Читать книгу Shear's Cysts of the Oral and Maxillofacial Regions - Paul M. Speight - Страница 47
Phase of Initiation
ОглавлениеIt is generally agreed that the source of epithelium for a radicular cyst is the epithelial cell rests of Malassez. During tooth development the epithelial root sheath of Hertwig maps out the shape of the roots and initiates dentine formation. When tooth formation is complete, the sheath disintegrates and epithelial remnants remain in the periodontal ligament as the rest cells of Malassez. There are two common misconceptions about these cells: first, that they are small islands; and second, that they have no normal function. It is now clear that the epithelial remnants form a network or mesh that lies in the periodontal ligament and surrounds or embraces the tooth root. Only in histological sections do they appear to be isolated islands (Figure 3.6). It is now also apparent that the cell rests of Malassez have a number of important functions in normal periodontal homeostasis, including cementogenesis, healing and regeneration (Keinan and Cohen 2013 ; Xiong et al. 2013 ). They are thus important in maintaining periodontal health during all the normal challenges of tooth movement and function as well as in responses to trauma, orthodontic tooth movement, and periodontitis. These properties are being exploited in the development of therapeutic approaches to promote periodontal regeneration in the management of periodontal diseases (Xiong et al. 2013 ).
Table 3.2 Biological factors that have a role in the pathogenesis of radicular cyst.
| Factors | Cell(s) of origin | Target cell (ligand(s)) | Key function |
|---|---|---|---|
| Bacterial factors | |||
| LPS (endotoxin) | Bacteria | Fibroblasts and many cell types (CD14/TLR) | Induces a wide range of mediators, including CXCL8/IL‐8, TNF‐α, IL‐1, RANKL, OPG. Indirectly stimulates bone resorption |
| Cytokines | |||
| IL‐1α | Macrophages, PMN, osteoclasts, epithelial cells, dendritic cells | Attracts and activates PMNs; stimulates production of prostaglandins, proteolytic enzymes, cytokines IL‐6, IL‐8; stimulates bone resorption and inhibits bone formation (originally called osteoclast‐activating factor, OAF) | |
| IL‐1β | Macrophages | Monocytes | Inhibits osteoclast formation and bone resorption |
| IL‐6 | Macrophages, epithelial cells, PMN, Th2 cells, B lymphocytes, endothelial cells, fibroblasts | Activates and stimulates PMNs and T cells; stimulates differentiation of B lymphocytes into plasma cells; stimulates osteoclasts and bone resorption; down‐regulates production of IL‐1 | |
| TNF‐α | Macrophages, Th1 cells, PMN, fibroblasts | Activates lymphocytes and macrophages; stimulates bone resorption | |
| IL‐17 | Th17 | Up‐regulates secretion of IL‐1, IL‐6, TNF‐α, and IL‐8 secretion; attracts PMNs; stimulates osteoclasts and bone resorption | |
| GM‐CSF | Macrophages, T lymphocytes, endothelial cells, PMN | Functionally activates macrophages and PMNs | |
| TGF‐β | Lymphocytes (Treg), macrophages, fibroblasts, osteoblasts, osteoclasts, epithelial cells | PMNs, macrophages | Anti‐inflammatory; suppresses T and B lymphocytes; down‐regulates production of IL‐1, IL‐6, TNF‐α, and IFN‐γ; blocks production of nitric oxide by macrophages; inhibits bone resorption; inhibits Th17 and promotes Treg formation |
| IFN‐γ | Th1 cells, dendritic cells | Th lymphocytes | Activates macrophages; induces IL‐1 production; inhibits RANKL and bone resorption |
| IL‐12 | Th1 cells, macrophages, dendritic cells | Up‐regulates IL‐1 and IFN‐γ; stimulates Th1 differentiation; suppresses Th2 differentiation | |
| IL‐10 | 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.
