Generation mechanism of RANKL+ effector memory B cells: relevance to the pathogenesis of rheumatoid arthritis

Ota, Yuri; Niiro, Hiroaki; Ota, Shun Ichiro; Ueki, N.; Tsuzuki, Hirofumi; Nakayama, Tsuyoshi; Mishima, Koji; Higashioka, Kazuhiko; Jabbarzadeh-Tabrizi, Siamak; Mitoma, Hiroki; Akahoshi, Mitsuteru; Arinobu, Yojiro; Kukita, Akiko; Yamada, Hisakata; Tsukamoto, Hiroshi; Akashi, Koichi

doi:10.1186/s13075-016-0957-6

Cited by 49 publications

(35 citation statements)

References 38 publications

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“…Although the reason for this difference between T and B cells is unclear, RANKL expressed by lymphocytes was found to be involved in supporting osteoclastogenesis in vitro . In other studies of B cells and the skeletal system as well as its related diseases, researchers found that B cells were prone to aggregate at the interface between bone marrow and inflammation hard tissues, in which osteoclastogenesis was active and cortical bone had been damaged . Mice with B cells lacking the RANKL gene showed a defensive effect of estrogen deficiency‐related osteopenia, indicating that B cells promote osteoclastogenesis by producing RANKL …”

Section: Discussionmentioning

confidence: 99%

Improved RANKL expression and osteoclastogenesis induction of CD27+CD38− memory B cells: A link between B cells and alveolar bone damage in periodontitis

Han

Jin

Miao

et al. 2018

J of Periodontal Research

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Background and Objective Periodontitis is a bacteria‐induced disease that often leads to alveolar bone damage. Its mechanisms were considered to be complicated, involving an imbalance of the formation and resorption of bone. We sought to disclose the antibody‐independent function of B cells during periodontitis. Material and Methods Production of receptor activator for nuclear factor‐κB ligand (RANKL) by total lymphocytes or sorted B‐cell subsets in gingiva from healthy or experimental periodontitis animals was examined by flow cytometry, real‐time polymerase chain reaction, and enzyme‐linked immunosorbent assay. To define the effects of lymphocytes or B‐cell subsets on osteoclastogenesis induction, bone marrow mononuclear cells were culture in culture medium of lymphocytes or cocultured with B‐cell subsets. Osteoclasts were enumerated by tartrate‐resistant acid phosphatase staining. Constituent ratio of B‐cell subsets in healthy or experimental periodontitis was also detected by flow cytometry. Result Gingiva B cells produce more RANKL and support more osteoclastogenesis than T and other lymphocytes, and this potential improved in periodontitis. Memory B cells (CD27+CD38−) decreased their percentage in periodontitis. Memory B cells have the highest propensity for RANKL production. Remarkably, memory B cells from periodontitis animals expressed significantly more RANKL compared to healthy controls. Memory B cells supported osteoclast differentiation in vitro in a RANKL‐dependent manner, and the number of osteoclasts was higher in cultures with memory B cells from periodontitis animals than in those derived from healthy ones. Other B‐cell subsets have limited impact on osteoclast formation. Conclusion Findings of this study further disclose the roles of B cells engaged in periodontal immunomodulation and reveal the considerable importance of memory B cells in alveolar bone homeostasis and their likely contribution to alveolar bone destruction in periodontitis.

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Section: Discussionmentioning

confidence: 99%

Improved RANKL expression and osteoclastogenesis induction of CD27+CD38− memory B cells: A link between B cells and alveolar bone damage in periodontitis

Han

Jin

Miao

et al. 2018

J of Periodontal Research

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“…Activated B lymphocytes have been suggested as a primary source of RANKL in inflamed liver . Recently, it was reported that B cells spontaneously produce RANKL and correspondingly promote osteoclastogenesis and contribute to bone erosion in patients with inflammatory arthritis . It has also been reported that RANKL‐producing regulatory T cells promote mammary cancer metastasis through activation of an inhibitor of nuclear factor kappa B (NF‐κB) kinase alpha (IκBα), suggesting that targeting RANKL–RANK can potentially modulate cancer metastasis .…”

