which is highly prevalent and has been associated with the development or increased chance of developing diseases like SLE, Sjögren's syndrome, and multiple sclerosis. ^[1][3] Another infectious link involves Group A Streptococcus bacteria, which can trigger autoimmune responses in the heart, joints, or brain, such as acute rheumatic fever. ^[3]

A proposed mechanism explaining this link is molecular mimicry, where a structure on a foreign pathogen (like a virus or bacteria) closely resembles a substance naturally found in the human body. ^[7] When the immune system creates antibodies or T cells to fight the invader, these immune cells mistakenly recognize the similar-looking self-tissue, mistaking it for the camouflage-wearing threat. ^[1][7] Furthermore, recent events, such as SARS-CoV-2 infection, have been reported to trigger new cases of autoimmune conditions like lupus and Guillain-Barré syndrome. ^[3]

# External Exposures

Beyond direct infection, various exogenous agents encountered occupationally or generally are implicated. ^[7][9] For instance, smoking cigarettes has been specifically linked to the development of Rheumatoid Arthritis (RA) in those who are genetically susceptible, as the chemicals produced may initiate an inflammatory response and dysregulate cytokines. ^[1][3] Toxic agents encountered in the workplace or general surroundings, such as silica dust, organic solvents (like benzene), and ultraviolet radiation, have also been associated with various autoimmune syndromes, including systemic sclerosis. ^[3][7]

Certain medications can also act as triggers, leading to drug-induced lupus or autoimmune hepatitis; thankfully, these drug-induced forms are often reversible once the offending medicine is stopped. ^[1][3]

# Gut Connection

A critical area of investigation involves the gastrointestinal tract, often called the body's largest immune organ, where a significant portion of immune regulation occurs. ^[10] Intestinal permeability, commonly referred to as leaky gut, is highly associated with autoimmunity. ^[10] This condition occurs when the tight junctions between gut cells loosen, allowing larger molecules—which may include undigested food proteins, bacteria, fungi, or toxins—to "leak" into the bloodstream where they should not be. ^[10]

The immune system detects these foreign or inappropriately sized molecules, triggering an inflammatory response that may eventually turn against the body’s own tissues. ^[10] This breakdown in oral tolerance—the immune system’s acceptance of harmless substances ingested through the mouth—is seen as a potentially critical, initiating step in the autoimmune cascade. ^[7][10] Furthermore, dysbiosis, an imbalance in the gut microbiota (too many bad bacteria or not enough good ones), is considered a chronic infection trigger for autoimmunity. ^[10] Small intestinal bacterial overgrowth (SIBO) is also frequently observed in individuals with established autoimmune conditions like celiac disease or Hashimoto’s. ^[10]

# Hormone Swing

A striking demographic pattern in autoimmunity is the pronounced gender disparity: overall, about 78% of people affected by autoimmune disease are female. ^[3] Conditions like SLE and Sjögren's syndrome predominantly affect women, sometimes reaching 95% of cases. ^[3] This disparity has led researchers to theorize that female sex hormones, particularly estrogen, may contribute to susceptibility. ^[5][7] Estrogen is known to potentially increase the antibody and autoantibody response produced by B cells. ^[9] Conversely, men who experience higher estrogen production (e.g., due to an extra X chromosome in some cases) have shown an increased risk for some autoimmune illnesses. ^[7]

This area, however, highlights a common complexity in medical research: clearly separating biological sex differences from socially constructed gender differences remains difficult, and many studies do not adequately disaggregate this data. ^[9] While the female predominance is clear for many diseases, exceptions exist; Type 1 diabetes, for example, sometimes shows a higher incidence in boys or men. ^[6][9]

# Cortisol Versus Estrogen

Hormonal balance extends beyond sex hormones to stress regulation. Chronic mental and emotional stress forces the body into a constant state of "fight or flight," leading to sustained high levels of the stress hormone cortisol. ^[10] While acute cortisol is anti-inflammatory, chronic elevation causes cortisol receptors to become less effective, effectively stripping cortisol of its protective anti-inflammatory power and resulting in net inflammation. ^[10] Furthermore, cortisol production draws from precursor hormones like progesterone, which normally helps balance estrogen's pro-inflammatory effects; when progesterone is depleted due to chronic stress, even normal estrogen levels can become inflammatory, pushing the immune system toward a destructive Th17 response. ^[10]

