A novel homozygous germline mutation in transferrin receptor 1 (TfR1) leads to combined immunodeficiency and provides new insights into iron-immunity axis
Date
2024
Authors
Aba, Ü.
Maslak, İ.C.
İpşir, C.
Pehlivan, D.
Warnock, N.I.
Tumes, D.J.
Cildir, G.
Erman, B.
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Journal article
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Journal of Clinical Immunology, 2024; 44(2, article no. 55):1-14
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Abstract
A homozygous missense mutation in the transferrin receptor 1 (TfR1), also known as CD71, leads to a rare inborn error of immunity (IEI) characterized by the impaired lymphocyte activation and proliferation due to defective iron uptake of cells. However, only one causative mutation (c.58T > C, p.Y20H) in the TFRC gene coding for TfR1 has been reported so far. We herein identified a new disease-causing homozygous germline mutation in the TFRC gene (c.64C > T, p.R22W) (referred to as TfR1ᴿ²²ᵂ from now on) in a Turkish patient with combined immunodeficiency (CID). TfR1ᴿ²²ᵂ results in impaired TfR1 internalization similar to previously defined TfR1Y20H mutation. We found that TfR1ᴿ²²ᵂ is associated with severely restricted B and T lymphocyte clonal diversity and impaired T cell activation and cytokine production as well as defective mitochondrial oxidative phosphorylation in helper T cells. In addition, circulating NK, Treg, and MAIT cell populations were significantly decreased in the patient. Using whole transcriptome analysis, we found dysregulated immune homeostasis and novel biological processes associated with TfR1ᴿ²²ᵂ. We also identified a considerable expansion of circulating low-density neutrophils (LDNs) in patient’s PBMCs. Overall, TfR1ᴿ²²ᵂ mutation expands the current understanding of the IEI associated with TfR1 dysfunction and provides new insights underlying impaired immune function, lymphocyte diversity, and granulocyte homeostasis.
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Data source: Supplementary Information, https://doi.org/10.1007/s10875-024-01658-0
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Copyright 2024 The Author(s). This article is licensed under a Creative Commons Attri-bution 4.0 International License. (http://creativecommons.org/licenses/by/4.0/)