Background

Patients with X-linked Hyper-IgM syndrome (X-HIGM) due to CD40 ligand (CD40L) deficiency often present episodic, cyclic or chronic neutropenia, suggesting abnormal neutrophil development in the absence of CD40L-CD40 interaction. However, even when not neutropenic and despite immunoglobulin (Ig) replacement therapy, CD40L-deficient patients are susceptible to life-threatening infections caused by opportunistic pathogens, suggesting impaired function of phagocytes and the need of novel therapeutic approaches.

Objectives

To analyze whether peripheral neutrophils from CD40L-deficient patients display functional defects and to explore the in vitro effects of recombinant human interferon (rhIFN)-γ on neutrophil function.

Methods

We investigated the microbicidal activity, respiratory burst and transcriptome profile of neutrophils from CD40L-deficient patients. In addition, we evaluated whether the lack of CD40L in mice also affects neutrophil function.

Results

Neutrophils from CD40L-deficient patients exhibited defective respiratory burst and microbicidal activity which were improved in vitro by rhIFN-γ, but not soluble CD40L (sCD40L). Moreover, neutrophils from patients showed reduced CD16 protein expression and a dysregulated transcriptome suggestive of impaired differentiation. Similar to CD40L-deficient patients, CD40L-knockout mice were found to have impaired neutrophil responses. In parallel, we demonstrated that sCD40L induces the promyelocytic cell line HL-60 to proliferate and mature by regulating the expression of genes of the same gene ontology categories (e.g. cell differentiation) when compared to those dysregulated in peripheral blood neutrophils from CD40L-deficient patients.

Conclusion

Our data suggest a non-redundant role of CD40L-CD40 interaction in neutrophil development and function that could be improved in vitro by rhIFN-γ, indicating a potential novel therapeutic application for this cytokine.

中文翻译：

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CD40配体缺乏导致外周嗜中性粒细胞功能缺陷，外源性IFN-γ可改善这种缺陷

背景

由于CD40配体（CD40L）缺乏而导致X连锁Hyper-IgM综合征（X-HIGM）的患者通常表现为发作性，周期性或慢性中性粒细胞减少，提示在缺乏CD40L-CD40相互作用的情况下嗜中性粒细胞发育异常。但是，即使不是中性粒细胞减少症，尽管进行了免疫球蛋白（Ig）替代治疗，但CD40L缺乏的患者仍容易受到机会性病原体引起的威胁生命的感染，提示吞噬细胞功能受损，需要新的治疗方法。

目标

分析来自CD40L缺陷患者的外周嗜中性粒细胞是否显示功能缺陷，并探讨重组人干扰素（rhIFN）-γ对嗜中性粒细胞功能的体外作用。

方法

我们调查了CD40L缺乏患者中性粒细胞的杀菌活性，呼吸爆发和转录组谱。此外，我们评估了小鼠中CD40L的缺乏是否也会影响嗜中性粒细胞的功能。

结果

来自CD40L缺乏症患者的嗜中性粒细胞表现出不良的呼吸爆发和杀菌活性，在体外可通过rhIFN-γ改善，但不能溶解可溶性CD40L（sCD40L）。此外，患者的中性粒细胞显示CD16蛋白表达降低，转录组失调，提示分化受损。与缺乏CD40L的患者相似，发现CD40L敲除小鼠的中性粒细胞反应受损。平行地，我们证明了与CD40L缺陷型患者外周血中性粒细胞失调的基因相比，sCD40L通过调节相同基因本体类别（例如细胞分化）的基因表达，诱导早幼粒细胞HL-60增殖和成熟。 。

结论

我们的数据表明CD40L-CD40相互作用在嗜中性粒细胞的发育和功能中具有非冗余作用，rhIFN-γ可以在体外改善这种作用，表明该细胞因子具有潜在的新型治疗应用。