Rethinking Immune System Plasticity: Towards Robustness in Dental, Oral, and Craniofacial Health

Integrative Biology and Infectious Diseases Branch, DER, NIDCR


This concept will encourage state-of-the-art, systematic research approaches to elucidate the role of immune system plasticity in health and in the pathogenesis of dental, oral, and craniofacial (DOC) diseases. This concept seeks to enhance the concepts of PAR-15-192, “Immune System Plasticity in the Pathogenesis and Treatment of Complex Dental, Oral, and Craniofacial Diseases”, and expand on areas of investigation to include immune mechanisms of autotherapies, and intersystem crosstalk of the immune system with other physiological systems. Autotherapies entail harnessing the body’s endogenous capacities to build, defend, and repair itself as a means of maintaining health, treating diseases or restoring biological robustness. Robustness is the ability of the immune system to dynamically maintain its functional role against internal and external perturbations. Plasticity is the ability of the immune system to undergo changes in both characteristics and functions, in response to physiological status of the environment. The expectation is that new knowledge derived from this research will facilitate development of novel, personalized immunomodulatory-based therapies that skew the balance between damaging and reparative effects toward the desirable state specific for any given patient.


Recent advances in understanding diseases and conditions involving DOC tissues – periodontitis, peri-implantitis, oral cancers, Sjögren’s Syndrome, and HIV/AIDS with its associated oral opportunistic infections - highlight that substantial changes occur in the immune system that contribute to disease onset, progression, and persistence. However, critical scientific gaps exist regarding our understanding of the relationship between the immune system control during maintenance of oral health and disease pathogenesis as well as across the lifespan; growth, development, aging. Specifically, how tissue- specific cues elicit immune responsiveness at these DOC sites to preserve tissue integrity and function during homeostasis, infection, and non-infectious perturbations, is minimally understood.

The oral mucosal barrier is constantly exposed to a plethora of triggers requiring immune control, including a diverse commensal microbiome, ongoing damage from mastication, and dietary and airborne antigens. How these tissue-specific cues participate in the training of immune responsiveness at this site and the mechanisms mediating homeostatic immunity at this interface are not yet fully defined.

While cancers can be viewed as the consequence of “under-healing”, autoimmune diseases can be considered a consequence of “over-repair” with excessive accumulation of extracellular matrix and failure to restore tissue function and architecture. Similarities between tumors and the inflammatory response associated with wound healing have been recognized. Inflammation-driven phenotypic plasticity and its effects on the immune landscape of oral tumors cells is yet to be understood, resulting in cancer progression and metastasis.

For example, mounting evidence demonstrates that impaired PD-1:PD-L function plays an important role in a variety of autoimmune diseases, such as Sjögren’s syndrome. Emerging antigen-specific immunotherapies, novel vaccination strategies with autoantigens, and new approaches for inducing immune tolerance to specific self-antigens are being successfully tested in animal models.

Research on chronic HIV infection has uncovered substantial information regarding oral and systemic effects of residual inflammation, immune activation, and microbial translocation in subjects treated with a combination of antiretroviral therapies. Understanding the plasticity of tissue-resident and hematopoietic immune sentinels enriched at the oral mucosal surfaces, and their crosstalk with the microenvironment, will shed light on persistence and immune memory in the oral cavity.

In addition, pain may accompany peripheral tissue damage associated with oral diseases. Neuronal control of immune cell function and age-related dysfunction in the peripheral systems such as salivary glands have been topics of recent studies in DOC tissue homeostasis. The role of neuro-immune crosstalk that shape aspects of DOC tissue robustness are not well understood.

Successful healing and regeneration of DOC tissues is critically dependent on the appropriate fine tuning of immune system’s plasticity to allow resolution of acute and chronic inflammation. Emerging evidence indicates that the immune system mediators may directly interact with stem cells niches to control stem cell homeostasis.

Research Opportunities

Studies showing the role of the immune system as a guardian of homeostasis, rather than as simply a safeguard against pathogens, has led to the recognition of its role in disease tolerance, in addition to resistance. These advances create an unprecedented opportunity to apply these discoveries towards understanding the robustness of the DOC environment and towards designing treatments for DOC diseases.

