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Evaluation of Clinical and Immunological Alterations Associated with ICF Syndrome

  • Original Article
  • Published:
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Abstract

Purpose

Immunodeficiency with centromeric instability and facial anomalies (ICF) syndrome is a rare autosomal recessive combined immunodeficiency. The detailed immune responses are not explored widely. We investigated known and novel immune alterations in lymphocyte subpopulations and their association with clinical symptoms in a well-defined ICF cohort.

Methods

We recruited the clinical findings from twelve ICF1 and ICF2 patients. We performed detailed immunological evaluation, including lymphocyte subset analyses, upregulation, and proliferation of T cells. We also determined the frequency of circulating T follicular helper (cTFH) and regulatory T (Treg) cells and their subtypes by flow cytometry.

Results

There were ten ICF1 and two ICF2 patients. We identified two novel homozygous missense mutations in the ZBTB24 gene. Respiratory tract infections were the most common recurrent infections among the patients. Gastrointestinal system (GIS) involvements were observed in seven patients. All patients received intravenous immunoglobulin replacement therapy and antibacterial prophylaxis; two died during the follow-up period. Immunologically, CD4+ T-cell counts, percentages of recent thymic emigrant T cells, and naive CD4+ T decreased in two, five, and four patients, respectively. Impaired T-cell proliferation and reduced CD25 upregulation were detected in all patients. These changes were more prominent in CD8+ T cells. GIS involvements negatively correlated with CD3+ T-, CD3+CD4+ T-, CD16+CD56+ NK-cell counts, and CD4+/CD8+ T-cell ratios. Further, we observed expanded cTFH cells and reduced Treg and follicular regulatory T cells with a skewing to a TH2-like phenotype in all tested subpopulations.

Conclusion

The ICF syndrome encompasses various manifestations affecting multiple end organs. Perturbed T-cell responses with increased cTFH and decreased Treg cells may provide further insight into the immune aberrations observed in ICF syndrome.

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Data Availability

The data generated during the study are included in this published article.

Code Availability

Not applicable.

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Funding

This work was supported by a grant from the Scientific and Technological Research Council of Turkey (318S202) to S.B.

Author information

Authors and Affiliations

  1. Pediatric Allergy and Immunology, Faculty of Medicine, Marmara University, Istanbul, Turkey

    Sevgi Bilgic Eltan, Ercan Nain, Mehmet Cihangir Catak, Asena Pınar Sefer, Ayca Kiykim, Burcu Kolukisa, Dilek Baser, Alper Bulutoglu, Nurhan Kasap, Melek Yorgun Altunbas, Ezgi Yalcin Gungoren, Ahmet Ozen, Elif Karakoc-Aydiner & Safa Baris

  2. Istanbul Jeffrey Modell Diagnostic and Research Center for Primary Immunodeficiencies, Istanbul, Turkey

    Sevgi Bilgic Eltan, Ercan Nain, Mehmet Cihangir Catak, Asena Pınar Sefer, Ayca Kiykim, Burcu Kolukisa, Dilek Baser, Alper Bulutoglu, Nurhan Kasap, Melek Yorgun Altunbas, Ezgi Yalcin Gungoren, Ahmet Ozen, Elif Karakoc-Aydiner & Safa Baris

  3. The Isil Berat Barlan Center for Translational Medicine, Division of Pediatric Allergy and Immunology, Marmara University, Istanbul, Turkey

    Sevgi Bilgic Eltan, Ercan Nain, Mehmet Cihangir Catak, Asena Pınar Sefer, Ayca Kiykim, Burcu Kolukisa, Dilek Baser, Alper Bulutoglu, Nurhan Kasap, Melek Yorgun Altunbas, Ezgi Yalcin Gungoren, Ahmet Ozen, Elif Karakoc-Aydiner & Safa Baris

  4. Department of Molecular Biology and Genetics, Faculty of Arts and Sciences, Bogazici University, Istanbul, Turkey

    Ege Ezen & Batu Erman

  5. Department of Pulmonary Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Nastaran Karimi

  6. Division of Pediatric Genetics, Umraniye Education and Research Hospital, University of Health Sciences, Istanbul, Turkey

    Yasemin Kendir Demirkol

  7. Division of Pediatric Immunology and Allergy, Faculty of Medicine, Ondokuz Mayıs University, Samsun, Turkey

    Seyhan Kutlug, Gonca Hancioglu & Alisan Yildiran

  8. Department of Pediatrics, Faculty of Medicine, Atlas University, Istanbul, Turkey

    Fatih Dilek

  9. Pediatric Allergy and Immunology, Marmara University Hospital, Istanbul, Turkey

    Safa Baris

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  1. Sevgi Bilgic Eltan
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  2. Ercan Nain
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Contributions

SB and SBE conceptualized and supervised the study. MCC, DB, and YKD performed the experiments. SBE, EN, APS, NK, AK, BK, NAK, MYA, EYG, SK, GH, FD, AY, EKA, AO, SB provided patient care, collected samples, and clinical data. EE and BE performed protein structure analysis. SBE, EN, SB, and MCC wrote the paper. All authors reviewed and approved the final version of the manuscript.

Corresponding author

Correspondence to Safa Baris.

Ethics declarations

Compliance with Ethical Standards

The study was approved by the Ethics Committee of Marmara University, School of Medicine (09.2022.32).

Consent to Participate

Informed consent for participation was obtained from all individuals.

Consent for Publication

Informed publication consent was obtained from all participants.

Conflict of Interest

Dr. Baris obtained a grant from the Scientific and Technological Research Council of Turkey. SBE, EN, MCC, EE, APS, NK, AK, BK, DB, NAK, MYA, EYG, YKD, SK, GH, FD, AY, AO, EKA, and BE have no conflict of interest to disclose.

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Supplementary Information

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Supplementary file1 (PDF 530 KB) Gating strategy for T-cell subpopulations.

10875_2023_1620_MOESM2_ESM.pdf

Supplementary file2 (PDF 74 KB) Overall survival curves in ICF patients. (A). Kaplan-Meier curve indicating the probability of survival of patients. End-organ involvements, including lung involvement (B), GIS (C), and autoimmune manifestations (E) and their effect on survival. ns: non-significant. 

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Bilgic Eltan, S., Nain, E., Catak, M.C. et al. Evaluation of Clinical and Immunological Alterations Associated with ICF Syndrome. J Clin Immunol 44, 26 (2024). https://doi.org/10.1007/s10875-023-01620-6

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  • DOI: https://doi.org/10.1007/s10875-023-01620-6

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