Journal
JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY
Volume 117, Issue 6, Pages 1462-1469Publisher
MOSBY-ELSEVIER
DOI: 10.1016/j.jaci.2006.01.037
Keywords
X-linked agammaglobulinemia; Bruton's tyrosine kinase; LPS signaling; mitogen-activated protein kinases; tumor necrosis factor alpha; IL-6; oxidative burst activity; monocytes
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Background: 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. Objective: 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. Methods: 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. Results: We show that in response to LPS, Btk-null monocytes from patients with XLA induce early mitogen-activated protein kinase activation and intracellular TNF-a 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. Conclusion: 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. Clinical implications: These findings provide a better understanding of XLA, and they show the differences between human XLA and murine Xid models.
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