# Lifestyle Load

Lifestyle factors contribute significantly by influencing the inflammatory state and the epigenome. ^[3]

# Obesity and Inflammation

Obesity is a recognized risk factor associated with over ten different autoimmune diseases, including psoriatic and rheumatoid arthritis. ^[3] Adipose (fat) tissue, when accumulated and dysfunctional, secretes compounds called adipokines, which tend to be pro-inflammatory. ^[3] This leads the body into a state of chronic, low-grade inflammation, which can critically threaten the proper function of an otherwise healthy immune response. ^[3]

# Nutritional Gaps

Nutrition is fundamental to immune health. ^[10] A diet high in sugar and refined carbohydrates contributes to the inflammatory insulin surges mentioned earlier, which can suppress anti-inflammatory T regulatory cells (${\text{T}}_{\text{reg}}\backslash text\{T\}\_\{\backslash text\{reg\}\}$). ^[10] Conversely, deficiencies in key nutrients can impair the body’s ability to regulate itself. ^[10] For example, Vitamin D deficiency is common in those with autoimmune disorders, and this vitamin supports a healthy immune response, including T cell circulation. ^[10] The master antioxidant, Glutathione, also plays a role in reducing oxidative stress and supporting Treg cell function; low levels resulting from poor nutrition or toxins can exacerbate issues. ^[10] Ensuring adequate intake of essential fatty acids like Omega-3s is also vital for immune regulation and modulating cytokine production. ^[10]

# Applying Environmental Control

Given the known triggers—infections, toxins, diet, and stress—readers have agency over the environmental component of the autoimmune equation. ^[1][3] It is important to remember that while you cannot change your genetics or your sex, you can exert control over your immediate environment and behavior. ^[3] In a practical sense, this involves being mindful of the inputs to your system. Since smoking and exposure to certain solvents or pollutants are implicated, minimizing exposure is a reasonable defensive step. ^[3][7] Similarly, addressing the gut health component by prioritizing whole, nutrient-dense foods and limiting processed items can help restore gut integrity and reduce the inflammatory load that might be contributing to intestinal permeability. ^[3][10] Structuring the day to incorporate appropriate physical movement and dedicated rest is also crucial, as sleep allows the body time for essential repair mechanisms to buffer the immune system from ongoing illness. ^[7]

# Coexisting Illness

It is not uncommon for an individual to develop more than one autoimmune condition over time, a situation sometimes referred to as Multiple Autoimmune Syndrome (MAS), seen in about 25% of patients. ^[3] Conditions like celiac disease, rheumatoid arthritis, and Hashimoto’s frequently cluster. ^[3] Historically, doctors classified these as "primary" or "secondary" based on which disease was diagnosed first, but modern understanding suggests this sequencing is misleading, as there is no evidence one causes the other—they likely share common underlying drivers. ^[9] Research supports that intra-person co-occurrence happens at higher-than-expected rates for several combinations, such as between autoimmune thyroiditis and type 1 diabetes. ^[9] This clustering underscores the theory that a set of shared underlying genetic and environmental mechanisms is overwhelming the body’s tolerance threshold. ^[3][9]

In summary, the question of what causes autoimmune disorders yields a complex answer rooted in an imperfect storm: a person inherits a susceptible genetic background, often involving multiple genes like those in the HLA region. ^[2][10] This inherited state can be modified by epigenetics, which primes the system for reactivity. ^[3] Then, environmental or physiological insults—such as a specific viral infection, chronic stress leading to adrenal fatigue, significant dietary challenges, or exposure to a toxin—act as the final trigger, causing the dysregulated immune system to lose its sense of "self" and initiate the attack that results in chronic disease. ^[1][2][10] The scientific community continues to seek better consensus on definitions and causality, but the current understanding points toward a highly individualized interplay of nature and nurture. ^[9]