Chronic Inflammation of the Oral Cavity - An Agent for Oral Mucosal Disease

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  1. Goal
  2. Background
  3. Gaps and Opportunities
  4. Impact
  5. Current Portfolio
  6. References

September 2022

Integrative Biology and Infectious Diseases Branch
Division of Extramural Research

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Goal

The goal of this initiative is to encourage interdisciplinary research that investigates the mechanisms driving chronic inflammation and its relationship with the physiology of the oral cavity, including oral manifestations of chronic systemic diseases. Chronic inflammation can create a heightened state that contributes to serious health conditions within the oral cavity. This initiative will encourage studies focusing on the mechanisms of chronic inflammation as they relate to onset and/or progression of oral diseases. This initiative excludes studies on microbial dysbiosis that results as a consequence of infection.

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Background

Multiple mechanisms may lead to a state of chronic inflammation within the oral cavity including those initiated by commensal or pathogenic microbiota, or through host immunity and mucosal homeostasis disruption. While it is recognized that oral chronic inflammation is associated with a variety of systemic conditions, the mechanisms by which this heightened state, primes immune memory and then affects the onset and progress of mucosal diseases of the oral cavity is less clear. For example, this chronic inflammatory state can lead to shifts in the commensal microbiota that may play a role in carcinogenesis. Elevated levels of oral Fusobacterium nucleatum are linked to extraoral cancer locations, such as in the gut tract, where these bacteria are not normally found1,2. F. nucleatum has also been associated with inflammation and poor survival in early-stage HPV-negative tongue cancer3. Amplified innate and adaptive immune responses observed following antigen exposure support a role for infections driving the immunopathology and acting as environmental risk factors, possibly involving molecular mimicry in immune hyperactivity4,5. In the context of plasminogen deficiency, commensal organisms trigger extravascular fibrin deposition in the oral mucosa, leading to tissue damage and chronic inflammation6.

Chronic inflammation following viral infections is known to lead to various autoimmune related conditions7. This has also been seen in some individuals following COVID-19 infection, where some patients develop multiple types of autoantibodies and autoimmune disease with potential implications for post-acute sequelae of SARS CoV-2 (PASC)8. Furthermore, active Epstein-Barr virus (EBV) infection selectively associates with ectopic lymphoid structures in the salivary glands of Sjögren’s Disease patients and appears to contribute to local growth and differentiation of disease-specific autoreactive B cells. Immune responses of treatment-naïve patients diagnosed with Sjögren’s Disease to an H1N1 influenza vaccine identified a mechanistic basis for B cell hyperactivity9,10. Low-level, chronic viral infections such as hepatitis delta virus in the salivary gland have been associated with the development of autoimmune Sjögren's Disease11.

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Gaps and Opportunities

The oral cavity is the gateway for numerous potential etiopathogenetic factors in different diseases. Opportunities exist to expand our knowledge on the role of chronic inflammation in the oral cavity and how it relates to onset and/or progression of oral diseases. Topics of interest include:

  • Understanding the functional role of chronic inflammation in post-viral infection sequelae.
  • Exploring the relationship of microbially induced chronic inflammation and onset and/or progression of oral related cancers and the understanding of the immune-oncology-microbiome axis.
  • Elucidating host - microbe interactions that induce autoreactivity, activating mechanisms such as molecular mimicry, epitope spreading, bystander activation, and immortalization of infected B cells that can lead to autoimmune related illnesses.
  • Developing treatments and therapeutic approaches for chronic inflammation focused on functional endpoints in the oral cavity.
  • Investigating mechanisms of oral manifestations of chronic inflammation such as oral lichen planus, inflammatory bullous pemphigus.
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Impact

This initiative will address chronic inflammation related manifestations in the oral cavity. A growing appreciation of the microbial assemblages associated with healthy oral mucosa, and the control of immune tolerance and trained memory presents an opportunity to understand and capitalize on the role of chronic inflammation. This understanding can help drive efforts toward prevention of the onset of chronic inflammation in oral cancer, autoimmunity, and other conditions and improve clinical management of diseases. This interdisciplinary effort will require collaborative experts from multiple disciplines including infectious diseases, cancer, microbiology, mucosal immunology and drug development to develop and adapt translational therapeutic approaches for the oral cavity.

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Current Portfolio

NIDCR has funded studies examining oral-systemic connections and inflammation as a consequence of acute infections. Studies examining the role of innate immunity and autoantibodies in Sjögren’s Disease, mechanistic research on resistance or susceptibility to oral infections and molecular mediators of immune activation in Sjögren Disease pathogenesis, and oral microbiota and immune signaling pathways in head and neck cancer are all well represented across the NIDCR portfolio. Studies exploring the onset or progression of oral diseases due to chronicity of inflammation represent a distinct gap in the NIDCR portfolio.

