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Variable Abnormalities in T and B Cell Subsets in Ataxia Telangiectasia

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Abstract

Background

Ataxia-telangiectasia (AT) is a rare genetic condition, caused by biallelic deleterious variants in the ATM gene, and has variable immunological abnormalities. This study aimed to examine immunologic parameters reflecting cell development, activation, proliferation, and class switch recombination (CSR) and determine their relationship to the clinical phenotype in AT patients.

Methods

In this study, 40 patients with a confirmed diagnosis of AT from the Iranian immunodeficiency registry center and 28 age-sex matched healthy controls were enrolled. We compared peripheral B and T cell subsets and T cell proliferation response to CD3/CD28 stimulation in AT patients with and without CSR defects using flow cytometry.

Results

A significant decrease in naïve, transitional, switched memory, and IgM only memory B cells, along with a sharp increase in the marginal zone-like and CD21low B cells was observed in the patients. We also found CD4+ and CD8+ naïve, central memory, and terminally differentiated effector memory CD4+ (TEMRA) T cells were decreased. CD4+ and CD8+ effector memory, CD8+ TEMRA, and CD4+ regulatory T cells were significantly elevated in our patients. CD4+ T cell proliferation was markedly impaired compared to the healthy controls. Moreover, immunological investigations of 15 AT patients with CSR defect revealed a significant reduction in the marginal zone, switched memory, and more intense defects in IgM only memory B cells, CD4+ naïve and central memory T cells.

Conclusion

The present study revealed that patients with AT have a broad spectrum of cellular and humoral deficiencies. Therefore, a detailed evaluation of T and B cell subsets increases understanding of the disease in patients and the risk of infection.

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Acknowledgments

The authors would like to thank Dr. Menno C. van Zelm (Monash University, Melbourne, Australia) for critical reading of the manuscript.

Funding

This research was supported by the Tehran University of Medical Sciences (grant no. 37222).

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Authors and Affiliations

  1. Department of Immunology, Semnan University of Medical Sciences, Semnan, Iran

    Tannaz Moeini Shad & Bahman Yousefi

  2. Research Center for Immunodeficiencies, Children’s Medical Center, Tehran University of Medical Sciences, Tehran, Iran

    Tannaz Moeini Shad, Parisa Amirifar, Samaneh Delavari, Hassan Abolhassani, Asghar Aghamohammadi & Reza Yazdani

  3. Department of Medical Genetics, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran

    Parisa Amirifar

  4. Cambridge Institute of Therapeutic Immunology and Infectious Disease, Jeffrey Cheah Biomedical Centre, Cambridge Biomedical Campus, Cambridge, UK

    William Rae

  5. Department of Medicine, University of Cambridge School of Clinical Medicine, Cambridge Biomedical Campus, Cambridge, UK

    William Rae

  6. Cancer Research Center, Semnan University of Medical Sciences, Semnan, Iran

    Parviz Kokhaei

  7. Department of Oncology-Pathology, BioClinicum, Karolinska University Hospital Solna and Karolinska Institutet, Stockholm, Sweden

    Parviz Kokhaei

  8. Research Center for Primary Immunodeficiencies, Iran University of Medical Sciences, Tehran, Iran

    Hassan Abolhassani

  9. Division of Clinical Immunology, Department of Laboratory Medicine, Karolinska Institute at Karolinska University Hospital Huddinge, Stockholm, Sweden

    Hassan Abolhassani

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  1. Tannaz Moeini Shad
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Fig. S1. Analysis of B cell subsets in control and AT patients (i): Two examples demonstrate the flow cytometric analysis of peripheral blood samples from one control (top panels) and on the patient (down panels). Gating Strategy (ii): CD19+ B-cells are gated within the lymphocyte scatter region. Naive B-cells (C), marginal zone-like B-cells (a), IgM-only memory B-cells (a), and switched memory B-cells (b) are defined within the IgM lymphoma based on the expression of CD27 and IgD. Also, transitional B-cells (d), plasmablasts (e), and CD21low B-cells (e) are defined within the CD21 lymphogate based on the expression of CD38 and IgM. Fig. S2. Analysis of T cell subsets in control and AT patients (i): Two examples demonstrate the flow cytometric analysis of peripheral blood samples from one control (top panels) and on the patient (down panels). Gating Strategy (ii): CD4+ and CD8+ T-cells are gated within the lymphocyte scatter region. Naive, central memory, effector memory, and TEMRA T-cells (a, c) are defined within each of the CD4+ and CD8+ lymphogate based on the expression of CD45RA and CD197. Also, regulatory T-cells (b) are defined within the CD25 and FOXP3 lymphogate based on the expression of CD127. Fig. S3. Gating strategy for T CD4+ Lymphocyte proliferation. (i): Unstimulated PBMCs, labeled with the fluorescent dye CFSE, were harvested and stained with anti-human CD4 as a negative control, then analyzed by flow cytometry. (ii): A sample stimulated with anti-CD3/CD28 mAbs, labeled with the fluorescent dye CFSE, was harvested and stained with anti-human CD4, then analyzed by flow cytometry. Pseudocolor plot representing the expression of lymphocyte trafficking marker CD4 in subsequent cell divisions (right panel). (iii): We used the proliferation platform from FlowJo (v10.4.1) software in which division index, percent divided, and proliferation index are illustrated. Percent divided defines the percentage of the cells of the original sample, which is divided at least once. Proliferation index is the average number of cell divisions of responding cells and reflects the proliferative capacity of responding cells and division index, is the average number of divisions of all cells, including undivided cells. (DOCX 4299 kb)

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Moeini Shad, T., Yousefi, B., Amirifar, P. et al. Variable Abnormalities in T and B Cell Subsets in Ataxia Telangiectasia. J Clin Immunol 41, 76–88 (2021). https://doi.org/10.1007/s10875-020-00881-9

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