autoimmune research, microbiome, oral health, Uncategorized

The Oral Origins of Autoimmune Diseases

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

Crohn’s, Lupus, and Celiac mean different things to different people. To some, they are completely foreign words that could pass as Pokemon names. To others, they are words occasionally mentioned in commercials about some medication with a million different side effects. But to the large majority of people, they have no clue at all what Crohn’s, Lupus, and Celiac are. In fact, 90% of Americans cannot name a single autoimmune disease despite the fact that these diseases affect 50 million people in the United States alone.

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So What is An Autoimmune Disease?

The most common understanding of an autoimmune disease is a disease in which the body’s own immune system mistakenly attacks healthy cells. In other words, consider people with peanut allergies. If one of allergenic peanut proteins is ingested or even inhaled, their immune systems respond with a ”type 1 IgE hypersensitivity reaction” where IgE antibodies start a cascade of cellular and cytokine reactions which lead to inflammation, hives, wheezing or even anaphylactic shock.

But people with autoimmune diseases do not need the presence of an external allergen or antigen in order for their bodies to elicit an immunological response (1). The classic understanding is that, in these cases, the immune system mistakes a normal component of its own cells (autoantigen) for a pathogenic antigen and mounts a response against the cells displaying such antigenic triggers. It’s more complex than that, of course, since we still don’t have a complete picture of how the immune system learns to tolerate its own cells and to recognize pathogenic molecules, nor how genetic susceptibility and environmental insults trigger the self-destructive immune response.

They are basically allergic to themselves…

However, new understandings of immune disorders place autoimmune diseases in a larger category of immune-mediated inflammatory diseases (IMID). IMID’s are conditions which result from abnormal activity of the body’s immune system. A subset of this, autoimmune diseases involve the immune system reacting specifically against its own cells and tissues. Researchers have also recently developed another sub-category of autoinflammatory diseases… but we’ll leave the specifics for another topic of discussion.

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Source: Villa Medica

In the last few years, we are seeing an increase in awareness focussed on providing care and health solutions for the millions suffering from autoimmune diseases. Therefore, researchers have been investigating potential causes and associated risk factors that increase individual susceptibility to autoimmune disorders. One of the newest research efforts explores the relationships between the oral microbiome and systemic diseases, with a unique focus on systemic autoimmune diseases.

The Oral Microbiome Connection

New understanding of the oral microbiome is shaping how we think about dental caries, periodontal and systemic diseases. While the traditional view held that these diseases were caused by a small number of pathogens, we now consider the oral microbiome to be a finely tuned ecosystem, a balanced (or unbalanced) community of microorganisms that mediates not only oral health and disease, but also some systemic diseases (2).

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

  • Metastatic Infection: Transient bacteria from oral infection or dental procedures can   gain entrance into the blood and circulate throughout the body. Such disseminated microorganisms may find favorable conditions, settle at a given site and after a certain time lag, start to multiply, colonize, and infect.
  • Metastatic Injury: Certain bacteria can produce toxins that, when excreted or introduced into a host body, trigger tissue damage, trigger an immune response or produce other pathological manifestations.
  • Metastatic Inflammation: Soluble molecules that enter the bloodstream may react with circulating antibodies to produce large complexes that give rise to acute and chronic inflammatory reactions. (3)

A number of autoimmune diseases have been linked to multiple pathogenic factors, including genetic susceptibilities, environmental triggers and dysregulated immune responses. Dysregulated immune responses may involve over-activated B-cells stimulated by toll-like receptors (TLRs), pattern recognition receptors (PRRs) that have evolved to detect proteins on or secreted by pathogens, production of various autoantibodies to nuclear and cytoplasmic autoantigens, and the presence of anti‐citrullinated protein antibodies (ACPA)  (4)(5). Such dysregulated immune responses can trigger progressive inflammation of certain tissues that manifests in particular autoimmune diseases such as Sjogren’s syndrome, Systemic Lupus Erythematosus, and Rheumatoid Arthritis.

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“We gonna break this thang down for just a few seconds”

    -Outkast

Sjogren’s Syndrome

Common Oral Symptom: Extremely Dry Mouth

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Source: Health

Sjogren’s Syndrome is an autoimmune disease that mainly affects the lachrymal (tear) and salivary glands. Thus, common symptoms include dry eyes and a significant decrease in saliva production, which can cause difficulty in speaking, eating and swallowing. Saliva is an important component in the composition of the oral microbiome due to its role in protein precipitation and biofilm formation. The deficiency of saliva is associated with high bacterial species count, as well as frequent occurrence of caries.

