Autoimmunity and the role of toxicants

Mild forms of autoimmune response likely occur naturally in most people. But for individuals with a predisposition to autoimmunity, environmental factors and toxins may trigger a full-fledged response, according to a 1999 press release from the National Institute of Health Sciences that Robert Rountree, MD, shared with attendees at the 2018 Institute for Functional Medicine (IFM) Annual International Conference.

Research relating to autoimmunity is challenging, said Rountree, because so many studies are government-backed, making it difficult to decipher the biased versus unbiased information. However, research consistently shows that environmental factors, including toxic chemicals, bacteria, and drugs, contribute to autoimmune disease.

A 2007 paper published in Scientific American shows that many autoimmune diseases do not develop spontaneously, but instead evolve through an extended germination period before they become clinically evident. Over 10 million people test positive for antinuclear antibodies years before they have symptoms, which implies the presence of additional environmental factors dampen or amplify the process over time, said Rountree.

Some environmental chemicals, acting as haptens, can bind to a high-molecular-weight carrier protein, such as human serum albumin (HSA), causing the immune system to misidentify self-tissue as an invader and launch an immune response against it, according to Rountree. This leads to autoimmunity. A 2015 study published in the Journal of Applied Toxicology found the levels of specific antibodies against 12 different chemicals bound to HSA were measured from 400 blood donors. The results showed that 10-17 percent of tested individuals showed significant antibody elevation against aflatoxin-HSA adduct. The percentage of elevation against the other 11 chemicals ranged from 8-22 percent and 13-18 percent. Further, detection of antibodies against various protein adducts may indicate chronic exposure to these chemical haptens in about 20 percent of the tested individuals.

“Not only are they not rare, they are happening all the time,” said Rountree. “Autoimmune is broken tolerance—that’s the core of the issue.”

Could environmental toxins be the missing link that pushed the immune system over the brink to permanently lose control of its tolerance to self-antigens? And does persistent presence of autoantibodies or autoreactive T cells imply an inevitable progression to full-blown autoimmune disease?

Rountree offered a case study on a patient with rheumatoid arthritis (RA). The most common testing method for RA is anti-cyclic citrullinated peptide antibody screening. Elevated tiers of this antibody can be detected over 10 years before onset of clinical disease, says Rountree. Sensitivity—the likelihood of a positive test—increases from 50 percent to 75 percent over the course of disease. This is a pathogenic process. Citrullinated peptide antibodies are highly expressed in inflamed joints and a positive test predicts joint erosion. Further, antigen-antibody complexes, when activated, are inflammatory.

When autoantibodies interact with citrullinated peptides, citrulline is formed by posttranslational modification of arginine residues by peptidyl arginine diminases (PADs). PADs are upregulated by inflammation, injury, and toxicants. Inflammation and injury increases citrullination of multiple synovial proteins. Many HLA-DR variants shared epitope associated with RA preferentially display citrullinated peptides, activating specific autoreactive T cells. Smoking increases risk of developing autoimmunity to some citrullinated proteins, says Rountree.

Autoimmunity to specific citrullinated proteins provides one of the first clues to the etiology of RA, says Rountree. Four citrullinated whole protein antigens—fibrinogen, vimentin, collagen type II, and alpha-enolase—are now well-established. Others are awaiting further characterization. All four proteins are expressed in the joint, and there is evidence that antibodies to citrullinated fibrinogen and collagen type II mediate inflammation by the formation of immune complexes. 

Antibodies to citrullinated proteins are associated with HLA shared epitope alleles. Porphyromonas gingivalis, pathogenic bacteria that is a major cause of periodontal disease, expresses endogenous citrullinated proteins. Thus, both smoking and porphyromonas gingivalis are attractive etiological agents for further investigation into the gene, environment, and autoimmunity triad of RA, says Rountree.

“Cigarette smoking has been strongly linked to numerous autoimmune diseases,” said Rountree. “It is the most conclusively established risk factor for RA and increased risk remains for 20 years after cessation.”

However, cigarette smoking isn’t the only toxin we breathe in that contributes to autoimmune disease. Air pollution can have a similar effect on the body, initiating chronic inflammatory events in the lungs. These, in turn, promote the release of enzymes that mediate conversion of various endogenous proteins to putative citrullinated autoantigens. For genetically susceptible individuals, these autoantigens trigger the production of autoantibodies to anti-citrullinated peptides, which preceses the development of RA, says Rountree.

While research clearly shows how smoking increases risk for a range of autoimmune diseases—including lupus, multiple sclerosis, Grave’s hyperthyroidism, and primary billary cirrhosis—it begs the question whether the diseases start in the gut, as traditionally thought, or in the lungs. Environmental pollutants, toxins, infections, and unhealthy diets all play a role in the development of autoimmune disease.

“Autoimmune disease doesn’t just fall from the sky,” says Rountree. “It’s in our environment, the air we breathe, the food we consume.”

Environmental toxicants, oxidized polyunsaturated fatty acids, excessive calories, refined sugars, and advanced glycation end products all increase inflammation and additional free radical production, which damages tissues, disrupts barriers, modifies DNA, and creates “foreign-like” tissues, such as anti-nuclear antibodies, that break down immune intolerance.

Rountree argues that localized tissue damage and chronic inflammation elicited by xenobiotic exposure leads to the release of self-antigens and damage-associated molecular patterns, as well as the appearance of ectopic lymphoid structures and secondary lymphoid hypertrophy. This provides a milieu for the production of autoreactive B and T cells that contribute to the development and persistence of autoimmunity in predisposed individuals.

For toxicants and autoimmunity, Rountree lists three general mechanisms:

  1. Effect on antecedents
  2. Effect on triggers
  3. Effect on mediators

Toxins can alter genetics and epigenetics, such as methylation and acetylation. They can damage membrane barriers in the gut, skin, brain, and elsewhere, allowing increased exposure to triggers. Immune disruption leads to increased susceptibility to triggers, and an overload in hepatic detoxification pathways.  

In regards to triggers, toxicants can result in a synergistic action. Chemical modifications of self-antigens make it appear foreign or immunogenic, and results in enhanced apoptosis. Toxins can also amplify inflammatory pathways, increase oxidative stress, and disrupt the pro-resolution counter-regulatory mechanisms.

Rountree developed a model, title Functional Toxicology, for autoimmune disease that is straightforward and clearly illustrates how autoimmune disease progresses:

Toxicants → Molecular Triggers (cell stressors)

Antecedents (Genomics, lifestyle)

Inflammatory mediators

Chronic Disease

Autoimmune and autoinflammatory diseases are steadily increasing in our society, says Rountree. The rise in exposure to environmental pollutants and other toxins is increasing the total body burden of xenobiotics. A central theme in the development of autoimmune diseases is the loss of immune tolerance. Immune tolerance can be broken down by disruption of barriers, such as the skin, lungs, gut, and brain, or immune dysregulation. Numerous xenobiotics have been shown to disrupt healthy barriers and dysregulate immune responses. Xenobiotics may play a central role in the initiation and perpetuation of autoimmune disease.

“We don’t often think that these environmental factors and toxicants, 10 years down the road, can cause autoimmune disease,” said Rountree. “But they do, and we need to think that way, both in policy and in science.”

Editor’s note: This article is part of Integrative Practitioner’s live coverage of the Institute of Functional Medicine’s 2018 Annual International Conference. For a full list of coverage, click here.