Eterna Integrative Team
If you’ve been diagnosed with an autoimmune condition—or you’re still looking for answers—you’ve probably wondered how this happened. Why did your immune system turn on you? Was it something you did? Something you were exposed to? Bad luck?
The honest answer: it’s usually a combination of things. And understanding that combination is the first step toward doing something about it.
What causes autoimmune disease isn’t a single smoking gun. It’s a convergence. Researchers have spent decades trying to understand why certain people develop autoimmunity while others don’t, and a clear model has emerged—one built on three interconnected factors. Think of it as a three-legged stool: take away any one leg, and the stool doesn’t stand.
The Three-Legged Stool of Autoimmunity
The first leg is genetic susceptibility. Certain genes—particularly those in a region called the major histocompatibility complex (MHC)—make the immune system more prone to mistaking the body’s own tissues for invaders. This doesn’t mean autoimmune disease is inevitable if it runs in your family. Having the genetic predisposition just means the door is unlocked. Something still has to push it open.
The second leg is an environmental trigger—an infection, a toxin, a period of intense stress, or a dietary factor that sets the immune system off. We’ll dig into these in detail below.
The third leg is increased intestinal permeability, commonly called leaky gut. This is where the research has gotten genuinely fascinating in recent years.
Gastroenterologist and researcher Dr. Alessio Fasano has proposed and backed with substantial evidence that all three factors must converge for autoimmune disease to develop. Genetic susceptibility alone isn’t enough. An environmental trigger alone isn’t enough. It’s the combination, with leaky gut as the critical bridge between the two, that tips the immune system into autoimmunity.
What Is Leaky Gut, and Why Does It Matter?
The gut lining is only one cell thick, but it’s one of the body’s most important barriers. Its job is to let nutrients in while keeping pathogens, undigested food particles, and toxins out. When that barrier becomes compromised and more permeable than it should be, things that shouldn’t enter the bloodstream do.
The key regulator of this barrier is a protein called zonulin. When zonulin levels rise (triggered by factors like gluten, dysbiosis, infections, stress, and certain medications), the tight junctions between gut cells loosen. Dysregulation of the zonulin pathway in genetically susceptible individuals is now strongly implicated in the development of autoimmune conditions including type 1 diabetes, celiac disease, multiple sclerosis, and lupus.
The mechanism is straightforward in concept: when the gut barrier breaks down, fragments of bacteria, undigested proteins, and other foreign material slip into systemic circulation. The immune system encounters them, mounts a response—and in someone with the right genetic background and the right trigger, that response can go sideways and begin targeting the body’s own tissue.
This is why gut health isn’t a peripheral concern in autoimmune disease. It’s often central to the story.
Environmental Triggers: What Starts the Fire?
The range of environmental factors implicated in autoimmunity is broad and still being mapped. But several categories have strong and consistent evidence behind them.
Infections
Infections are among the most well-established autoimmune triggers. The mechanism most studied is molecular mimicry: a pathogen carries protein fragments that closely resemble the body’s own tissue. The immune system launches an attack on the pathogen but because the enemy looks so much like self, it keeps firing on both.
Epstein-Barr virus (EBV), the virus that causes mono, is one of the most thoroughly studied examples. Nearly all adults have been infected with EBV at some point, but for a subset of people, that infection appears to leave a lasting mark on immune function. EBV has now been linked to multiple sclerosis, lupus, rheumatoid arthritis, and Sjögren’s syndrome—not as the sole cause, but as a significant contributor through molecular mimicry and the dysregulation of B and T cell responses.
Streptococcal infections have long been connected to autoimmune heart and joint conditions. Gut infections from certain bacteria can precede inflammatory bowel disease and autoimmune arthritis. COVID-19 has also been associated with new autoimmune diagnoses in a meaningful subset of patients, adding to the evidence that viral infections can act as a key autoimmune disease trigger—particularly in those with underlying susceptibility.
Stress
For the immune system, stress is genuinely destabilizing and the research backs this up.
A landmark study published in JAMA followed over 100,000 people in Sweden diagnosed with stress-related disorders including PTSD and acute stress reactions, comparing them to more than one million people without such diagnoses. The result: people with stress-related disorders had a 36% higher risk of developing an autoimmune condition. Those with PTSD specifically had up to a 46% higher risk. The association held even when researchers compared affected individuals to their own siblings controlling for both genetics and early environment.
Why? Chronic stress dysregulates the HPA axis (the body’s stress-response system), alters cortisol patterns, promotes systemic inflammation, and—crucially—compromises the gut barrier. Stress is a direct trigger of leaky gut. It also increases the production of pro-inflammatory cytokines that can prime the immune system toward autoimmune activity.
Toxins and Chemical Exposures
Air pollution, pesticides, heavy metals, and industrial chemicals have all been associated with higher rates of autoimmune disease in exposed populations. Air pollution in particular has been linked to lupus flares, increased rheumatoid arthritis activity, and autoimmune thyroid conditions. Wildfire smoke, now a growing concern in many regions, combines particulate matter, toxic compounds, and acute stress in a way that can compound immune burden significantly.
Certain medications, including NSAIDs and steroids used long-term, can also contribute to gut permeability over time, creating a vulnerability that may compound other triggers.
Diet and the Gut Microbiome
An ultra-processed diet, low in fiber and high in refined sugars and food additives, consistently degrades the gut microbiome and weakens the intestinal barrier. The microbiome isn’t just along for the ride in autoimmunity—it actively regulates immune tolerance. A disrupted microbiome reduces the diversity of immune-regulatory signals, making it easier for autoreactive immune responses to gain traction.
What Causes Autoimmune Flares?
For people already living with an autoimmune condition, flares are often the most pressing concern. Understanding autoimmune flare causes is, in many ways, the same exercise as understanding what triggered the disease in the first place. The same stressors that initiated the immune dysregulation can reactivate it.
The most common flare triggers are:
- Infections: even a common cold or gastrointestinal bug can temporarily destabilize immune regulation
- Acute or chronic stress: life stressors, poor sleep, and burnout all suppress immune regulation and promote inflammation
- Dietary changes: for many people, reintroducing inflammatory foods or gluten after a period of avoidance triggers measurable gut barrier disruption within hours
- Hormonal shifts: menstrual cycle changes, pregnancy, perimenopause, and thyroid fluctuations are all common flare triggers, a likely reason why autoimmune disease is far more prevalent in women
- Toxin or allergen exposure: mold, certain chemicals, and even pollen can tip the immune system into a flare in sensitized individuals
One insight from functional and integrative medicine that’s gaining traction in research: flares often have a cumulative trigger load. No single stressor may be enough on its own, but the combination—stress plus a viral illness plus a dietary indiscretion plus a missed night of sleep—can be enough to push a controlled disease into active inflammation.
Where This Leaves You
Understanding the mechanics of autoimmunity changes the conversation from “what’s wrong with me?” to “what are my immune system’s specific vulnerabilities, and which of those can I address?”
Genetics can’t be changed. But the gut barrier can be strengthened. Stress can be regulated more effectively. Infections can be treated promptly. Environmental exposures can be reduced. Inflammatory dietary patterns can be shifted.
None of this is about perfection or eliminating every risk factor. It’s about reducing the total burden on an immune system that’s already working hard. For many people with autoimmune conditions, that reduction—approached systematically and with the right support—makes a real clinical difference.
That’s the work of integrative medicine, and it starts with understanding your triggers.