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 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.
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DOI：
10.4049/jimmunol.1500496
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发表时间：
2015-08-15
期刊：
影响因子：
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通讯作者：
Hajishengallis G
中科院分区：
文献类型：
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作者：
Abe T;AlSarhan M;Benakanakere MR;Maekawa T;Kinane DF;Cancro MP;Korostoff JM;Hajishengallis G
B系细胞（B淋巴细胞和浆细胞）在慢性牙周炎的炎症浸润中占主导地位。然而，它们在疾病发病机制中的作用以及它们在慢性病变中持续存在的因素尚不清楚。在这方面，TNF配体超家族中的两种细胞因子，即增殖诱导配体（四月份）和B淋巴细胞刺激剂（BLyS），对B细胞的存活、增殖和成熟都很重要。因此，我们假设APRIL和/或BLyS在牙周炎中上调，并有助于诱导牙周骨质流失。这一假设在人类和小鼠实验系统中都得到了验证。我们发现，相对于健康对照，在人类和小鼠的自然牙周炎和实验性牙周炎中，APRIL和BLyS mRNA和蛋白的表达分别上调。这些细胞因子的表达升高与两种动物B细胞/浆细胞数量增加有关。此外，APRIL和BLyS在上皮-结缔组织界面与表达kappa轻链的B系细胞部分共定位。与野生型对照相比，结扎诱导的牙周炎导致B细胞缺陷小鼠的骨质流失明显减少。在野生型小鼠中，抗体介导的APRIL或BLyS的中和可减少牙龈组织中B细胞的数量并抑制骨质流失，但在B细胞缺陷小鼠中无此作用。综上所述，参与B细胞生长和分化的特定细胞因子参与了牙周骨丢失。此外，APRIL和BLyS已被确定为牙周炎的潜在治疗靶点。
B-lineage cells (B lymphocytes and plasma cells) predominate in the inflammatory infiltrate of human chronic periodontitis. However, their role in disease pathogenesis and the factors responsible for their persistence in chronic lesions are poorly understood. In this regard, two cytokines of the TNF ligand superfamily, namely a proliferation-inducing ligand (APRIL) and B-lymphocyte stimulator (BLyS), are important for the survival, proliferation, and maturation of B cells. We thus hypothesized that APRIL and/or BLyS are upregulated in periodontitis and contribute to induction of periodontal bone loss. This hypothesis was addressed in both human and mouse experimental systems. We show that, relative to healthy controls, the expression of APRIL and BLyS mRNA and protein was upregulated in natural and experimental periodontitis in humans and mice, respectively. The elevated expression of these cytokines correlated with increased numbers of B cells/plasma cells in both species. Moreover, APRIL and BLyS partially colocalized with kappa light chain-expressing B lineage cells at the epithelial-connective tissue interface. Ligature-induced periodontitis resulted in significantly less bone loss in B cell-deficient mice compared to wild-type controls. Ab-mediated neutralization of APRIL or BLyS diminished the number of B cells in the gingival tissue and inhibited bone loss in wild-type but not in B cell-deficient mice. In conclusion, B cells and specific cytokines involved in their growth and differentiation contribute to periodontal bone loss. Moreover, APRIL and BLyS have been identified as potential therapeutic targets in periodontitis.