Recent basic science and clinical research advances have shown that the innate and adaptive immune systems can regulate gene networks in a cell-, environment-, and time-dependent manner contributing to robustness in health and disease. These advances highlight the importance of immune memory of interconnected molecular and cellular events/processes, rather than solely of molecular and cellular players. Secondly, clinical successes of immunotherapies for cancers, offer a model of cellular microenvironment manipulation adaptable to other diseases and disorders, especially for autoimmune diseases.  Additionally, successful clinical trials using bioelectronic devices provide a path for therapeutic modality for targeting neural mechanisms influencing immunity and inflammation. Finally, studies have shown that inflammatory mediators interact with the vasculature and stem cell niche with implications toward development of autotherapies.

Taken together, these and other critical advances identified a strong need to: 1) advance knowledge of immune plasticity of DOC health and diseases, and 2) develop tools and technologies for precise and robust modulation of immune plasticity to restore robustness. This concept will pursue both goals.

Specific Areas of Interest

  • Identifying molecular and cellular processes that contribute to immune robustness in DOC tissues
  • Deriving approaches and models to target functional plasticity reflecting the health and disease of human DOC environment across lifespan
  • Investigating mechanisms of intersystem crosstalk of the immune system with other physiological systems
  • Developing clinically-applicable strategies to maintain DOC health, and treat or prevent DOC disease
  • Validating and optimizing immune strategies that have shown promise in small animals; assessing safety and therapeutic efficacy of these strategies demonstrated using clinically relevant outcomes
  • Developing tools and technologies to non-invasively monitor immune system responses in real-time to precisely and predictably modulate immune system function towards realization of robustness


Chavan SS, Pavlov VA, Tracey KJ. Mechanisms and Therapeutic Relevance of Neuro-immune Communication. Immunity. 2017 Jun 20;46(6):927-942.

Dominguez-Villar M, Hafler DA. Regulatory T cells in autoimmune disease. Nat Immunol. 2018 Jun 20. doi: 10.1038/s41590-018-0120-4. [Epub ahead of print]

Eberl G, Pradeu T.  Towards a General Theory of Immunity?  Trends Immunol. 2018 Apr;39(4):261-263.

Dutzan N, Abusleme L, Bridgeman H, Greenwell-Wild T, Zangerle-Murray T, Fife ME, Bouladoux N, Linley H, Brenchley L, Wemyss K, Calderon G, Hong BY, Break TJ, Bowdish DME, Lionakis MS, Jones SA, Trinchieri G, Diaz PI, Belkaid Y, Konkel JE, Moutsopoulos NM. On-going Mechanical Damage from Mastication Drives Homeostatic Th17 Cell Responses at the Oral Barrier. Immunity. 2017 Jan 17;46(1):133-147.

Hölzel M, Bovier A, Tüting T. Plasticity of tumour and immune cells: a source of heterogeneity and a cause for therapy resistance? Nat Rev Cancer. 2013 May;13(5):365-76

Laurent P, Jolivel V, Manicki P, Chiu L, Contin-Bordes C, Truchetet ME, Pradeu T.  Immune-Mediated Repair: A Matter of Plasticity.  Front Immunol. 2017 Apr 24;8:454.

Mantovani A. Wandering pathways in the regulation of innate immunity and inflammation. J. Autoimmun. 2017 Dec;85:1-5.

Mitroulis I, Kalafati L, Hajishengallis G, Chavakis T. Myelopoiesis in the Context of Innate Immunity. J Innate Immun. 2018 Jun 6:1-8

Moutsopoulos NM, Moutsopoulos HM. The oral mucosa: A barrier site participating in tissue-specific and systemic immunity. Oral Dis. 2018 Mar;24(1-2):22-25.

Pozsgay J, Szekanecz Z, Sármay G. Antigen-specific immunotherapies in rheumatic diseases. Nat Rev Rheumatol. 2017 Sep;13(9):525-537.

Truchetet ME, Pradeu T.  Re-thinking our understanding of immunity: Robustness in the tissue reconstruction system.  Semin Immunol. 2018 Apr; 36:45-55.

Veiga-Fernandes H, Freitas AA. The S(c)ensory Immune System Theory. Trends Immunol. 2017 Oct;38(10):777-788

Wynn TA, Vannella KM. Macrophages in Tissue Repair, Regeneration, and Fibrosis. Immunity. 2016 Mar 15;44(3):450-462.


Last Reviewed
September 2018