LITMIR.BIZ

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Macrophages, dendritic cells, lymphocytes (Treg) Anti‐inflammatory; down‐regulates IL‐1 and IFN‐γ; inhibits action of RANKL and bone resorption IL‐4 Th2 cells Inhibits bone resorption; inhibits Th17 formation; down‐regulates IL‐1 RANKL Normally present on osteoblasts; also Th1cells, endothelial cells, fibroblasts, PMNs, epithelial cells; may be soluble Osteoclasts and precursors (RANK) Activates osteoclasts; positively regulates bone resorption OPG Osteoblasts, some epithelial cells, endothelial cells, B cells Osteoblasts (RANKL) Decoy receptor for RANKL and blocks RANK/RANKL pathway; inhibits osteoclastogenesis and negatively regulates bone resorption Chemokines CXCL8 (IL‐8) Macrophages, PMN, Th1 cells, Th17 cells CXCR1‐2 Attracts PMNs and macrophages; chemotaxis and differentiation of osteoclasts CXCL12 (SDF‐1α) Endothelial cells Osteoclast precursors (CXCR4); PMNs Chemotaxis and differentiation of osteoclasts; attracts PMNs; up‐regulates MMPs CCL7 (MCP‐3) Endothelial cells, lymphocytes, fibroblasts, plasma cells Osteoclasts and precursors Chemotaxis and differentiation of osteoclasts CCL5 (RANTES) T cells, fibroblasts, osteoclasts, osteoblasts Osteoclasts and precursors (CCR1, CCR5) Chemotaxis and differentiation of osteoclasts CCL‐2 (MCP‐1) Osteoblasts Osteoclasts and precursors (CCR2) Chemotaxis and differentiation of osteoclasts CCL3 (MIP‐1α) Fibroblasts, osteoclasts, osteoblasts Macrophages (CCR1), lymphocytes/Th1 (CCR5) Chemotaxis and differentiation of osteoclasts; attracts macrophages CCL4 (MIP‐1β) Th1 cells Chemotaxis and differentiation of osteoclasts; activates macrophages Prostaglandins Prostaglandins (PGE₂) Macrophages, fibroblasts, inflammatory cells, epithelial cells, endothelial cells Osteoclasts (receptors EP₁–EP₄) Stimulates osteoclasts and bone resorption

      GM‐CSF, granulocyte‐macrophage colony‐stimulating factor; IFN, interferon; IL, interleukin; LPS, lipopolysaccharides; MCP, monocyte chemoattractant protein; MIP, macrophage inflammatory protein; MMP, matrix metalloproteinase; OPG, osteoprotegerin; PMN, polymorphonuclear leukocyte; RANK, receptor activator of nuclear factor kappa B; RANKL, receptor activator of nuclear factor kappa B ligand; RANTES, regulated upon activation, normal T cell expressed and presumably secreted; SDF, stromal cell‐derived factor; TGF, transforming growth factor; TLR, Toll‐like receptor; TNF, tumour necrosis factor; Treg, regulatory T cell.

Figure 3.6 Rest cells of Malassez appear as multiple small islands of epithelium (arrows) within the periodontal ligament.

      There is no doubt that the start of the process of cyst formation involves the proliferation of the epithelial cell rests within the inflamed tissues of a periapical granuloma. As discussed previously, LPS is the key factor that initiates the inflammatory and immune response, but it may also directly cause epithelial proliferation. In their study of fluids and explants from radicular cysts, keratocysts, and follicular cysts, Meghji et al. (1996 ) showed high levels of LPS in radicular cysts and demonstrated that it could directly stimulate epithelial proliferation in a dose‐dependent manner. They proposed that bacterial LPS, derived from the necrotic pulp, is the key initiating factor in the pathogenesis of radicular cysts. In this same study they also provided evidence that cytokines can directly stimulate epithelial proliferation. All cysts contained IL‐1α and IL‐6, but radicular cyst explants produced significantly more IL‐6 than either keratocysts or follicular cysts. Further experiments showed that IL‐1 and IL‐6, and culture supernatants from cyst fibroblasts, were able to stimulate epithelial proliferation in a dose‐dependent manner. Significantly, this activity was further enhanced by the addition of LPS.

In earlier experiments, the same research group (Meghji et al. 1989 ; Bando et al. 1993 ) used immunocytochemistry to localise cytokines and adhesion molecules in the walls of radicular cysts. All cysts showed positive staining for IL‐1α, IL‐1β, and IL‐6 in the epithelial lining and in vascular endothelial cells. Tumour necrosis factor (TNF) and CXCL8/IL‐8 were occasionally seen in macrophages. The cell adhesion molecules ICAM‐1 and ELAM‐1 (E‐selectin) were also identified in all lesions and were localised to endothelial cells, epithelium, and inflammatory cells.

      Kusumi et al. (2004 ) produced further evidence that IL‐6 has an important role. They used reverse transcriptase polymerase chain reaction (RT‐PCR) to study a number of cytokines in tissues from 19 radicular cysts and compared expression with normal gingivae and periodontal ligament. They found variable expression of cytokines in all tissues, but most cysts expressed IL‐1β, IL‐6, CXCL8/IL‐8, TNF‐α, interferon (IFN)‐γ, and TGF‐β1, and most of these showed increased expression compared with normal tissues. All the cytokines were expressed at low levels except for IL‐6, which showed high levels of secretion from fibroblasts extracted from the radicular cysts.

      These studies confirmed that the walls and epithelial lining of radicular cysts synthesise a range of cytokines and growth factors that are known to be involved in epithelial proliferation (Table 3.2).

      The role of abscess formation in the formation of a cyst will be discussed below, but there is good evidence that an acute inflammatory cell infiltration may be directly associated with epithelial proliferation, since many early studies were able to demonstrate large numbers of PMNs in the proliferating epithelium (Shear 1963a , 1964 ; Cohen 1979 ; Johannessen 1986 ). As mentioned above, LPS from the root canal stimulates CXCL8/IL‐8 secretion from periodontal fibroblasts via the co‐receptors CD14 and Toll‐like receptor (mainly TLR4). In addition, epithelial cells in periapical lesions have been shown to express CD14/TLR4 (Leonardi et al. 2015 ), and there is evidence that CXCL8/IL‐8 may directly cause epithelial proliferation as well as being a chemoattractant for PMNs (Silva et al. 2007 ; Marton and Kiss 2014 ). This would explain the association of proliferating epithelium and PMNs in early lesions.

Phase of Cyst Formation

      The next phase in the

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