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References

  1. Kostic AD, Chun E, Robertson L, Glickman JN, Gallini CA, Michaud M, Clancy TE, Chung DC, Lochhead P, Hold GL, El-Omar EM, Brenner D, Fuchs CS, Meyerson M, Garrett WS. Fusobacterium nucleatum potentiates intestinal tumorigenesis and modulates the tumor-immune microenvironment. Cell Host Microbe. 2013 Aug 14;14(2):207-15.
  2. Parhi L, Alon-Maimon T, Sol A, Nejman D, Shhadeh A, Fainsod-Levi T, Yajuk O, Isaacson B, Abed J, Maalouf N, Nissan A, Sandbank J, Yehuda-Shnaidman E, Ponath F, Vogel J, Mandelboim O, Granot Z, Straussman R, Bachrach G. Breast cancer colonization by Fusobacterium nucleatum accelerates tumor growth and metastatic progression. Nature Communications. Volume 11, Article number: 3259 (2020).
  3. Desai S, Dharavath B, Manavalan S, Rane A, Redhu AK, Sunder R, Butle A, Mishra R, Joshi A, Togar T, Apte S, Bala P, Chandrani P, Chopra S, Bashyam MD, Banerjee A, Prabhash K, Nair S, Dutt A. Fusobacterium nucleatum is associated with inflammation and poor survival in early-stage HPV-negative tongue cancer. NAR Cancer. 2022 Mar 4;4(1):zcac006.
  4. Haaheim LR, Halse AK, Kvakestad R, Stern B, Normann O, Jonsson R. Serum antibodies from patients with primary Sjögren's syndrome and systemic lupus erythematosus recognize multiple epitopes on the La(SS-B) autoantigen resembling viral protein sequences. Scand J Immunol. 1996 Jan;43(1):115-21.
  5. Maślińska M. The role of Epstein-Barr virus infection in primary Sjögren's syndrome. Curr OpinRheumatol. 2019 Sep;31(5):475-483.
  6. Silva LM, Doyle AD, Greenwell-Wild T, Dutzan N, Tran CL, Abusleme L, Juang LJ, Leung J, Chun EM, Lum AG, Agler CS, Zuazo CE, Sibree M, Jani P, Kram V, Martin D, Moss K, Lionakis MS, Castellino FJ, Kastrup CJ, Flick MJ, Divaris K, Bugge TH, Moutsopoulos NM. Fibrin is a critical regulator of neutrophil effector function at the oral mucosal barrier. Science. 2021 Dec; 374 (6575). doi: 10.1126/science.abl5450
  7. Smatti MK, Cyprian FS, Nasrallah GK, Al Thani AA, Almishal RO, Yassine HM. Viruses and Autoimmunity: A Review on the Potential Interaction and Molecular Mechanisms. Viruses. 2019 Aug; 11(8): 762.
  8. Dotan A, Muller S, Kanduc D, David P, Halpert G, Shoenfeld Y. The SARS-CoV-2 as an instrumental trigger of autoimmunity. Autoimmun Rev. 2021 Apr;20(4):102792.
  9. Croia C, Astorri E, Murray-Brown W, Willis A, Brokstad KA, Sutcliffe N, Piper K, Jonsson R, Tappuni AR, Pitzalis C, Bombardieri M. Implication of Epstein-Barr virus infection in disease-specific autoreactive B cell activation in ectopic lymphoid structures of Sjögren's syndrome. Arthritis Rheumatol. 2014 Sep;66(9):2545-57.
  10. Brauner S, Folkersen L, Kvarnström M, Meisgen S, Petersen S, Franzén-Malmros M, Mofors J, Brokstad KA, Klareskog L, Jonsson R, Westerberg LS, Trollmo C, Malmström V, Ambrosi A, Kuchroo VK, Nordmark G, Wahren-Herlenius M. H1N1 vaccination in Sjögren's syndrome triggers polyclonal B cell activation and promotes autoantibody production. Ann Rheum Dis. 2017 Oct;76(10):1755-1763.
  11. Björk A, Thorlacius GE, Mofors J, Richardsdotter Andersson E, Ivanchenko M, Tingström J, James T, Brokstad KA, Cox RJ, Jonsson R, Kvarnström M, Wahren-Herlenius M. Viral antigens elicit augmented immune responses in primary Sjögren's syndrome. Rheumatology (Oxford). 2020 Jul 1;59(7):1651-1661. doi:10.1093/rheumatology/kez509
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Last Reviewed
April 2024