Nat Immun：科学家发现儿童抗体免疫缺陷发病原因

科学家近日发现了儿童抗体免疫缺陷病的发病原因，抗体免疫缺陷病是一种能导致呼吸道反复感染以及增加过敏反应的疾病。相关报告发表在本月出版的《自然—免疫学》Nature Immunology上。该项研究结果或有助研发出针对免疫缺陷患者的更有效的疫苗和治疗方法。

由于体内缺少相应抗体，患有DOCK8蛋白突变的儿童容易发生重复感染。此类儿童体内缺少一类被称为IgE的抗体，而该抗体也与过敏反应有关。因此，除了免疫缺陷外，他们还更易患上严重的过敏症。

Raif Geha等人从分子水平上研究了DOCK8蛋白在具有抗体产生功能的B免疫细胞中的作用。他们发现，DOCK8中的信号连锁反应是正常的抗体产生和B细胞记忆反应的产生所必需的。DOCK8作为一种平台，将内在信号分子特别是那些会利用到MyD88的分子，和处于下游位置的具有活化转录因子STAT3作用的激酶关联起来。一旦DOCK8和MyD88的相互作用以及STAT3的活化被阻断，便容易导致抗体缺少。

doi:​10.1038/ni.2305
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DOCK8 functions as an adaptor that links TLR-MyD88 signaling to B cell activation

Haifa H Jabara, Douglas R McDonald, Erin Janssen, Michel J Massaad, Narayanaswamy Ramesh, Arturo Borzutzky, Ingrid Rauter, Halli Benson, Lynda Schneider, Sachin Baxi, Mike Recher, Luigi D Notarangelo, Rima Wakim, Ghassan Dbaibo, Majed Dasouki, Waleed Al-Herz, Isil Barlan, Safa Baris, Necil Kutukculer, Hans D Ochs, Alessandro Plebani, Maria Kanariou, Gerard Lefranc, Ismail Reisli, Katherine A Fitzgerald et al.

The adaptors DOCK8 and MyD88 have been linked to serological memory. Here we report that DOCK8-deficient patients had impaired antibody responses and considerably fewer CD27+ memory B cells. B cell proliferation and immunoglobulin production driven by Toll-like receptor 9 (TLR9) were considerably lower in DOCK8-deficient B cells, but those driven by the costimulatory molecule CD40 were not. In contrast, TLR9-driven expression of AICDA (which encodes the cytidine deaminase AID), the immunoglobulin receptor CD23 and the costimulatory molecule CD86 and activation of the transcription factor NF-κB, the kinase p38 and the GTPase Rac1 were intact. DOCK8 associated constitutively with MyD88 and the tyrosine kinase Pyk2 in normal B cells. After ligation of TLR9, DOCK8 became tyrosine-phosphorylated by Pyk2, bound the Src-family kinase Lyn and linked TLR9 to a Src–kinase Syk–transcription factor STAT3 cascade essential for TLR9-driven B cell proliferation and differentiation. Thus, DOCK8 functions as an adaptor in a TLR9-MyD88 signaling pathway in B cells.