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A Novel CEBPE Variant Causes Severe Infections and Profound Neutropenia

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Abstract

Purpose

Specific granule deficiency (SGD) is a rare inborn error of immunity resulting from loss-of-function variants in CEBPE gene (encoding for transcription factor C/EBPε). Although this genetic etiology has been known for over two decades, only a few patients with CEBPE variant-proven SGD (type I) have been reported. Herein, we describe two siblings with a novel homozygous CEBPE deletion who were noted to have profound neutropenia on initial evaluation. We aimed to evaluate the immunohematological consequences of this novel variant, including profound neutropenia.

Methods

Light scatter characteristics of granulocytes were examined on various automated hematology analyzers. Phagocyte immunophenotype, reactive oxygen species generation, and Toll-like receptor (TLR) signaling were assessed using flow cytometry. Relative expression of genes encoding various granule proteins was studied using RT-PCR. Western blot analysis and luciferase reporter assay were performed to explore variant C/EBPε expression and function.

Results

Severe infections occurred in both siblings. Analysis of granulocyte light scatter plots revealed automated hematology analyzers can provide anomalously low neutrophil counts due to abnormal neutrophil morphology. Neutrophils displayed absence/marked reduction of CD15/CD16 expression and overexpression (in a subset) of CD14/CD64. Three distinct populations of phagocytes with different oxidase activities were observed. Impaired shedding of CD62-ligand was noted on stimulation with TLR-4, TLR-2/6, and TLR-7/8 agonists. We demonstrated the variant C/EBPε to be functionally deficient.

Conclusion

Homozygous c.655_665del variant in CEBPE causes SGD. Anomalous automated neutrophil counts may be reported in patients with SGD type I. Aberrant TLR signaling might be an additional pathogenetic mechanism underlying immunodeficiency in SGD type I.

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Data Availability

Pertinent anonymized data are available in the Electronic Supplementary Material. The unanonymized datasets for this article are not publicly available due to concerns regarding participant/patient privacy/anonymity. Requests to access these datasets should be directed to the corresponding author.

Abbreviations

BPI:

bactericidal permeability-increasing protein

CAP18:

Cationic/cathelicidin antimicrobial protein–18 kDa

CBCs:

complete blood counts

CD62L:

CD62-ligand (L-selectin)

C/EBP:

CCAAT/enhancer-binding protein

ECP:

eosinophil cationic protein

f-MLF:

N-formylmethionyl-leucyl-phenylalanine

HEK:

human embryonic kidney

IEI:

inborn error of immunity

LCN2:

lipocalin-2

LPS:

lipopolysaccharide

LTF:

lactoferrin

MBP:

major basic protein

MRSA:

methicillin-resistant Staphylococcus aureus

NADPH:

nicotinamide adenine dinucleotide phosphate hydrogen

NBT:

nitroblue tetrazolium

NC:

neutrophil collagenase

P1 :

patient 1

PMA:

phorbol 12-myristate 13-acetate

RBC:

red blood cell

ROS:

reactive oxygen species

SDS-PAGE:

sodium dodecyl sulfate–polyacrylamide gel electrophoresis

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Acknowledgements

The authors acknowledge the patients and their parents for agreeing to participate in the study. The authors also acknowledge the technical staff of Hematology laboratories in the Department of Pediatrics and Research Block-A, PGIMER, Chandigarh, for their kind help. We sincerely thank Dr. Deepak B Salunke, Department of Chemistry and Centre of Advanced Studies in Chemistry, Panjab University, Chandigarh, India, for providing TLR-2/6 and -7/8 agonists.

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Authors and Affiliations

  1. Allergy Immunology Unit, Department of Pediatrics, Advanced Pediatrics Center (APC), Post Graduate Institute of Medical Education and Research (PGIMER), Chandigarh, 160012, India

    Aaqib Zaffar Banday, Anit Kaur, Dharmagat Bhattarai, Jhumki Das, Kanika Arora, Gurjit Kaur, Vignesh Pandiarajan, Ankur Kumar Jindal, Deepti Suri, Amit Rawat & Surjit Singh

  2. Department of Life, Environment, and Applied Chemistry, Faculty of Engineering, Fukuoka Institute of Technology, Fukuoka, Japan

    Tadayuki Akagi

  3. Department of Pediatrics, School of Medicine Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, Japan

    Masahiro Muraoka & Taizo Wada

  4. Cedars-Sinai Medical Center, Division of Hematology/Oncology, UCLA School of Medicine, Los Angeles, CA, USA

    Masahiro Muraoka & H. Phillip Koeffler

  5. Department of Hematology, Research Block-A, PGIMER, Chandigarh, India

    Diksha Dev, Man Updesh Singh Sachdeva, Indrani Karmakar & Jasmina Ahluwalia

  6. Cancer Science Institute, National University of Singapore, Singapore, Singapore

    H. Phillip Koeffler

  7. Department of Child Health and Development, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo, Japan

    Hirokazu Kanegane

  8. Department of Pediatrics, Hematology Unit, APC, PGIMER, Chandigarh, India

    Prateek Bhatia

Authors
  1. Aaqib Zaffar Banday
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  2. Anit Kaur
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  3. Tadayuki Akagi
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Contributions

AZB: inception of idea, writing of initial draft of manuscript, editing and revision of manuscript, patient evaluation and management, data acquisition and analysis, and review of literature.

AK, JD, IK, KA, GK: editing and revision of manuscript, performed experiments, and data acquisition and analysis.

TA, MM, TW: writing of initial draft of manuscript, editing and revision of manuscript, performed experiments, data acquisition and analysis, and review of literature.

DB: writing of initial draft of manuscript, editing and revision of manuscript, patient evaluation and management, data analysis, and review of literature.

DD: writing of initial draft of manuscript, editing and revision of manuscript, performed experiments, data acquisition and analysis, and review of literature.

MUSS, VP, AKJ, DS, JA, PB: editing and revision of manuscript, patient evaluation and management, data analysis, and review of literature.

HPK, HK, SS: editing and revision of manuscript, data analysis, and review of literature.

AR: editing and revision of manuscript, patient evaluation, data acquisition and analysis, review of literature, and overall supervision of manuscript preparation.

Corresponding authors

Correspondence to Aaqib Zaffar Banday or Amit Rawat.

Ethics declarations

Ethics Approval

This study was conducted in accordance with the Helsinki Declaration and was approved by the Departmental Review Board, Department of Pediatrics, Advanced Pediatrics Center, PGIMER, Chandigarh. Volumes of blood obtained (by venipuncture) for the experiments were as follows – complete blood counts: 0.5–1.0 mL, peripheral blood immunophenotyping: 2 mL, dihydrorhodamine-123 and CD62-ligand shedding assays: 2 mL, Sanger sequencing and RT-PCR: 1 mL.

Consent to Participate/Publish

The patients and their parents consented to participate in the study and publish the manuscript.

Competing Interests

The authors declare no competing interests.

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Data regarding serial complete blood counts and serial granulocyte scatter plots (on XN-1000 automated hematology analyzer) of our patient with SGD type II have not been published previously. Also, these details are not part of any other manuscript submitted for publication. However, the clinical profile of our patient with SGD type II is currently submitted as a separate case report/letter to the editor.

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Banday, A.Z., Kaur, A., Akagi, T. et al. A Novel CEBPE Variant Causes Severe Infections and Profound Neutropenia. J Clin Immunol 42, 1434–1450 (2022). https://doi.org/10.1007/s10875-022-01304-7

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