The lack of BTK does not impair monocytes and polymorphonuclear cells functions in X-linked agammaglobulinemia under treatment with intravenous immunoglobulin replacement.

Filomena Monica Cavaliere,Isabella Quinti,Alessandro Prezzo,Caterina Bilotta,Metello Iacobini

doi:10.1371/journal.pone.0175961

Filomena Monica Cavaliere, Isabella Quinti + Show 3 more

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https://doi.org/10.1371/journal.pone.0175961

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Journal: PloS one	Publication Date: Apr 19, 2017
Citations: 19	License type: CC BY 4.0

Affiliation: Sapienza University of Rome

Abstract

The lack of BTK in X-linked agammaglobulinemia (XLA) patients does not affect monocytes and polymorphonuclear cells (PMN) phenotype and functions. In this study, we show that XLA patients had an increased frequency of the intermediate monocytes subset and that BTK-deficient monocytes and PMN had a normal expression of receptors involved in the activation and cellular responses. We demonstrate that BTK is not required for migration, phagocytosis and the production of reactive oxygen species (ROS) following engagement of FC gamma receptors (FcγR). XLA monocytes and PMN showed an efficient calcium (Ca2+)-independent activation of oxidative burst, suggesting that oxidative burst is less dependent by Ca2+ mobilization. The phagocytosis was functional and it remained unaltered also after Ca2+ chelation, confirming the independence of phagocytosis on Ca2+ mobilization. Intravenous immunoglobulin (IVIg) infusion exerted an anti-inflammatory effect by reducing the frequency of pro-inflammatory monocytes. In monocytes, the IVIg reduce the oxidative burst and phagocytosis even if these functions remained efficient.

Highlights

X-linked agammaglobulinemia (XLA) is a symptomatic primary antibody deficiency (PAD) caused by mutations in the Bruton’s tyrosine kinase (BTK) gene located on the long arm of Xchromosome encoding the cytoplasmic BTK [1, 2]
We show that monocyte and polymorphonuclear cells (PMN) from XLA patients normally express those receptors involved in their activation, suggesting that they did not exhibit an altered activation status
In agreement with previous studies [44, 55], the phagocytosis and respiratory burst induced through FcγR were preserved in monocytes and PMN confirming that the BTK kinase activity is bypassed during the engagement of FcγR

Summary

Introduction

X-linked agammaglobulinemia (XLA) is a symptomatic primary antibody deficiency (PAD) caused by mutations in the Bruton’s tyrosine kinase (BTK) gene located on the long arm of Xchromosome encoding the cytoplasmic BTK [1, 2]. These mutations lead to the nearly complete arrest of B cell differentiation in the bone marrow at the pre-B cell stage resulting in absent or very low peripheral B cells, agammaglobulinemia, absence of B cell-dependent lymphoid tissues and inability to mount specific antibody responses [3,4,5]. The antigen engagement of the FcγRs is able to induce the activation of Syk [10,11,12] that activates the axis BTK-PLCγ2/Ca2+ signaling pathway [13, 14]

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