Min Y-N, Wang C-Y, Li X-X, Hou Y, Qiu J-H, Ma J, Shao L-L, Zhang X, Wang Y-W, Peng J, Hou M, Shi Y
Hematology Oncology Center, Qilu Hospital, Shandong University, Jinan, Shandong, China.
Department of General Medicine, Second Hospital of Shandong University, Jinan, Shandong, China.
J Thromb Haemost. 2016 Mar;14(3):559-71. doi: 10.1111/jth.13246. Epub 2016 Feb 17.
ESSENTIALS: Dysfunctional B-cell-activating factor (BAFF) system is related to many autoimmune diseases. The regulatory functions of BAFF/BAFF receptors were investigated in an in vitro coculture system. Different regulatory roles of BAFF were investigated via different receptors in immune thrombocytopenia. The upregulated BAFF receptors on autoreactive lymphocytes lead to their hypersensitivity to BAFF.
The pathogenesis of immune thrombocytopenia (ITP) remains enigmatic. B-cell-activating factor (BAFF) and its receptors (BAFF receptor [BAFF-R], transmembrane activator and calcium modulator and cyclophilin ligand interactor [TACI], and B-cell maturation antigen) play central roles in the integrated homeostatic regulation of lymphocytes.
To investigate the pathologic roles of BAFF receptors in regulating the bioactivities of lymphocytes in ITP.
An in vitro culture system was established by stimulating CD14(-) peripheral lymphocytes with platelet-preloaded dendritic cells in the presence of recombinant human BAFF (rhBAFF; 20 ng mL(-1)). The functions of BAFF receptors were specifically blocked with blocking antibodies.
BAFF-R, besides prolonging the survival of B cells in both patients and healthy controls, prominently promoted the survival of CD8(+) T cells and the proliferation of B cells in patients with ITP. TACI, as a positive regulator, not only promoted the proliferation of CD4(+) and CD8(+) T cells, but also significantly enhanced the secretion of interleukin-4 in patients with ITP, but not in controls. Besides revealing the pathologic roles of BAFF receptors, these results also indicate that lymphocytes of patients with ITP have enhanced antiapoptotic or proliferative capacity as compared with those from healthy controls when exposed under similar stimulation of rhBAFF. Further study demonstrated that activated autoreactive B cells and CD4(+) T cells from patients with ITP showed significantly higher expression of BAFF-R or TACI than those from healthy controls.
Both BAFF-R and TACI are pathogenic participants in ITP. Their dysregulated expression in patients with ITP may lead to hyperreactivity of activated autoreactive lymphocytes in response to rhBAFF, and thus is highly significant in the pathogenesis of ITP.
要点：功能失调的B细胞激活因子（BAFF）系统与多种自身免疫性疾病相关。在体外共培养系统中研究了BAFF/BAFF受体的调节功能。通过不同受体研究了BAFF在免疫性血小板减少症中的不同调节作用。自身反应性淋巴细胞上BAFF受体上调导致其对BAFF超敏。
免疫性血小板减少症（ITP）的发病机制仍不清楚。B细胞激活因子（BAFF）及其受体（BAFF受体[BAFF-R]、跨膜激活剂和钙调蛋白及亲环素配体相互作用分子[TACI]以及B细胞成熟抗原）在淋巴细胞的整体稳态调节中起核心作用。
研究BAFF受体在调节ITP患者淋巴细胞生物活性中的病理作用。
通过在重组人BAFF（rhBAFF；20 ng/mL）存在的情况下，用血小板预负载的树突状细胞刺激CD14（-）外周淋巴细胞建立体外培养系统。用阻断抗体特异性阻断BAFF受体的功能。
BAFF-R除了延长患者和健康对照中B细胞的存活时间外，还显著促进ITP患者中CD8（+）T细胞的存活和B细胞的增殖。TACI作为一种正向调节因子，不仅促进ITP患者中CD4（+）和CD8（+）T细胞的增殖，还显著增强ITP患者中白细胞介素-4的分泌，而在对照中则不然。这些结果除了揭示BAFF受体的病理作用外，还表明与健康对照者相比，ITP患者的淋巴细胞在受到类似的rhBAFF刺激时具有增强的抗凋亡或增殖能力。进一步研究表明，ITP患者活化的自身反应性B细胞和CD4（+）T细胞中BAFF-R或TACI的表达明显高于健康对照者。
BAFF-R和TACI都是ITP的致病参与者。它们在ITP患者中的表达失调可能导致活化的自身反应性淋巴细胞对rhBAFF反应过度，因此在ITP的发病机制中具有重要意义。
