Deficiencies in innate immune responses

Individuals with PMN defects, including chronic granulomatous disease, cyclic neutropenia, Papillon- Lefèvre
syndrome, Chédiak-Higashi syndrome, and leukocyte adhesion deficiencies (LADs), have an increased incidence
and severity of bacterial infection, including oral (periodontal) infections. 93–95 Best studied are the LADs, of which
there are two recognized types. 96–98 LAD-1 is due to a genetic defect in the β chain of integrins, which are important
for leukocyte transmigration across the blood vessel wall. LAD-2 is due to a defect in the sialyl Lewis X ligand on
leukocytes to which P- and E-selectins on endothelial cells bind, an interaction that mediates the initial “rolling
adhesion” of leukocytes to the blood vessel wall (see Fig 11-2). In both conditions, the adhesion deficiency
significantly reduces the ability of PMNs to migrate from the vascular system into tissues.
Patients present with severe infections and elevated numbers of circulating PMNs and macrophages
(leukocytosis), yet no pus is formed. In addition, they exhibit early-onset or prepubertal marginal periodontitis. 98–102
Based on these considerations, it is not surprising that a recent case report of a patient with an LAD-1
immunodeficiency described numerous examples of infected, necrotic teeth with apical periodontitis. 103 Others have
provided case reports of patients with cyclic neutropenia who showed an increased prevalence of apical
periodontitis.
104
Older studies have attempted to determine the role of innate immune cells such as PMNs and
monocyte/macrophages in periapical responses to infection. The administration of cyclophosphamide, which causes
severe neutropenia, was reported to increase periapical bone destruction. 105 In cyclophosphamide-treated animals,
bacteria were observed both in the pulp and in the periapical lesion, suggesting increased bacterial invasion in the
absence of PMNs. However, methotrexate treatment, which also causes neutropenia, has been reported to inhibit the
development of apical peri-unclear; however, although the effects of the immunosuppressive agents are correlated
with neutropenia, both cyclophosphamide and methotrexate also profoundly affect the production and responses of
lymphocytes, so these effects could not be solely attributed to PMNs.
Knockout mice deficient in both P- and E-selectins (P/E –/–) have been developed as a model of human
LAD-2. P/E–/– mice have defective rolling adhesion and leukocytosis and increased susceptibility to various
infections, but few reported defects in adaptive immunity.107 Interestingly, P/E–/– mice have been shown to develop
much larger periapical lesions than their normal, wild-type counterparts (Fig 12-8), which correlated with both
decreased PMN infiltration of periapical tissues and increased periapical expression of the bone resorptive cytokine
IL-1.108
Another experimental approach has been to use immunomodulators to increase the number and
function of innate immune cells and subsequently to determine the effect on pulpal and periapical resistance to
infection. Granulocyte colony-stimulating factor (G-CSF) is a cytokine that stimulates the production of
granulocytes by the bone marrow and increases the antimicrobial function of mature neutrophils. The effect of G-
CSF was recently examined in a rat pulpitis model following methotrexate-induced neutropenia. 109 Pulpal
inflammation, necrosis, and abscesses rapidly progressed in animals with neutropenia, and pulpal inflammation
rapidly extended to the periapical area after pulpal exposure. In contrast, G-CSF injection increased PMN counts
and reduced pulpal necrosis and limited intrapulpal abscesses to a small area adjacent to the site of pulpal exposure.
However, generalized pulpal and periapical inflammation was absent.
Poly-β-1-6-glucotriosyl-β-1-3-glucopyranose (PGG) glucan is a biologic-response modifier derived from
yeast that effectively increases host antibacterial responses without inducing inflammation, including a complete
lack of proinflammatory cytokine production (IL-1 and tumor necrosis factor α [TNF-α]) by macrophages and other
cells.110–112 Systemic administration of PGG glucan increased PMN production and primed phagocytic and
bactericidal activity in vivo113 and prevented postsurgical infections in humans.114
In the pulpal exposure model, PGG glucan reduced periapical bone destruction by 40% 19 (Fig 12-9).
Animals in which PGG glucan was administered had increased numbers of circulating PMNs and monocytes, which
possessed enhanced phagocytic activity ex vivo. The protective effect on periapical bone was secondary to
decreased pulpal necrosis; only 3% of pulps exhibited complete pulpal necrosis in PGG glucan–treated animals
compared with 41% of pulps in control animals. These results clearly indicate that PMNs are predominantly
protective against pulpal infections and as a consequence reduce periapical bone destruction.
Osteopontin (OPN) is a multifunctional cytokine that regulates inflammation, bone metabolism, tumor
progression, and metastasis. OPN–/– mice exhibit larger periapical lesions than do wild-type animals (Fig 12-10); this
difference is accompanied by a larger area of PMN infiltration and upregulation of neutrophil elastase gene
compared to that found in wild-type controls. 20 However, OPN also affects the development of T H1 and possibly
other immune responses, so it is possible that the increased PMN infiltration in this study was compensating for the
lack of another protective immune function. Further studies are needed to dissect the mechanism underlying the
observed increase in bone loss.
PMNs clearly protect the host and host tissues against pulpal infections. 115,116 At the same time, recent data
indicate that LPS-stimulated PMNs have the capacity to express surface RANKL via TLR- 4 signaling, which
potentially could stimulate osteoclastogenesis and bone resorption. 117 Furthermore, PMNs may play a role in
neurogenic inflammation, which has been described in inflamed pulp and periradicular lesions. 118–121 Substance P,
which is secreted by sensory nerves, affects vascular permeability and the release of histamine from mast cells. 122
Substance P also enhances immune complex inflammation.123 This mediator is highly expressed by PMNs in human
periapical lesions.119 Therefore, PMN-derived substance P could mediate neurogenic inflammation via this pathway,
leading to a hyperoxidative burst124 and upregulation of proinflammatory cytokines.125
Given that these data represent correlations that have not yet been confirmed by functional studies, it is
uncertain at this time whether PMN RANKL expression or neurogenic inflammatory responses play a major role in
periapical pathogenesis.