Pérez de Diego Rebeca, López-Granados Eduardo, Pozo Maite, Rodríguez Cristina, Sabina Prado, Ferreira Antonio, Fontan Gumersindo, García-Rodríguez Maria Cruz, Alemany Susana
Immunology Unit, University Hospital "La Paz," Madrid, Spain.
J Allergy Clin Immunol. 2006 Jun;117(6):1462-9. doi: 10.1016/j.jaci.2006.01.037. Epub 2006 Mar 31.
X-linked agammaglobulinemia (XLA) is characterized by impaired B-cell differentiation caused by mutations in the Bruton's tyrosine kinase (Btk) gene. The natural disease model, the X-linked immunodeficiency mouse, shows a less severe phenotype, indicating a different requirement of Btk in human and mouse B cells. Btk is also expressed in the myeloid line and participates in LPS signaling. Deficient oxidative burst and myeloid differentiation have been reported in the X-linked immunodeficiency mouse, but the precise mechanism and relevance of Btk activity in human monocytes is poorly understood.
The apparent absence in XLA of clinical manifestations of myeloid deficiency prompted us to explore the relevance of complete Btk absence in human myeloid cells.
Seven patients with XLA with BTK mutations conditioning a null protein expression were included in the study. Monocyte LPS-induced mitogen-activated protein kinase activation, TNF-alpha and IL-6 production in monocytes, and oxidative burst in monocytes and granulocytes were analyzed by means of flow cytometry.
We show that in response to LPS, Btk-null monocytes from patients with XLA induce early mitogen-activated protein kinase activation and intracellular TNF-alpha and IL-6 production with the same intensity as cells from age- and sex-matched control subjects. In addition, the oxidative burst in response to LPS and other stimulants was completely normal in Btk-null monocytes and neutrophils.
Our results indicate that Btk is not essential for early LPS signaling in human monocytes and that different Btk dependency might exist between human and mouse myeloid cells.
These findings provide a better understanding of XLA, and they show the differences between human XLA and murine Xid models.
X连锁无丙种球蛋白血症（XLA）的特征是由于布鲁顿酪氨酸激酶（Btk）基因突变导致B细胞分化受损。自然疾病模型，即X连锁免疫缺陷小鼠，表现出较轻的表型，表明Btk在人和小鼠B细胞中的需求不同。Btk也在髓系中表达并参与LPS信号传导。X连锁免疫缺陷小鼠中已报道有氧化爆发和髓系分化缺陷，但Btk活性在人单核细胞中的精确机制和相关性尚不清楚。
XLA中明显缺乏髓系缺陷的临床表现促使我们探讨人髓系细胞中完全缺乏Btk的相关性。
研究纳入了7例因BTK突变导致无蛋白表达的XLA患者。通过流式细胞术分析单核细胞LPS诱导的丝裂原活化蛋白激酶激活、单核细胞中TNF-α和IL-6的产生以及单核细胞和粒细胞中的氧化爆发。
我们发现，对LPS的反应中，XLA患者的Btk缺失单核细胞诱导早期丝裂原活化蛋白激酶激活以及细胞内TNF-α和IL-6产生的强度与年龄和性别匹配的对照受试者的细胞相同。此外，Btk缺失的单核细胞和中性粒细胞对LPS和其他刺激物的氧化爆发完全正常。
我们的结果表明，Btk对人单核细胞早期LPS信号传导不是必需的，并且人和小鼠髓系细胞之间可能存在不同的Btk依赖性。
这些发现有助于更好地理解XLA，并显示了人XLA和小鼠Xid模型之间的差异。
