Salivary Biology and Immunology Program
Integrative Biology and Infectious Diseases Branch
Division of Extramural Research
The objective of this concept is to encourage studies that examine immune mechanisms of protection against recurrence of infectious and autoimmune diseases of dental, oral, and craniofacial (DOC) tissues, and to develop immunomodulatory approaches to protect against episodic recurrence.Back to top
Episodic recurrence of inflammation in response to infections or autoimmune conditions has been a long-standing issue in recalcitrant disease manifestations of DOC tissues. Conditions with recurrence are characterized by patterns of exacerbation and quiescent periods. The oral cavity is one of the sites of early manifestation of recurrent systemic diseases and these diseases in turn lead to poor oral health. Due to their poorly understood etiology and resultant challenge for medical treatment and patient management, recurrent diseases attract much attention. In case of autoimmune oral lichen planus (OLP), oral lesions are known to recur more persistently compared to skin manifestations. Sex differences in recurrence-related sequelae have also been described. In women, OLP lesions are more likely to develop into oral leukoplakia, and patients with oral leukoplakia are at increased risk of oral squamous cell carcinoma. Advances in treatment management of recurrent conditions have led to further questions on the underlying mechanisms of observed outcomes. In HIV-infected patients with low CD4 counts, significantly lower number of episodes of oropharyngeal candidiasis and other invasive fungal infections were observed with continuous fluconazole therapy, compared with episodic fluconazole treatment for recurrences. GWAS analysis of recurrent aphthous stomatitis have identified associations at immune regulatory loci in the etiology of mouth ulcers. Additionally, recent mechanistic studies on the immunology front have shown that the epigenetic signature of LPS-induced tolerance is reversed upon ‘training’ with β-glucan; implying that a role for immune memory in innate immunity and has come to be termed as “trained memory”. This “training” has been shown to reinstate the proper cytokine responses of human macrophages after LPS-induced immunological tolerance.
Immune memory, the ability to remember and respond more robustly against a second encounter, is maintained by distinct populations of long-lived memory cells that can persist without residual antigen. Traditionally, this memory has been attributed to the adaptive arm of immunity. The concept of “trained immunity” refers to an enhanced state of immunity to a future inflammatory or microbial challenge that is based on innate immune memory. Recently, this kind of immune memory has been described in organisms lacking T and B cells and in myeloid cells. Induction of trained memory appears to be mediated by long-term adaptations that persist over time despite the loss/cessation of the inductive stimulus.
Changes in immune and neuroendocrine signaling, metabolic pathways coupled with changes in transcriptional regulation of epigenetic modifications may be explained by some of the long-term rewiring of the trained memory. Understanding the mechanisms of trained immunity that mediate protective immunity against subsequent stress associated with infectious and inflammatory challenges are essential to immune robustness in health and in disease and immunomodulatory therapies for preventing/tolerating recurrence of such diseases of the oral cavity.Back to top
Gaps and Opportunities
Significant knowledge gaps currently exist in our understanding of protective mechanisms underlying recurrence of DOC disease including infections, autoimmune conditions, oral manifestation of systemic conditions. The role of immunological memory and plasticity of the tissue microenvironment in protective effects against episodic recurrences oral conditions and oral sequelae of systemic conditions has remained unexplored. Overcoming knowledge gaps in this area is expected to generate immunomodulatory approaches toward achieving robustness in DOC tissues, and a better understanding of resilience factors in episodic recurrent conditions in DOC tissues. This will enable development of therapies to prevent and tolerate recurrence of DOC diseases and conditions.
This area of interest is aligned with NIDCR’s interest in immune robustness of DOC tissues. This topics folds into NIDCR’s greater interests expressed in PAR 19-172, -173 on Achieving Tissue Robustness Through Harnessing Immune System Plasticity. The proposed area shares interest with NIAMS who is also partnering in these parent funding opportunity announcements.
Currently, funded NIDCR studies address host immune mechanisms for long-term protection by regulatory immune cells. Immunological studies of re-occurrence of post-cancer events is currently covered by actively funded projects. However, projects addressing the protective aspects against episodic recurrence and persistence of DOC infections and autoimmune conditions are not covered in the portfolio. NIAID supports studies in immunological memory and several of those investigators presented at the Keystone meeting titled Immunological Memory: Innate, Adaptive and Beyond.Back to top
Scientific Areas of Interest
Areas of interest include, but are not limited to:
- Mechanisms of cross talk between oral tissues and systemic health in mediating tissue-resident immunity.
- A strong understanding of how cellular metabolism in immune cells and non-immune cells regulating trained memory.
- Changes in transcriptional programming and epigenetic rewiring that lead to downstream effects of immune memory at the oral mucosal barrier.
- The role of sex differences and age in protection against disease recurrence.
- Development and use of animal models that allow examination of molecular and cellular events/processes involved in protective immunity against recurrence.
New opportunities to probe these knowledge gaps are now possible by recent advances in various fields, including immune engineering, immunometabolism, and immune memory and tissue-resident immunity.Back to top
Penkov S, Mitroulis I, Hajishengallis G, Chavakis T. Immunometabolic Crosstalk: An Ancestral Principle of Trained Immunity? Trends Immunol. 2019, Jan;40(1):1-11.
Dan JM, Havenar-Daughton C, Kendric K, Al-Kolla R, Kaushik K, Rosales SL, Anderson EL, LaRock CN, Vijayanand P, Seumois G, Layfield D, Cutress RI, Ottensmeier CH, Lindestam Arlehamn CS, Sette A, Nizet V, Bothwell M, Brigger M, Crotty S. Recurrent group A Streptococcus tonsillitis is an immunosusceptibility disease involving antibody deficiency and aberrant TFH cells. Sci Transl Med. 2019 Feb 6;11(478).
Sanchez KK, Chen GY, Schieber AMP, Redford SE, Shokhirev MN, Leblanc M, Lee YM, Ayres JS. Cooperative Metabolic Adaptations in the Host Can Favor Asymptomatic Infection and Select for Attenuated Virulence in an Enteric Pathogen. Cell. 2018 Sep 20;175(1):146-158.e15.
Villani AC, Shekhar K. Single-Cell RNA Sequencing of Human T Cells. Methods Mol Biol. 2017;1514:203-239.
Netea MG, Joosten LA, Latz E, Mills KH, Natoli G, Stunnenberg HG, O'Neill LA, Xavier RJ. Trained immunity: A program of innate immune memory in health and disease. Science. 2016 Apr 22;352(6284):aaf1098.
Novakovic B, Habibi E, Wang SY, Arts RJW, Davar R, Megchelenbrink W, Kim B, Kuznetsova T, Kox M, Zwaag J, Matarese F, van Heeringen SJ, Janssen-Megens EM, Sharifi N, Wang C, Keramati F, Schoonenberg V, Flicek P, Clarke L, Pickkers P, Heath S, Gut I, Netea MG, Martens JHA, Logie C, Stunnenberg HG. β-Glucan Reverses the Epigenetic State of LPS-Induced Immunological Tolerance. Cell. 2016 Nov 17;167(5):1354-1368.e14.
Thom JT, Weber TC, Walton SM, Torti N, Oxenius A. The Salivary Gland Acts as a Sink for Tissue-Resident Memory CD8(+) T Cells, Facilitating Protection from Local Cytomegalovirus Infection. Cell Rep. 2015 Nov 10;13(6):1125-1136.Back to top