Variant Type X91 <sup>+</sup> Chronic Granulomatous Disease: Clinical and Molecular Characterization in a Chinese Cohort

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Abstract

Purpose

We aimed to report the clinical and immunological characteristics of variant type X91 ⁺ chronic granulomatous disease (CGD) in a Chinese cohort.

Methods

The clinical manifestations and immunological phenotypes of patients with X91 ⁺ CGD were collected. A dihydrorhodamine (DHR) analysis was performed to evaluate neutrophil function. Gp91 ^phox protein expression was determined using extracellular staining with the monoclonal antibody (mAb) 7D5 and flow cytometry.

Results

Patients with X91 ⁺ CGD accounted for 8% (7/85) of all patients with CGD. The median age of onset in the seven patients with X91 ⁺ CGD was 4 months. Six patients received the BCG vaccine, and 50% (3/6) had probable BCG infections. Mycobacterium tuberculosis infection was prominent. The most common sites of infection were the lung (6/7), lymph nodes (5/7), and soft tissue (3/7). Two patients experienced recurrent oral ulcers. The stimulation index (SI) of the patients with X91 ⁺ CGD ranged widely from 1.9 to 67.3. The difference in the SI among the three groups of patients (X91 ⁺ CGD, X91 ⁻ CGD, and X91 ⁰ CGD) was statistically significant ( P = 0.0071). The three groups showed no significant differences in onset age, diagnosis age, or severe infection frequency. CYBB mutations associated with X91 ⁺ CGD were commonly located in the second transmembrane or intracellular regions. Three novel X91 ⁺ CGD–related mutations (c.1462–2 A > T, c.1243C > T, and c.925G > A) were identified.

Conclusions

Variant type X91 ⁺ CGD may result in varied clinical manifestations. Moreover, the laboratory findings might indicate a moderate neutrophil SI. We should deepen our understanding of variant X91 ⁺ CGD to prevent missed diagnoses.

Supplementary Information

The online version contains supplementary material available at 10.1007/s10875-022-01324-3.

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Most cited references 63

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The NOX family of ROS-generating NADPH oxidases: physiology and pathophysiology.

Karen Bedard, Karl-Heinz Krause (2007)

For a long time, superoxide generation by an NADPH oxidase was considered as an oddity only found in professional phagocytes. Over the last years, six homologs of the cytochrome subunit of the phagocyte NADPH oxidase were found: NOX1, NOX3, NOX4, NOX5, DUOX1, and DUOX2. Together with the phagocyte NADPH oxidase itself (NOX2/gp91(phox)), the homologs are now referred to as the NOX family of NADPH oxidases. These enzymes share the capacity to transport electrons across the plasma membrane and to generate superoxide and other downstream reactive oxygen species (ROS). Activation mechanisms and tissue distribution of the different members of the family are markedly different. The physiological functions of NOX family enzymes include host defense, posttranlational processing of proteins, cellular signaling, regulation of gene expression, and cell differentiation. NOX enzymes also contribute to a wide range of pathological processes. NOX deficiency may lead to immunosuppresion, lack of otoconogenesis, or hypothyroidism. Increased NOX activity also contributes to a large number or pathologies, in particular cardiovascular diseases and neurodegeneration. This review summarizes the current state of knowledge of the functions of NOX enzymes in physiology and pathology.

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Flow cytometric analysis of the granulocyte respiratory burst: a comparison study of fluorescent probes.

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Chronic granulomatous disease (CGD) is a rare recessive disorder caused by defects in the NADPH oxidase enzyme complex of phagocytes (neutrophils, eosinophils and monocytes). CGD phagocytes fail to produce superoxide and other reactive oxygen species following cell activation (Malech, 1993). The products of oxidase activation can be measured in individual cells by flow cytometry using specific fluorescent probes that increase fluorescence upon oxidation (Trinkle et al., 1987). This approach can be used to confirm a diagnosis of CGD, and to detect the normal/abnormal phagocyte mixture that characterizes the X-linked CGD carrier state. Three fluorescent probes have been described as useful for this purpose: 2'7'-dichlorofluorescin diacetate (DCF) (Bass et al., 1983), 5,6-carboxy-2'7'-dichlorofluorescein diacetate, bis(acetoxymethyl) ester (C-DCF) (Hockenbery et al., 1993) and dihydrorhodamine 123 (DHR) (Rothe et al., 1988; Kinsey et al., 1987). A direct comparison between these three probes has not been reported. In this study we performed a direct comparison between these three probes, evaluating their ability in flow cytometric analysis to maximize fluorescent separation between activated CGD patient and normal granulocytes. Using a whole blood technique with phorbol myristate acetate (PMA) as an activator, it was found that DHR loaded normal granulocytes had a fluorescence intensity which, upon activation, was 48-fold higher than that of C-DCF loaded granulocytes and seven-fold higher than DCF loaded granulocytes (P < 0.001). Use of sodium azide to decrease the catabolism of H2O2 enhanced the fluorescence of DCF by 140%, C-DCF by 45% and DHR by 25%, suggesting that DCF is primarily sensitive to H2O2. DCF and DHR were then evaluated for sensitivity in the detection of small percentages of normal cells in a CGD/normal granulocyte mixture. Normal sub-populations as small as 0.1% could clearly be distinguished using DHR, while DCF was insensitive at this level. Based on these findings, we used DHR in an effort to detect normal granulocytes in a CGD patient following therapeutic granulocyte transfusion. We were able to detect normal granulocytes in the circulation for up to 18 h after transfusion. With these data we show that DHR is the most sensitive flow cytometric indicator for the detection of oxygen reactive species in activated granulocytes and is the best probe for evaluating CGD patients and carriers. In addition, our data suggest that DHR is a useful tool for monitoring circulating normal granulocytes in CGD patients following transfusion, and potentially will be a sensitive probe for assessing the success of such future technologies as gene therapy for CGD.