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confidence: 99%

The Immunobiology of Receptor Activator for Nuclear Factor Kappa B Ligand and Myeloid‐Derived Suppressor Cell Activation in Immunoglobulin G4–Related Sclerosing Cholangitis

et al. 2018

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The primary function of myeloid-derived suppressor cells (MDSCs) is reflected in their immune modulatory role in several immune-mediated diseases. In immunoglobulin G4 (IgG4)-related disease (IgG4-RD), it has been hypothesized that there are selective regulatory defects that lead to a T helper 2 (Th2) bias immune response. Herein we have taken advantage of a large cohort of patients with IgG4-related sclerosing cholangitis (IgG4-SC), the most common extrapancreatic involvement of IgG4-RD, as well as controls consisting of primary sclerosing cholangitis, autoimmune hepatitis, and healthy volunteers, to study MDSCs. We report dramatically increased levels of receptor activator for nuclear factor kappa B ligand (RANKL) expression in serum and liver from patients with IgG4-SC compared to both liver-disease and healthy controls. Moreover, in IgG4-SC liver, RANKL-secreting cells specifically colocalized with cluster of differentiation 38-positive plasma cells and MDSCs, particularly monocytic MDSCs, and express the RANKL receptor in liver. Similarly, the frequency and number of peripheral blood MDSCs were significantly increased. Importantly, serum expression levels of RANKL were inversely correlated with the serum level of gamma-glutamyltransferase but significantly positively correlated with the frequency of MDSCs. Moreover, we confirmed that RANKL induced the expansion and activation of MDSCs through the RANKL/RANK/nuclear factor kappa B signal pathway. Of note, RANKL-treated MDSCs suppressed T-cell proliferation and induced Th2 differentiation. Conclusion: Our data suggest that plasma cell-derived RANKL induces the expansion and activation of MDSCs, which suppress T-cell proliferation and contribute to the Th2-type response characteristic of IgG4-SC.

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“…Moreover, anti-B cells therapy leads to a reduction of bone resorption in RA and seems to be beneficial in improving periodontitis [ 14 ]. In RA, activation through BCR and CD40 induces switched memory B cells to express RANKL and leads to the activation of osteoclastogenesis [ 47 ]. A similar mechanism could be suspected in periodontitis and could explain the general increase in the observed RANKL expression on B cells in our study.…”

Section: Discussionmentioning

confidence: 99%

B cell subset distribution is altered in patients with severe periodontitis

et al. 2018

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Several studies have recently highlighted the implication of B cells in physiopathogenesis of periodontal disease by showing that a B cell deficiency leads to improved periodontal parameters. However, the detailed profiles of circulating B cell subsets have not yet been investigated in patients with severe periodontitis (SP). We hypothesised that an abnormal distribution of B cell subsets could be detected in the blood of patients with severe periodontal lesions, as already reported for patients with chronic inflammatory diseases as systemic autoimmune diseases. Fifteen subjects with SP and 13 subjects without periodontitis, according to the definition proposed by the CDC periodontal disease surveillance work group, were enrolled in this pilot observational study. Two flow cytometry panels were designed to analyse the circulating B and B1 cell subset distribution in association with the RANKL expression. A significantly higher percentage of CD27+ memory B cells was observed in patients with SP. Among these CD27+ B cells, the proportion of the switched memory subset was significantly higher. At the same time, human B1 cells, which were previously associated with a regulatory function (CD20+CD69-CD43+CD27+CD11b+), decreased in SP patients. The RANKL expression increased in every B cell subset from the SP patients and was significantly greater in activated B cells than in the subjects without periodontitis. These preliminary results demonstrate the altered distribution of B cells in the context of severe periodontitis. Further investigations with a larger cohort of patients can elucidate if the analysis of the B cell compartment distribution can reflect the periodontal disease activity and be a reliable marker for its prognosis (clinical trial registration number: NCT02833285, B cell functions in periodontitis).

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Generation mechanism of RANKL+ effector memory B cells: relevance to the pathogenesis of rheumatoid arthritis

Cited by 49 publications

References 38 publications

Improved RANKL expression and osteoclastogenesis induction of CD27+CD38− memory B cells: A link between B cells and alveolar bone damage in periodontitis

Improved RANKL expression and osteoclastogenesis induction of CD27+CD38− memory B cells: A link between B cells and alveolar bone damage in periodontitis

The Immunobiology of Receptor Activator for Nuclear Factor Kappa B Ligand and Myeloid‐Derived Suppressor Cell Activation in Immunoglobulin G4–Related Sclerosing Cholangitis

B cell subset distribution is altered in patients with severe periodontitis

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