Impaired inhibitory Fcγ receptor IIB expression on B cells in chronic inflammatory demyelinating polyneuropathy
Impaired inhibitory Fcγ receptor IIB expression on B cells in chronic inflammatory demyelinating polyneuropathy
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DOI：
10.1073/pnas.0807319106
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发表时间：
2009-03-24
影响因子：
11.1
通讯作者：
Luenemann, Jan D.
中科院分区：
文献类型：
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作者：
Tackenberg, Bjoern;Jelcic, Ilijas;Luenemann, Jan D.
抑制性 Fc-γ 受体 Fc γ RIIB 在骨髓和 B 细胞上表达，在耐受性和自身免疫的平衡中具有关键作用，并且是各种小鼠疾病模型中静脉注射 Ig (IVIG) 的抗炎活性所必需的。然而，Fc γ RIIB 的功能及其在人类自身免疫性疾病中受 IVIG 的调节尚不清楚。慢性炎症性脱髓鞘性多发性神经病 (CIDP) 是最常见的可治疗的获得性慢性多发性神经病，IVIG 广泛用作一线初始治疗和维持治疗。我们发现，与人口统计学匹配的健康对照相比，未经治疗的 CIDP 患者在幼稚 B 细胞上表现出持续较低的 Fc γ RIIB 表达水平，并且随着 B 细胞从幼稚期进展到记忆区室，未能上调或维持 Fc γ RIIB 的上调。与此同时，罕见的 -386C/-120A Fc gamma RIIB 启动子多态性导致先前与自身免疫表型相关的启动子活性降低，在 CIDP 中出现过多。此外，在临床有效的 IVIG 治疗后，单核细胞和 B 细胞上的 Fc gamma RIIB 蛋白表达上调。因此，我们的结果表明，抑制性 Fc γ RIIB 在 CIDP 的关键 B 细胞分化检查点受损，调节 Fc γ RIIB 表达可能是有效限制 CIDP 中抗体介导的免疫病理学的有前途的方法。
The inhibitory Fc-gamma receptor Fc gamma RIIB, expressed on myeloid and B cells, has a critical role in the balance of tolerance and autoimmunity, and is required for the antiinflammatory activity of intravenous Ig (IVIG) in various murine disease models. However, the function of Fc gamma RIIB and its regulation by IVIG in human autoimmune diseases are less well understood. Chronic inflammatory demyelinating polyneuropathy (CIDP) is the most common treatable acquired chronic polyneuropathy, and IVIG is widely used as a first-line initial and maintenance treatment. We found that untreated patients with CIDP, compared with demographically matched healthy controls, showed consistently lower Fc gamma RIIB expression levels on naive B cells, and failed to up-regulate or to maintain up-regulation of Fc gamma RIIB as B cells progressed from the naive to the memory compartment. Concomitantly, the rare -386C/-120A Fc gamma RIIB promoter polymorphism resulting in reduced promoter activity previously associated with autoimmune phenotypes was overrepresented in CIDP. Also, Fc gamma RIIB protein expression was up-regulated on monocytes and B cells after clinically effective IVIG therapy. Thus, our results suggest that the inhibitory Fc gamma RIIB is impaired at a critical B cell differentiation checkpoint in CIDP, and that modulating Fc gamma RIIB expression might be a promising approach to efficiently limit antibody-mediated immunopathology in CIDP.