The Oral Origins of Autoimmune Diseases
The Mouth's influence on Autoimmune Diseases

This post will explore the oral origins of autoimmune diseases. But first, what are autoimmune diseases? For example, have you heard of Crohn’s, Lupus, and Celiac? Or Sjogren’s syndrome and rheumatoid arthritis (RA)? To many, these are foreign words that could pass as Pokemon characters. To others, these are words they hear in ads about medications with a million different side effects. As a matter of fact, 90% of Americans cannot name a single autoimmune disease despite that some 50 million people in the United States alone suffer from them. Of course, this means that it has crossed very few people’s minds that what goes on in their mouths has anything to do with these unfamiliar diseases.

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What are autoimmune diseases?

Autoimmune diseases are conditions in which the body’s immune system mistakenly attacks its own healthy cells and tissues. Such a misdirected attack causes vague, nonspecific, waxing and waning but relentlessly worsening symptoms. Eventually, patients develop serious irreversible damage to specific tissues. For example, lupus is a systemic autoimmune disease where the autoantigen target may be the patient’s own DNA! This leads to tissue damage disseminated through joints, skin, kidneys and maybe fascia. Another example is Crohn’s disease, in which the immune system attacks the lining of the gut. Also, celiac disease, in which hypersensitivity to gluten protein (the one that allows bread to rise into a fluffy loaf) triggers an inflammatory immune reaction. Wait, what does this have to do with the oral origins of autoimmune diseases? Hang in there, we’ll get to that.

It’s important to realize that healthy immune systems target antigens, proteins found on or inside pathogens like bacteria. In particular, a well-balanced immune system trains its cells to ignore its own healthy (self) cells and tissues. However, people with autoimmune diseases do not need external antigens to elicit an immune response (1). This means that the immune system mistakes normal proteins on its own cells (autoantigens) for foreign antigens. As a result, the body mounts an immune response against the cells displaying these autoantigens. It’s more complex than that, of course. But we still don’t have a complete picture of how the immune system learns to tolerate its own cells and recognize pathogenic molecules. Nor do we completely understand how genes and environmental triggers influence autoimmune reactions.

Autoimmune diseases are immune-mediated inflammatory disorders

However, new understanding of immune disorders place autoimmune diseases in a larger category of immune-mediated inflammatory diseases (IMID). To emphasize, IMID’s are a catch-all term for conditions that result from abnormal activity of the body’s immune system. Autoimmune diseases are a subset of IMIDs in which the immune system reacts against specific self cells and tissues. Researchers have also recently developed another sub-category of autoinflammatory diseases… but we’ll leave the specifics for another post.

facts-about-autoimmune-diseases
Source: Villa Medica

The oral origins of autoimmune diseases

In the last few years, we have seen increased awareness of and research into autoimmune diseases. Therefore, scientists have been investigating potential causes and risk factors that may increase individual risk or trigger flares. In particular, one of the newer research efforts explores the possible oral origins of autoimmune diseases. Specifically, does oral microbiome dysbiosis cause systemic diseases, particularly autoimmune diseases?

An unbalanced oral microbiome may trigger systemic diseases

New understanding of the oral microbiome is shaping how we think about dental caries, periodontal disease, and systemic diseases. Therefore, we are moving beyond the traditional view that these diseases are caused by a small number of pathogens. Instead, we now understand the oral microbiome to be a finely tuned ecosystem. That is, a balanced (or unbalanced) community of microorganisms that mediates not only oral health and disease, but also some systemic diseases (2). Examples include heart disease, cancer, even Alzheimer’s dementia.

So far, three pathways that link oral infections to secondary systemic effects have been proposed:

  1. Metastatic Infection: Bacteria from oral infection or dental procedures enter the blood and circulate throughout the body. These disseminated microorganisms may find favorable conditions at a given site, settle, and multiply.
  2. Metastatic Injury: Certain bacteria can produce toxins that, when excreted or introduced into a host body, trigger tissue damage, elicit an immune response, or produce other pathological responses.
  3. Metastatic Inflammation: Soluble molecules that enter the bloodstream may react with circulating antibodies to produce large complexes that give rise to acute inflammatory reactions. (3)

Multiple pathogenic factors in autoimmune diseases

Researchers have linked autoimmune diseases to multiple pathogenic factors. Specifically, these include genetic susceptibilities, environmental triggers, and dysregulated immune responses. More explicitly, dysregulated acquired immune responses involve several factors. Of particular importance are misdirected immune white blood cells (B-cells and T-cells) that release cytokines (signalling chemicals) and antibodies that attack self cells. Similarly, innate immune system pattern recognition receptors (PRRs) that have evolved to detect proteins on or secreted by pathogens may misidentify self proteins. Additionally, the body may produce autoantibodies to nuclear and cytoplasmic autoantigens. Finally, the presence of anti‐citrullinated protein antibodies (ACPA) is a biomarker of early autoimmune disease (4)(5). These dysregulated immune responses can trigger inflammation such as that seen in autoimmune diseases like Sjogren’s syndrome, Systemic lupus erythematosus (SLE or more commonly lupus), and Rheumatoid Arthritis (RA).

confused about autoimmune disease? Jackie feels you.

