Department of Immunology, University Medical Center, Rotterdam, The Netherlands.
Am J Respir Crit Care Med. 2013 Feb 15;187(4):406-16. doi: 10.1164/rccm.201206-1024OC. Epub 2012 Dec 13.
Recent observations of abnormal immunoglobulin responses and case reports describing successful B-cell ablative therapy suggest involvement of B cells in the pathogenesis of sarcoidosis.
To investigate how abnormal B-cell maturation and function in patients with sarcoidosis contribute to disease.
Patients with sarcoidosis (n = 32) were included for detailed analysis by immunohistochemistry of tissue, flow cytometry of blood B-cell subsets, and serum immunoglobulin levels. Vaccination responses in patients with sarcoidosis to influenza virus and encapsulated bacteria and molecular analysis of immunoglobulin heavy chain transcripts were studied for functional analysis of immunoglobulin responses.
Perigranuloma localization of IgA-producing plasma cells and numerous B cells were found in affected tissues. Total blood B-cell numbers were normal, CD27(+) memory B cells were significantly reduced, and CD27(-)IgA(+) B cells were significantly increased; the results are normalized in patients treated with TNF-α blockers. Despite this, patients had normal serum immunoglobulin levels and normal antigen-specific immunoglobulin responses. IgA and IgG transcripts, however, showed high frequencies of somatic hypermutations and increased usage of downstream IgG subclasses, suggestive for prolonged or repetitive responses.
The large B-cell infiltrates in granulomatous tissue and increased molecular signs of antibody maturation are indicative of direct involvement of B cells in local inflammatory processes in patients with sarcoidosis. Moreover, CD27(-)IgA(+) B cells could be a marker for treatment with TNF-α blockers. These findings of B cells as emerging key players provide a rationale for a systematic study on B-cell ablative therapy in patients with sarcoidosis.
最近的观察发现异常免疫球蛋白反应，以及描述成功进行 B 细胞耗竭治疗的病例报告，提示 B 细胞可能参与了结节病的发病机制。
研究结节病患者异常 B 细胞成熟和功能如何导致疾病发生。
通过对组织的免疫组织化学、血液 B 细胞亚群的流式细胞术以及血清免疫球蛋白水平，对 32 例结节病患者进行了详细分析。研究了结节病患者对流感病毒和有囊膜细菌的疫苗接种反应以及免疫球蛋白重链转录本的分子分析，以研究免疫球蛋白反应的功能。
在受影响的组织中发现了围绕肉芽肿的 IgA 浆细胞和大量 B 细胞。全血 B 细胞数量正常，CD27(+)记忆 B 细胞显著减少，CD27(-)IgA(+)B 细胞显著增加；在接受 TNF-α 阻滞剂治疗的患者中结果正常。尽管如此，患者的血清免疫球蛋白水平正常，抗原特异性免疫球蛋白反应正常。然而，IgA 和 IgG 转录本显示出高频的体细胞超突变和下游 IgG 亚类的使用增加，提示存在延长或重复的反应。
肉芽肿组织中大量 B 细胞浸润和增加的抗体成熟分子标志物表明，B 细胞直接参与了结节病患者局部炎症过程。此外，CD27(-)IgA(+)B 细胞可能是 TNF-α 阻滞剂治疗的标志物。这些 B 细胞作为新出现的关键参与者的发现，为系统性研究结节病患者的 B 细胞耗竭治疗提供了依据。
