Thymic and T-cell intrinsic critical roles associated with severe combined immunodeficiency and Omenn syndrome due to a heterozygous variant (G201R) in PSMB10
Hye Sun Kuehn PhD , Marita Bosticardo PhD , Antonio C. Arrieta MD , Jennifer L. Stoddard BS , Francesca Pala PhD , Julie E. Niemela MS , Agustin A. Gil Silva BS , Paighton L. King CPNP-PC , Ana Esteve-Sole PhD , Amreen Naveen MS , Eduardo Anaya MS , Pooi Meng Truong RN, BSN , Ottavia M. Delmonte MD, PhD , David K. Buchbinder MD , Sergio D. Rosenzweig MD, PhD , Luigi D. Notarangelo MD
{"title":"Thymic and T-cell intrinsic critical roles associated with severe combined immunodeficiency and Omenn syndrome due to a heterozygous variant (G201R) in PSMB10","authors":"Hye Sun Kuehn PhD , Marita Bosticardo PhD , Antonio C. Arrieta MD , Jennifer L. Stoddard BS , Francesca Pala PhD , Julie E. Niemela MS , Agustin A. Gil Silva BS , Paighton L. King CPNP-PC , Ana Esteve-Sole PhD , Amreen Naveen MS , Eduardo Anaya MS , Pooi Meng Truong RN, BSN , Ottavia M. Delmonte MD, PhD , David K. Buchbinder MD , Sergio D. Rosenzweig MD, PhD , Luigi D. Notarangelo MD","doi":"10.1016/j.jaci.2024.12.1082","DOIUrl":null,"url":null,"abstract":"<div><h3>Background</h3><div>Heterozygous immunoproteasome 20 S subunit beta 10 (PSMB10) mutations can cause severe combined immunodeficiency and Omenn syndrome. Hematopoietic stem cell transplantation in these patients is associated with severe complications and poor immune reconstitution, often resulting in death.</div></div><div><h3>Objective</h3><div>We sought to perform immunologic and molecular characterization of an infant with a <em>PSMB10</em> heterozygous variant.</div></div><div><h3>Methods</h3><div>A heterozygous variant in <em>PSMB10</em> (p.G201R) was identified in the index patient but not her parents. Detailed immunophenotyping and functional studies, including flow cytometry, immunoblotting, and T-cell development in artificial thymic organoids, were performed.</div></div><div><h3>Results</h3><div>The patient presented with severe B-, natural killer–, and T-cell lymphopenia, with a progressive increase in memory CD4<sup>+</sup> T cells and loss of CD8<sup>+</sup> T cells, diminished Vbeta family diversity, and abnormal IL-7 signaling. Immunoproteasome protein expression (PSMB9 and PSMB10) was markedly reduced in the patient’s cells, including PBMCs, EBV-transformed B cells, and fibroblasts, the mutation likely acting in a dominant-negative fashion. The patient’s CD34<sup>+</sup> cells showed a normal early T-cell development but slightly impaired generation of CD3<sup>+</sup>TCR αβ<sup>+</sup> cells in artificial thymic organoids, and human thymus single-cell RNA sequencing demonstrated that <em>PSMB10</em> is expressed in different subsets of cortical and medullary thymic epithelial cells. Collectively, these data indicate that <em>PSMB10</em> mutations affect positive selection of CD8 T cells, generation of a diverse T-cell repertoire, and negative selection of autoreactive T cells.</div></div><div><h3>Conclusions</h3><div>The PSMB10 G201R variant is associated with reduced immunoproteasome expression levels that appear to play vital roles in hematopoietic and extrahematopoietic immune system development and function. PSMB10-associated thymoproteasome dysfunction leads to impaired thymopoiesis and the development of severe combined immunodeficiency and Omenn syndrome, suggesting possible benefit from thymus implantation.</div></div>","PeriodicalId":14936,"journal":{"name":"Journal of Allergy and Clinical Immunology","volume":"155 4","pages":"Pages 1378-1385.e2"},"PeriodicalIF":11.4000,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Allergy and Clinical Immunology","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0091674924024163","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"ALLERGY","Score":null,"Total":0}
引用次数: 0
Abstract
Background
Heterozygous immunoproteasome 20 S subunit beta 10 (PSMB10) mutations can cause severe combined immunodeficiency and Omenn syndrome. Hematopoietic stem cell transplantation in these patients is associated with severe complications and poor immune reconstitution, often resulting in death.
Objective
We sought to perform immunologic and molecular characterization of an infant with a PSMB10 heterozygous variant.
Methods
A heterozygous variant in PSMB10 (p.G201R) was identified in the index patient but not her parents. Detailed immunophenotyping and functional studies, including flow cytometry, immunoblotting, and T-cell development in artificial thymic organoids, were performed.
Results
The patient presented with severe B-, natural killer–, and T-cell lymphopenia, with a progressive increase in memory CD4+ T cells and loss of CD8+ T cells, diminished Vbeta family diversity, and abnormal IL-7 signaling. Immunoproteasome protein expression (PSMB9 and PSMB10) was markedly reduced in the patient’s cells, including PBMCs, EBV-transformed B cells, and fibroblasts, the mutation likely acting in a dominant-negative fashion. The patient’s CD34+ cells showed a normal early T-cell development but slightly impaired generation of CD3+TCR αβ+ cells in artificial thymic organoids, and human thymus single-cell RNA sequencing demonstrated that PSMB10 is expressed in different subsets of cortical and medullary thymic epithelial cells. Collectively, these data indicate that PSMB10 mutations affect positive selection of CD8 T cells, generation of a diverse T-cell repertoire, and negative selection of autoreactive T cells.
Conclusions
The PSMB10 G201R variant is associated with reduced immunoproteasome expression levels that appear to play vital roles in hematopoietic and extrahematopoietic immune system development and function. PSMB10-associated thymoproteasome dysfunction leads to impaired thymopoiesis and the development of severe combined immunodeficiency and Omenn syndrome, suggesting possible benefit from thymus implantation.
期刊介绍:
The Journal of Allergy and Clinical Immunology is a prestigious publication that features groundbreaking research in the fields of Allergy, Asthma, and Immunology. This influential journal publishes high-impact research papers that explore various topics, including asthma, food allergy, allergic rhinitis, atopic dermatitis, primary immune deficiencies, occupational and environmental allergy, and other allergic and immunologic diseases. The articles not only report on clinical trials and mechanistic studies but also provide insights into novel therapies, underlying mechanisms, and important discoveries that contribute to our understanding of these diseases. By sharing this valuable information, the journal aims to enhance the diagnosis and management of patients in the future.