Three autoimmune diseases with oral origins or connections

Sjogren’s Syndrome

Oral Connection: Extremely Dry Mouth

Dry mouth illustration for Sjogren's syndrome.
SSjogrenSource: Health

Sjogren’s Syndrome is an autoimmune disease that mainly affects the lacrimal (tear) and salivary (spit) glands. Thus, common symptoms include dry eyes and a significant decrease in saliva production. This results in a condition know as “dry mouth,” which can cause difficulty in speaking, eating, and swallowing. And dry mouth is no fun! Furthermore, saliva is an important component of the oral microbiome due to its role in protein precipitation and biofilm formation. The lack of saliva is associated with a high bacterial species count and higher rates of cavities.

In this disease, cytokines and lymphocytes (white blood cell) infiltrate into exocrine glands. These are glands that secrete through ducts onto epithelial surfaces, such as sweat, salivary, lacrimal and mammary. This causes damage that reduces secretion. Activated B-cells and T-cells stimulated by TLRs (Toll-Like Receptors– innate immune system proteins that communicate to immune cells) produce increased levels of IFN-𝛾 and IL-17 inflammatory cytokines. These signalling chemicals disrupt epithelial cells in the salivary and lacrimal glands, inhibiting production of saliva or tears and altering the mucin (sugar-proteins in mucus) content. (6).

Systemic Lupus Erythematosus (SLE)

Oral connection: Lichenoid Lesions, Lupus Cheilitis

SLE is a complex, multifactorial connective-tissue autoimmune disease that affects joints, skin, kidneys and other organ systems (7). In particular, the disease is characterized by the presence of autoantibodies in response to nuclear and cytoplasmic autoantigens. To be specific, oral symptoms of SLE include lichenoid lesions and lupus cheilitis. Lichenoid lesions look like lichen, or a white spider web on the inner cheeks, tongue, and roof of the mouth. Lupus cheilitis may appear as a rash on the lips and surrounding areas of the mouth.

So far there are a few theories that link the oral microbiome to SLE. The first suggests that certain viral infections of the mouth, such as Epstein-Barr Virus (EBV, more commonly known as “mono”), can trigger SLE pathogenesis. These EBV antigens have structural and functional similarities to SLE autoantigens. Impaired EBV-specific T-cell responses trigger autoantibody responses to self-cellular antigens (8).

But I’m one of you!

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Source: Beatrice the Biologist

In other words, EBV antigens share molecular similarities to SLE antigens and other cellular components. Consequently, the defenders of our bodies–the T & B-cells of our acquired immune system–mistakenly attack cells free of viral infection. Another proposal that links SLE to oral microbiomes is based on recent research that organisms in blood (blood microbiomes) are associated with a number of non-communicable chronic diseases. Although many pathogenic microbes enter the blood through the gut microbiome, the mouth is another source for translocated microbes (9). A high dormant blood microbiome (i.e., the presence of detectable, but not culturable microbes) is associated with chronic inflammatory diseases including SLE.

Rheumatoid Arthritis

Oral connection: Periodontal disease

Rheumatoid Arthritis is a well-known disease. However, many people are unaware that it is categorized as an autoimmune disease. The abnormal immune reaction triggers inflammation and causes the tissue lining inside of joints to thicken. Not only are joints affected, but also these inflammatory reactions can affect many other tissues (including heart tissue). At the molecular level, the presence of autoantibodies (and anti-citrullinated proteins) contributes to a loss of immune tolerance to self-antigens, and is one of the first steps toward inflammation (4). In simpler terms, the immune system fails to recognize self cells as friends and instead treats them as foes (pathogens).

“Anti-citrullinated proteins (ACPAs) appear up to 10 years before the onset of clinical manifestations of Rheumatoid Arthritis…The presence of ACPA predicts the evolution to Rheumatoid Arthritis” (10)(11)

ACPAs are a group of autoantibodies found in 50-70% of RA patients. Such ACPAs are frequently associated with other diseases in healthy individuals. Therefore, this makes them strong predictive factors for disease pathogenesis. ACPAs, and the maturation of ACPA response mechanisms are biomarkers of the disease that show up before any clinically-apparent symptoms. Moreover, this preclinical or prodromal RA is a entire subset of the disease as broadly defined by the European League Against Rheumatism (EULAR).

