cells outnumbered T‐helper cells in periapical granulomas, T‐helper cells predominated in the cysts that they examined. A more recent study (Liapatas et al. 2003 ) has confirmed most of these findings. It showed that T cells predominated and that helper cells predominated over cytotoxic/suppressor cells in most periapical granulomas and cysts. In cysts, however, they found increased numbers of plasma cells, suggesting that humoral immune reactions may take on a more important role in cysts. These studies illustrate the complex nature of the immune interactions in periapical lesions and may explain the discrepancy in the results reported by different workers.
The proportion of B lymphocytes has been reported to be about 20% (Kontiainen et al. 1986 ), with plasma cells varying from 2% (Kontiainen et al. 1986 ) to 13% (Stern et al. 1982 ). As would be expected, the vast majority (over 75%) of plasma cells express immunoglobulin (Ig)G, with 15–20% IgA and very few IgE or IgM (Stern et al. 1981 ; Smith et al. 1987 ). Other cell types that play a role in periapical lesions include macrophages, mast cells, and Langerhans cells (Pulver et al. 1978 ; Kontiainen et al. 1986 ; Drazic et al. 2010 ). Langerhans cells may be of particular interest because they have been found in the epithelial linings of radicular cysts (Contos et al. 1987 ; Matthews and Browne 1987 ; Gao et al. 1988a ; Liapatas et al. 2003 ) and are most prominent in areas of heavy inflammation. Although they are known to be important in antigen presentation, it has been suggested that they may also be associated with epithelial proliferation (Carillo et al. 2010 ). Non‐immune cells, including fibroblasts, endothelial cells, and epithelial cells, are also present and may be involved in producing relevant cytokines and growth factors. Lesions also contain PMNs and primary or secondary abscess formation may be a key factor in cyst formation (see later in this chapter).
Although the main initiating factor of a periapical lesion is bacterial LPS, the lesions are then sustained by a complex network of inflammatory mediators, including cytokines, chemokines, and the eicosanoids (mainly prostaglandins). These have multiple roles in cell activation and migration, in epithelial proliferation, and in bone resorption. In early lesions there is good evidence that the chemokine CXCL8/IL‐8 is important since it is absent in normal pulp, but found in about 95% of periapical lesions. LPS stimulates periodontal ligament fibroblasts to secrete CXCL8/IL‐8, which has a pivotal role in PMN migration and therefore in lesion initiation (reviewed in Silva et al. 2007 ; Graunaite et al. 2012 ; Marton and Kiss 2014 ). This chemokine is also important in bone resorption. Other pivotal cytokines are the interleukins, especially IL‐1 and IL‐6, which have roles in activating PMNs and lymphocytes, and in bone resorption (reviewed in Graunaite et al. 2012 ). Table 3.2 lists a number of selected biological factors that may be involved in the pathogenesis of radicular cysts. Mostly this list is derived from the reviews mentioned previously (Bernardini et al. 2015 ; Marton and Kiss 2014 ; Graunaite et al. 2012 ; Graves et al. 2011 ; Silva et al. 2007 ; Lin et al. 2007 ; Nair 2004 ). The actions of those factors thought to have important or specific roles in the formation of radicular cysts are discussed in the sections that follow.
Phase of Initiation
It 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
| |