As the oral mucosa provides a favorable niche for many microbial species, it becomes the responsibility of the host immunity to differentiate pathogen from commensal. Colonization itself is a harmless state; however, the fact that, under certain conditions, some microbial residents can turn pathogenic presents a quandary for oral immunity because the question is no longer how to differentiate friend from foe but rather how to determine when a friend becomes a foe. Therefore, setting the “rules of engagement” by the host immune system is an exceedingly complex and dynamic task. In essence, the immune responses in the oral cavity need to be naturally oriented towards a more tolerogenic state, which has led to the assertion that the oral mucosa is an immune-privileged site . Mounting an aggressive immune response against colonizing microbes that pose no threat would be unnecessary, metabolically wasteful, and potentially damaging to host tissues.
The oral mucosa maintains resident dendritic cells, which act as antigen-presenting cells (APCs) releasing proinflammatory cytokines that activate adaptive immunity (Fig 1B) . However, the mucosal dendritic cells are predisposed to a tolerogenic state, resulting in the secretion of anti-inflammatory immunomodulators such as interleukin 10 (IL-10), transforming growth factor beta (TGF-β), and Prostaglandin E2 . These effectors act in suppressing the activity of the immune system and generating T regulatory cells (T-regs) in the tissue, thereby propagating a tolerant state . Although it is not well understood how mucosal dendritic cells induce a state of tolerance, some studies have cited the role of immune exhaustion, in which APCs are no longer activated in response to specific commensal antigens, essentially becoming desensitized . While the immune interactions of pathogens with the oral mucosa remain ambiguous, the pathogen-associated molecular patterns (PAMPs) of normal mucosa do not trigger an inflammatory response. Unfortunately, the expression and character of these PAMPs do not necessarily change during a pathogenic shift because the transition is not always associated with novel antigenic features in some pathogens. However, the expression of virulence factors such as adhesins and enzymes does remain a hallmark of pathogenesis and aids in the detection of commensal-turned-pathogen for the immune system. Overall, the detection of commensal from pathogen at mucosal tissues remains a highly complex and nuanced dynamic.
Other secondary and local oral immune effectors play an important supportive role in providing mucosal protection, such as the salivary antibody secretory immunoglobulin A (sIgA), which acts in noninflammatory mediated neutralization of microbes, a phenomenon termed “immune exclusion” . Additionally, antimicrobial peptides (AMPs), most notably histatins, defensins, and cathelicidin LL-37, often constitute the first line of defense against microbes in the oral cavity and can interact synergistically in limiting microbial colonization . In essence, maintenance of oral health reflects the continuous negotiations between resident inflammatory immune cells and the microbial ecology in the oral cavity.
Complexity of the oral microbial flora and host immune responses.
(A) A false-colored scanning electron image demonstrating the diversity of the microbial population residing in the deep subgingival pockets where the environment is anaerobic. (B) A schematic illustrating the complexity of the host immune responses involved in maintaining homeostasis in the oral cavity. Under tolerogenic conditions, resident DCs sample the microbial species in the millieu. In the absence of damage and infection, this recognition of microbial antigens or PAMPs results in the secretion of immunosuppressive cytokines and growth factors by the DC. This cytokine profile induces the differentiation of T-regs, which release a series of cytokines to further maintain the tolerogenic state. B cells, which mature into plasma cells, produce sIga, which neutralizes microorganisms in a noninflammatory manner to limit colonization, a process termed “immune exclusion.” Additionally, T-regs also induce a tolerogenic state in resident MΦs and neutrophils, triggering the release of AMPs into the microenvironment. AMP, antimicrobial peptide; DC, dendritic cell; IL, interleukin; MΦ, macrophage; PAMP, pathogen-associated molecular pattern; PGE2, Prostaglandin E2; sIga, secretory immunoglobulin A; T-regs, T regulatory cells; TGF-β, transforming growth factor beta.
Sultan AS1, Kong EF1,2,3, Rizk AM1, Jabra-Rizk MA. The oral microbiome: A Lesson in coexistence.PLoS Pathog. 2018 Jan 25;14(1):e1006719.