In this disease cytokines and lymphocytic infiltrates in exocrine glands cause damage that reduces secretion. Activated B-cells and T-cells stimulated by TLRs produce increased levels of IFN-𝛾 and IL-17–inflammatory cytokines–which disrupt epithelial cells in the salivary and lacrimal glands, inhibiting their production of saliva or tears and altering the mucin content. (6).

Systemic Lupus Erythematosus (SLE)

Common Oral Symptom: Lichenoid Lesions, Lupus Cheilitis

SLE is a complex, multifactorial connective-tissue disease that commonly affects joints and many organ systems including the skin, joints, heart, lungs, kidneys, and nervous system (7). The disease is characterized by the presence of autoantibodies in response to nuclear and cytoplasmic autoantigens. Oral symptoms of SLE include lichenoid lesions and lupus cheilitis. Lichenoid lesions look like a white spider web or film on the inner cheeks, tongue, and roof of the mouth. Lupus cheilitis may appear as a rash on or swelling of the upper and lower lip, sometimes including the surrounding areas of the mouth.

So far there are a couple proposals 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”), have been implicated in SLE pathogenesis. These EBV antigens demonstrate structural and functional molecular similarities to SLE autoantigens. Impaired EBV-specific T-cell response results in autoantibody responses to cellular antigens (8).

 

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Source: Beatrice the Biologist

In other words, EBV antigens share molecular similarities to SLE antigens and other cellular components, so the defenders of our bodies–the cells of our acquired immune system–mistakenly attack cells free of viral infections. 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 the gut microbiome is the main site of origin for pathogenic microbes that infiltrate the blood, the oral cavity 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

Common Oral Symptom: Presence or Early Indication of Onset 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 triggering inflammation that causes the tissue lining inside of joints to thicken. Not only joints may be affected, but also other tissues, especially the heart. At the molecular level, the presence of autoantibodies, like anti‐citrullinated protein antibodies (ACPAs) contributes to a loss of immune tolerance to self-antigens, and is one of the first steps toward inflammation (4).

“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, and infrequently associated with other diseases or found in healthy individuals, making them uniquely predictive factors for disease pathogenesis. The presence of ACPAs, along with the maturation of ACPA response mechanisms, are associated with the prodrome of the disease that precedes the onset of clinically apparent RA. This preclinical RA is a entire subset disease itself, and has been broadly defined and broken down into six phases 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 in response to bacterial accumulations, or dental plaque, on the teeth (12). Although it originates in the mouth, it has also been linked to other systemic diseases–more information can be found here. The image below also illustrates the step-wise process in further detail on how periodontal disease can eventually lead to chronic inflammation in rheumatoid arthritis. Associated pathogenic microbiota, such as P. gingivalis, are other factors that plays into the overall mechanism.

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Source: Current Rheumatology Reports

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 clear or well-understood root cause, they are difficult to diagnose and treat. However, recognizing similarities between the diseases will provide more insight into the pathophysiological processes that will perhaps be able to determine the underlying causes. 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 potential use as treatments for autoimmune diseases.


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., doi:10.1289/ehp.99107s5661.
  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., doi:10.1038/nm.3914.
  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., doi:10.4103/0973-029x.84477.
  4. Nikitakis, Ng, et al. “The Autoimmunity-Oral Microbiome Connection.” Oral Diseases, vol. 23, no. 7, 2016, pp. 828–839., doi:10.1111/odi.12589.
  5. Browne, Edward P. “Regulation of B-Cell Responses by Toll-like Receptors.” Immunology, vol. 136, no. 4, Feb. 2012, pp. 370–379., doi:10.1111/j.1365-2567.2012.03587.x.
  6. Gonzales, S, et al. “Oral Manifestations and Their Treatment in Sjogren′s Syndrome.” Oral Diseases, vol. 5, pp. 153–161., doi:10.1111/odi.12105.
  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., doi:10.3238/arztebl.2015.0423.
  8. Draborg, Anette Holck, et al. “Epstein-Barr Virus and Systemic Lupus Erythematosus.” Clinical and Developmental Immunology, vol. 2012, 2012, pp. 1–10., doi:10.1155/2012/370516.
  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., doi:10.1093/femsre/fuv013.
  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., doi:10.1038/nrrheum.2011.204.
  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, doi:10.1186/ar4342.
  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., doi:10.1097/bor.0b013e32835fb8ec.

 

 

 

 

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