But, what’s more important to note about ACPAs is this:

Periodontitis causes the production of ACPAs

Periodontal disease refers to inflammatory processes in the tissues surrounding the teeth. This inflammation is usually in response to bacterial accumulations, or dental plaque, on the teeth (12). Although periodontal disease originates in the mouth, it has also been linked to other systemic diseases (click here to learn more). The image below illustrates how periodontal disease can eventually lead to rheumatoid arthritis. Pathogenic microbiota, such as P. gingivalis, are other factors that influence its overall development.

Possible oral origins of other autoimmune diseases

In conclusion, an increasing number of researchers are investigating the possible oral origins of autoimmune diseases. Specifically, Sjogren’s and lupus have been targets of research because patients usually or often have oral symptoms. On the other hand, periodontal disease is not usually considered a primary symptom of RA. Perhaps it should be! It’s clear that periodontal disease and RA have a bidirectional relationship. Of course, the research focus on gut diseases like Crohn’s and celiac has been on the gut microbiome. But the mouth is the gateway to the gut, so there may well be a connection between oral microbiome dysbiosis and gut diseases.

Keep In Mind…

Autoimmune disease is an umbrella term for more than 100 different illnesses, each presenting a variable array of symptoms. Due to the fact that autoimmune diseases do not have a well-understood cause, they are difficult to diagnose and treat. However, recognizing similarities between the diseases will provide more insight into the processes behind the underlying causes. Though a little dense, the mounting research on the oral microbiome and its connection to systemic autoimmune diseases is exciting! Not only could the detection of imbalances in the microbial composition facilitate the early diagnosis of autoimmune diseases, but correction of these microbial imbalances may have the potential to treat autoimmune diseases.

Written by: Hailey Motooka, Bonnie Feldman, DDS, MBA, Ellen M. Martin

For further reading from our blog


References

  1. Smith, D A, and D R Germolec. “Introduction to Immunology and Autoimmunity.” Environmental Health Perspectives, vol. 107, no. Suppl 5, Jan. 1999, pp. 661–665.
  2. Zhang, Xuan, et al. “The Oral and Gut Microbiomes Are Perturbed in Rheumatoid Arthritis and Partly Normalized after Treatment.” Nature Medicine, vol. 21, no. 8, 2015, pp. 895–905.
  3. Babu, Nchaitanya, and Andreajoan Gomes. “Systemic Manifestations of Oral Diseases.” Journal of Oral and Maxillofacial Pathology, vol. 15, no. 2, 2011, pp. 144–147.
  4. Nikitakis, Ng, et al. “The Autoimmunity-Oral Microbiome Connection.” Oral Diseases, vol. 23, no. 7, 2016, pp. 828–839.
  5. Browne, Edward P. “Regulation of B-Cell Responses by Toll-like Receptors.” Immunology, vol. 136, no. 4, Feb. 2012, pp. 370–379.
  6. Gonzales, S, et al. “Oral Manifestations and Their Treatment in Sjogren′s Syndrome.” Oral Diseases, vol. 5, pp. 153–161.
  7. Kuhn, Annegret, et al. “The Diagnosis and Treatment of Systemic Lupus Erythematosus.” Deutsches Ärzteblatt, vol. 112, no. 25, 19 June 2015, pp. 423–432.
  8. Draborg, Anette Holck, et al. “Epstein-Barr Virus and Systemic Lupus Erythematosus.” Clinical and Developmental Immunology, vol. 2012, 2012, pp. 1–10.
  9. Potgieter, Marnie, et al. “The Dormant Blood Microbiome in Chronic, Inflammatory Diseases.” FEMS Microbiology Reviews, vol. 39, no. 4, 4 May 2015, pp. 567–591.
  10. Willemze, Annemiek, et al. “The Influence of ACPA Status and Characteristics on the Course of RA.” Nature Reviews Rheumatology, vol. 8, no. 3, 2012, pp. 144–152.
  11. Arkema, Elizabeth V, et al. “Anti-Citrullinated Peptide Autoantibodies, Human Leukocyte Antigen Shared Epitope and Risk of Future Rheumatoid Arthritis: a Nested Case–Control Study.” Arthritis Research & Therapy, vol. 15, no. 5, 2013
  12. Bingham, Clifton O., and Malini Moni. “Periodontal Disease and Rheumatoid       Arthritis.” Current Opinion in Rheumatology: the Evidence Accumulates for Complex Pathobiologic Interactions, vol. 25, no. 3, May 2013, pp. 345–353.

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