Pathogen Recognition and Activation of Cellular

Innate Responses. If plaque bacteria and their products

penetrate the periodontal tissues, specialized “sentinel cells” of the
immune system recognize their presence and signal protective
immune responses. These cells include macrophages and dendritic
cells, which express a range of pattern recognition receptors
(PRRs) that interact with specific molecular structures on microorganisms
called MAMPs. The activation of PRRs activates innate
immune responses to provide immediate protection, and adaptive
immunity is also activated with the aim of establishing a sustained
antigen-specific defense. Excessive and inappropriate or dysregulated
immune responses lead to chronic inflammation and the concomitant
tissue destruction associated with periodontal disease. A
glossary of terms relevant to periodontal immunobiology is presented
in Table 5-6.
The best studied of the signaling systems involved in the recognition
of plaque bacteria is the interaction of bacterial LPS with
TLRs: P. gingivalis, A. actinomycetemcomitans, and F. nucleatum
all possess LPS molecules that interact with TLR-4 to activate
myeloid immune cells. However, individual species of plaque bacteria
have a wide variety of MAMPs, which may interact with
PRRs. For example, P. gingivalis LPS signals via TLRs (predominantly
TLR-2), and fimbriae, proteases, and DNA from P. gingivalis
are all recognized by host cells through interaction with specific
PRRs. A number of nonimmune cells in the periodontium (e.g.,
epithelial cells, fibroblasts) also express PRRs and may recognize
and respond to MAMPs from plaque bacteria.
Although the signaling pathways activated by PRRs may be
diverse, in general terms, they converge to elicit similar host cell
responses in the form of the upregulation of cytokine secretion and,
in the case of APCs such as dendritic cells, cell differentiation that
leads to enhanced signaling of the adaptive immune response.
Dendritic cells also have C-type lectin receptors (e.g., mannose
receptor, langerin, DC-SIGN) that recognize glycans on pathogens.
However, the role of these interactions in periodontal disease is not
known.
The signaling of cytokine responses via PRRs influences innate
immunity (e.g., neutrophil activity), adaptive immunity (e.g., T-cell
effector phenotype), and the development of destructive inflammation
(e.g., the activation of fibroblasts and osteoclasts). A number
of cytokines are particularly important to innate immune signaling,
and there is now good evidence that these have a role in immune
responses in the periodontium. The archetypal pro-inflammatory
cytokine is IL-1β, which exerts its action directly by activating
other cells that express the IL-1R1 receptor (e.g., endothelial cells)
or by stimulating the synthesis and secretion of other, secondary
mediators such as PGE2 and nitrous oxide. The effect of IL-1β is
amplified via a synergistic action with other cytokines such as
TNF-α. The upregulation of ICAM-1 and E-selectin on endothelial
cells is central to the migration of neutrophils into the periodontium,
and this is stimulated by IL-1β and TNF-α. IL-1β also stimulates
the secretion of the chemokine IL-8, which stimulates
neutrophil chemotaxis; this is described in more detail in the next
section of this chapter. IL-1β and TNF-α also activate MMP secretion
from fibroblasts and osteoclasts; this facilitates the movement
of neutrophils through the connective tissues (and thus protective
innate responses) but also contributes to the tissue destruction
associated with periodontal disease, along with MMPs from
neutrophils.
Other cytokines that are upregulated as a result of the activation
of PRRs include IL-6, which influences the development of a
number of immune cells (e.g., B cells, dendritic cells) and stimulates
osteoclast differentiation and thus bone turnover. Other cytokines
provide specific signals that contribute to the development
of specific CD4+ T-helper cell subsets (e.g., IL-4, IL-12, IL-18; see
the section of this chapter entitled “Adaptive Immunity”). In addition
to cytokines that activate immune responses, other cytokines
are upregulated that have a role in immune regulation by suppressing
cytokine activity; these include IL-1Ra, IL-10, and TGF-β.
Cytokines from T-cell subsets feedback to and modify innate
immune responses; for example, IFN-γ from Th1 cells activates
macrophages, IL-17 from Th17 cells synergizes with IL-1β and
TNF-α to reinforce inflammatory reactions, and IL-10 and TGF-β
suppress immune responses. The action of many cytokines produced
in the periodontium is not limited to one aspect of the host
immune response; in other words, cytokines are pleiotropic (i.e.,
they have multiple effects).