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Review
. 2017 Oct;75(1):116-151.
doi: 10.1111/prd.12181.

Revisiting the Page & Schroeder model: the good, the bad and the unknowns in the periodontal host response 40 years later

George Hajishengallis, Jonathan M Korostoff
Review

Revisiting the Page & Schroeder model: the good, the bad and the unknowns in the periodontal host response 40 years later

George Hajishengallis et al. Periodontol 2000. 2017 Oct.

Abstract

In their classic 1976 paper, Page & Schroeder described the histopathologic events and the types of myeloid cells and lymphocytes involved in the initiation and progression of inflammatory periodontal disease. The staging of periodontal disease pathogenesis as 'initial', 'early', 'established' and 'advanced' lesions productively guided subsequent research in the field and remains fundamentally valid. However, major advances regarding the cellular and molecular mechanisms underlying the induction, regulation and effector functions of immune and inflammatory responses necessitate a reassessment of their work and its integration with emerging new concepts. We now know that each type of leukocyte is actually represented by functionally distinct subsets with different, or even conflicting, roles in immunity and inflammation. Unexpectedly, neutrophils, traditionally regarded as merely antimicrobial effectors in acute conditions and protagonists of the 'initial' lesion, are currently appreciated for their functional versatility and critical roles in chronic inflammation. Moreover, an entirely new field of study, osteoimmunology, has emerged and sheds light on the impact of immunoinflammatory events on the skeletal system. These developments and the molecular dissection of crosstalk interactions between innate and adaptive leukocytes, as well as between the immune system and local homeostatic mechanisms, offer a more nuanced understanding of the host response in periodontitis, with profound implications for treatment. At the same time, deeper insights have generated new questions, many of which remain unanswered. In this review, 40 years after Page & Schroeder proposed their model, we summarize enduring and emerging advances in periodontal disease pathogenesis.

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Figures

Fig. 1
Fig. 1. Innate-adaptive immune interplay leading to inflammatory tissue damage and bone loss in periodontitis
Periodontitis arises from complex interactions between the host and the subgingival dysbiotic microbiota that lead to excessive or dysregulated inflammatory responses involving elements of both innate (complement, phagocytes) and adaptive immunity (regulatory and effector lymphocytes). Shown is a simplified view of cytokine- and chemokine-mediated cross-talk interactions between innate and adaptive immune cells leading to destruction of connective tissue and bone in periodontitis. See text with figure-1 callouts for details. Abbreviations in the figure: Abs, antibodies; APRIL, a proliferation-inducing ligand; B, B cell; BLyS, B lymphocyte stimulator; C, complement; DC, dendritic cell; FB, fibroblast; G-CSF, granulocyte-colony stimulating factor; Mφ, macrophage; MMP, matrix metalloproteinases; IL, interleukin; IFN, interferon; N, neutrophil; OBL, osteoblast; OCL, osteoclast, P, plasma cell; RANKL, receptor activator of nuclear factor-κB ligand; ROS, reactive oxygen species; TGFβ, transforming growth factor-β; TNF, tumor necrosis factor; Treg, T regulatory cell; Th-1,-2,-17, T helper type -1,-2, -17 cells.
Fig. 2
Fig. 2. Regulatory neutrophil cross-talk with other leukocyte types
Neutrophils can potentially suppress T cell activation by releasing arginase-1 (depletes arginine required for T cell activation) or by delivering H2O2 into the immunological synapse in a Mac-1 integrin–dependent manner. Neutrophils can also indirectly suppress T cell activation through myeloperoxidase- or elastase-dependent mechanisms that inhibit dendritic cell (DC) function. Furthermore, neutrophils can release ectosomes that can down-regulate the inflammatory activity of innate immune cells, such as macrophages and natural killer (NK) cells.
Fig. 3
Fig. 3. Biological functions of interleukin-17 and their potential impact on periodontitis
Interleukin-17 acts predominantly on innate immune and stromal cells (e.g., fibroblasts, endothelial and epithelial cells) to promote innate immunity, especially neutrophil-mediated antimicrobial and inflammatory responses. In this regard, interleukin-17 promotes granulopoiesis and neutrophil recruitment by up-regulating granulocyte-colony stimulating factor and CXC chemokines and by down-regulating developmental endothelial locus-1, an endogenous inhibitor of neutrophil adhesion and extravasation. Interleukin-17 can moreover induce the production of epithelial cell-derived antimicrobial molecules. On the other hand, interleukin-17 can contribute to the destruction of both connective tissue and the underlying bone by stimulating the production of matrix metalloproteinases and RANKL from the indicated stromal cell types. Interleukin-17 is thus an immunological double-edged sword with both protective and destructive functions. As indicated, the current burden of evidence from human and animal model studies suggests that the net effect of interleukin-17 signaling promotes periodontal disease development. Abbreviations in the figure: developmental endothelial locus-1; developmental endothelial locus-1; G-CSF, granulocyte-colony stimulating factor; MMPs; matrix metalloproteinases; RANKL, receptor activator of nuclear factor-κB ligand. From Zenobia and Hajishengallis [ref. (298)]; used by permission.
Fig. 4
Fig. 4. Protective and destructive functions of B-lineage cells within the periodontium
The junctional epithelium is situated in close proximity to the bacterial biofilm that develops on teeth. Quantitative and compositional changes of the microbiota (dysbiosis) induce innate immune signaling pathways that lead to the development of an adaptive immune response within the gingival connective tissue. Regarding the humoral component of the response, pathogen-specific antibody that diffuses into the gingival sulcus (or pocket) or remains in the connective tissue can, in principle, inhibit the bacterial challenge via a number of potential mechanisms (indicated). However, the antibody response has not been associated with protection in clinical studies. In fact, antibody-mediated activation of complement and innate immune cells can enhance gingival inflammation and contribute to tissue breakdown. Moreover, recent evidence has demonstrated the potential for B-lineage cells to express proinflammatory cytokines, matrix metalloproteinases, and RANKL. B-lineage cells therefore directly and indirectly participate in the degradation of the soft and hard tissue components of the periodontium, as indicated. The details are discussed in the text. Abbreviations in the figure: APRIL, a proliferation-inducing ligand; BLyS, B lymphocyte stimulator; MMP, matrix metalloproteinases; IL, interleukin; LPS, lipopolysaccharide; RANK; receptor activator of nuclear factor-κB; RANKL, receptor activator of nuclear factor-κB ligand; TNF, tumor necrosis factor.
Fig. 5
Fig. 5. Developmental pathways of CD4-positive T cells, their functions and associations with particular diseases
Naïve CD4-positive Th cells differentiate into distinct lineages depending on the indicated cytokine milieu during activation by antigen-presenting cells. As shown, each of these effector or regulatory T cell subsets has a characteristic cytokine expression pattern and hence distinct functions and roles in autoimmune or inflammatory diseases, including periodontitis. Ag, antigen; B, B cell; DC, dendritic cell.
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