Periodontitis in the absence of B cells and specific anti‐bacterial antibody

Abstract

Periodontitis (PD) results from complex interactions between a dysbiotic oral microbiota and a dysregulated host immune response. The inflammatory infiltrate in the gingiva of PD patients includes an abundance of B cells, implicating these cells in the immunopathology. We sought to investigate the role of B cells in PD using a murine model. Wild-type or B-cell-deficient (μMT) mice were orally infected with Porphyromonas gingivalis. One or six weeks following infection, lymphocyte populations in the gingiva and cervical draining lymph nodes (dLN) were analysed by flow cytometry; serum anti-P. gingivalis IgG antibody titers were measured by enzyme-linked immunosorbent assay, and alveolar bone loss was determined. In wild-type mice, the percentage of gingival B cells expressing receptor activator of nuclear factor-κB ligand (RANKL) was significantly increased 1 week post-infection (5.36% control versus 11% PD, P < 0.01). The percentage of Fas(+) GL7(+) germinal centre B cells in the dLN was significantly increased at both 1 week (2.03% control versus 6.90% PD, P < 0.01) and 6 weeks (4.45% control versus 8.77% PD, P < 0.05) post-infection. B-cell-deficient mice were protected from P. gingivalis-induced alveolar bone loss, with a lack of B-cell proliferation and lack of CD4(+) CD44(+) CD62L(-) T-cell generation in the dLN, and absence of serum anti-P. gingivalis antibodies. Our data imply a pathological role for B cells in PD, and that selective targeting of this immune axis may have a role in treating severe periodontal disease.

The B Cell–Stimulatory Cytokines BLyS and APRIL Are Elevated in Human Periodontitis and Are Required for B Cell–Dependent Bone Loss in Experimental Murine Periodontitis

“…Our data implicating B cells in periodontal bone loss in C57BL/6J mice are consistent with an earlier study using a different model of mouse periodontitis (oral gavage) (19). Although the authors associated the absence of B cells with protection from bone loss, they did not monitor the appearance of B cells in WT C57BL/6J mice (19).…”

“…We first determined the time-course of appearance of B cells/plasma cells in the murine gingiva following initiation of periodontitis. Moreover, in view of conflicting results in the literature (18, 19), we examined whether the B-lineage cells are indeed involved in periodontal bone loss.…”

“…This study, however, did not detect B cells in the periodontal tissue of normal (non-obese) mice (18), suggesting that the model used or the specific experimental conditions do not readily support the development of a B cell infiltrate that is characteristic of human periodontitis. In contrast, Oliver-Bell et al showed that B-cell KO mice are protected from P. gingivalis -induced bone loss relative to WT controls (19). In sum, correlative human studies and certain animal model-based studies provide suggestive evidence for B cell involvement in plaque-induced periodontal bone loss.…”

Immunology of Gut-Bone Signaling

“…In human chronic periodontitis B-lineage cells (B lymphocytes and plasma cells) have been revealed to dominate the inflammatory infiltrate suggesting that these cells play a key role in the associated bone loss (79). This is supported by murine studies in the ligature-induced periodontitis model and the P. gingivalis oral infection model, where reduced bone loss was observed in B cell-deficient mice (μMT) compared to wild-type controls (80,81). Furthermore, antibody neutralization of a proliferation-inducing ligand (APRIL) or B-lymphocyte stimulator (BLys), two cytokines important for the maturation and survival of B cells, diminished the number of B cells in the gingival tissue and inhibited bone loss in wild-type but not in B cell- deficient mice (80).…”

Response to Comment on “The B Cell–Stimulatory Cytokines BLyS and APRIL Are Elevated in Human Periodontitis and Are Required for B Cell–Dependent Bone Loss in Experimental Murine Periodontitis”

“…The same study does indicate a role for B cells in pathogeninduced bone loss in obese mice. Oliver-Bell et al (8) detected osteoclastogenic RANKL-expressing gingival B cells and reported that infected WT mice had modest bone loss versus sham-infected WT controls, whereas infected B cell-deficient mice were protected from bone loss. Whereas obesity is known to exacerbate periodontitis, in part by acting on B cells (7), it is not a requirement for B cell involvement, as outlined below.…”