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X-Linked chronic granulomatous disease: mutations in the CYBB gene encoding the gp91-phox component of respiratory-burst oxidase.

P Newburger, I Rae, P Hopkins … (1998)

Chronic granulomatous disease (CGD) is a hereditary disorder of host defense due to absent or decreased activity of phagocyte NADPH oxidase. The X-linked form of the disease derives from defects in the CYBB gene, which encodes the 91-kD glycoprotein component (termed "gp91-phox") of the oxidase. We have identified the mutations in the CYBB gene responsible for X-linked CGD in 131 consecutive independent kindreds. Screening by SSCP analysis identified mutations in 124 of the kindreds, and sequencing of all exons and intron boundary regions revealed the other seven mutations. We detected 103 different specific mutations; no single mutation appeared in more than seven independent kindreds. The types of mutations included large and small deletions (11%), frameshifts (24%), nonsense mutations (23%), missense mutations (23%), splice-region mutations (17%), and regulatory-region mutations (2%). The distribution of mutations within the CYBB gene exhibited great heterogeneity, with no apparent mutational hot spots. Evaluation of 87 available mothers revealed X-linked carrier status in all but 10. The heterogeneity of mutations and the lack of any predominant genotype indicate that the disease represents many different mutational events, without a founder effect, as is expected for a disorder with a previously lethal phenotype.

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Author and article information

Contributors

Jia Hou:

ORCID: http://orcid.org/0000-0001-5963-644X

doctorhoujia@hotmail.com

Xiaochuan Wang: xchwang@shmu.edu.cn

Journal

Journal ID (nlm-ta): J Clin Immunol

Journal ID (iso-abbrev): J Clin Immunol

Title: Journal of Clinical Immunology

Publisher: Springer US (New York )

ISSN (Print): 0271-9142

ISSN (Electronic): 1573-2592

Publication date (Electronic): 7 July 2022

Publication date PMC-release: 7 July 2022

Publication date (Print): 2022

Volume: 42

Issue: 7

Pages: 1564-1579

Affiliations

[1 ]GRID grid.411333.7, ISNI 0000 0004 0407 2968, Department of Clinical Immunology, , Children’s Hospital of Fudan University, ; 399 Wanyuan Road, Shanghai, 201102 China

[2 ]GRID grid.11841.3d, ISNI 0000 0004 0619 8943, Department of Clinical Medicine, , Shanghai Medical College, Fudan University, ; Shanghai, 200032 China

[3 ]GRID grid.452742.2, Department of Pediatrics, , Shanghai Songjiang District Central Hospital, ; Shanghai, 201600 China

[4 ]Shanghai Institute of Infectious Disease and Biosecurity, Shanghai, 200032 China

Author information

Jia Hou http://orcid.org/0000-0001-5963-644X

Article

Publisher ID: 1324

DOI: 10.1007/s10875-022-01324-3

PMC ID: 9674757

PubMed ID: 35796921

SO-VID: 9eb5957b-032d-47b1-b9c0-56d92b164287

License:

Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

History

Date received : 18 December 2021

Date accepted : 29 June 2022

Custom metadata

ScienceOpen disciplines: Immunology

Keywords: chronic granulomatous disease,gp91phox,neutrophil respiratory burst,stimulation index,nadph oxidase

Data availability:

ScienceOpen disciplines: Immunology

Keywords: chronic granulomatous disease, gp91phox, neutrophil respiratory burst, stimulation index, nadph oxidase