Recent advances in host defense mechanisms/therapies against oral infectious diseases and consequences for systemic disease

Abstract

The innate and adaptive immune systems are both crucial to oral disease mechanisms and their impact on systemic health status. Greater understanding of these interrelationships will yield opportunities to identify new therapeutic targets to modulate disease processes and/or increase host resistance to infectious or inflammatory insult. The topics addressed reflect the latest advances in our knowledge of the role of innate and adaptive immune systems and inflammatory mechanisms in infectious diseases affecting the oral cavity, including periodontitis and candidiasis. In addition, several potential links with systemic inflammatory conditions, such as cardiovascular disease, are explored. The findings elucidate some of the defense mechanisms utilized by host tissues, including the role of IL-17 in providing immunity to oral candidiasis, the antimicrobial defense of mucosal epithelial cells, and the pro-resolution effects of the natural inflammatory regulators, proresolvins and lipoxins. They also describe the role of immune cells in mediating pathologic bone resorption in periodontal disease. These insights highlight the potential for therapeutic benefit of immunomodulatory interventions that bolster or modulate host defense mechanisms in both oral and systemic disease. Among the promising new therapeutic approaches discussed here are epithelial cell gene therapy, passive immunization against immune cell targets, and the use of proresolvin agents.

Keywords: bacterial invasion; cytokines; fungal immunity; lipoxins; oropharyngeal candidiasis; periodontal bone resorption.

Figure 1.

Old vs. new model of Th-cell-based immunity to Candida albicans. Prior to the recognition of the Th17 cell subset, it was considered in the field that the dominant T-cell response to C. albicans was mediated by Th1 cells via IFN_γ. This was premised on the observation that mice lacking the IL-12p40 subunit were susceptible to disease. However, IFNγ-deficient mice were not susceptible (Farah et al., 2006). The discovery of Th17 cells and the shared use of IL-12p40 with the cytokine IL-23 led to a revision of the paradigm, in which Th17 cells and IL-17 are essential for immunity to OPC (Conti et al., 2009).

Figure 2.

IL-17-based immunity to Candida albicans. Antigen-presenting cells (mainly dendritic cells and macrophages) express pattern recognition receptors for fungi, including Toll-like receptors (TLRs), C-type lectin receptors (CLRs, such as Dectin-1 and Dectin-2), and NOD-like receptors, such as NLRP3. Signaling through these molecules, particularly the CLR adaptor CARD9, leads to the expression of IL-1_β, IL-23, and IL-6, all of which are inductive for the Th17 lineage via the transcription factors STAT3 and ROR_γt. IL-17 and IL-22 production from Th17 cells, in turn, acts on target cells to induce expression of effector molecules that protect against candidiasis, including antimicrobial peptides such as defensins and neutrophil-recruiting chemokines.

Figure 3.

Autonomous intracellular innate immunity in mucosal epithelial cells. In this model, current evidence suggests that, upon entry into the cell, invading bacteria encounter S100A8/A9 in the cytoplasm and LL-37 in the endoplasmic reticulum. Bacterial invasion also stimulates the release of intracellular IL-1_α to be bound by the IL-1 receptor (R) on the plasma membrane. Engagement of the IL-1R signals through p38 MAP kinase to promote binding of the transcription factor C/EBP_β and up-regulated transcription and translation of S100A8/A9 and cathelicidin antimicrobial peptide (CAMP). CAMP is cleaved to the more potent LL-37. S100A8/A9 in mucosal epithelial cells can be hypothesized to function as a direct antimicrobial peptide by chelating Zn++ and Mn++, both essential for bacterial growth. Likewise, S100A8/A9 is known to activate NADPH oxidase on the cytoplasmic face of the plasma membrane, resulting in increased production of reactive oxygen species (ROS) and other antimicrobial compounds. These several S100A8/A9- and CAMP-dependent mechanisms function to provide intra-epithelial innate immunity against invading pathogens.

Figure 4.

For the past two millennia, physicians have understood the cardinal signs of inflammation; for the past 1,000 years, they have understood the concept of pro-inflammatory mediators’ regulation of the inflammatory response. The new discovery of the late 20th century was the pathways of resolution of inflammation, an active process mediated by de novo synthesis of eicosanoids that bind to specific receptors.

Figure 5.

Reduction of periodontal inflammation by high-dose atorvastatin. Periodontal inflammation was measured via FDG uptake by PET scan before and after dosing with 80-mg vs. 10-mg atorvastatin for 12 wk. The change in periodontal inflammation with 80-mg atorvastatin was significantly greater than that with 10 mg and correlated with reductions in carotid inflammation (r = 0.58, p = .001) (figure derived from Subramanian et al., 2013). Statin anti-inflammatory activity is mediated, at least in part, by the production of resolvins (Spite and Serhan, 2010). Compliance with medication regimens in the trial were tracked through reductions in serum cholesterol (inset).