LTβR deficiency causes lymph node aplasia and impaired B cell differentiation

Secondary lymphoid organs (SLOs) provide the confined microenvironment required for stromal cells to interact with immune cells to initiate adaptive immune responses resulting in B cell differentiation. Here, we studied three patients from two families with functional hyposplenism, absence of tonsils, and complete lymph node aplasia, leading to recurrent bacterial and viral infections. We identified biallelic loss-of-function mutations in <i>LTBR,</i> encoding the lymphotoxin beta receptor (LTβR), primarily expressed on stromal cells. Patients with LTβR deficiency had hypogammaglobulinemia, diminished memory B cells, regulatory and follicular T helper cells, and dysregulated expression of several tumor necrosis factor family members. B cell differentiation in an ex vivo coculture system was intact, implying that the observed B cell defects were not intrinsic in nature and instead resulted from LTβR-dependent stromal cell interaction signaling critical for SLO formation. Collectively, we define a human inborn error of immunity caused primarily by a stromal defect affecting the development and function of SLOs.

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Publication Details

Journal
Science Immunology
Published
2024-11-22
DOI
https://doi.org/10.1126/sciimmunol.adq8796
Citations
8
Primary Topic
Immunodeficiency and Autoimmune Disorders
Type
article
Field-Weighted Citation Impact
1.92

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article

LTβR deficiency causes lymph node aplasia and impaired B cell differentiation

Sabahat İnanır, Safa Barış, Florian Halbritter, Jana Block et al.
8 citations
Science Immunology
Immunodeficiency and Autoimmune Disorders
1.92
article

LTβR deficiency causes lymph node aplasia and impaired B cell differentiation

Sabahat İnanır, Safa Barış, Florian Halbritter, Jana Block, Horst von Bernuth, Marta Rizzi, Bettina Huber, Matthias Farlik, Gökçen Dilşa Tuğcu, Sevgi Köstel Bal, Elif Karakoç-Aydıner, Ayça Aslan Kıykım, Selin Kesim, Anna Segarra‐Roca, Irinka Castanon, Baran Erman, Kaan Boztuǧ, Alexei V. Tumanov, Ana Krolo, Marini Thian, Cheryl van de Wetering, Michael J. Kraakman, Aylin Çomak, Alexandra Frohne, Ingrid Simonitsch‐Klupp, Ömer Aydıner, Christoph Hafemeister, Michael Svatoň, Robert Pazdzior, Melek Yorgun Altunbaş, Stefan Kubicek, Sevgi Bilgiç Eltan, Bernhard Ransmayr, Ümran Aba, Ayşe Metìn, Ahmet Özen
article en
8 citations

Abstract

Secondary lymphoid organs (SLOs) provide the confined microenvironment required for stromal cells to interact with immune cells to initiate adaptive immune responses resulting in B cell differentiation. Here, we studied three patients from two families with functional hyposplenism, absence of tonsils, and complete lymph node aplasia, leading to recurrent bacterial and viral infections. We identified biallelic loss-of-function mutations in <i>LTBR,</i> encoding the lymphotoxin beta receptor (LTβR), primarily expressed on stromal cells. Patients with LTβR deficiency had hypogammaglobulinemia, diminished memory B cells, regulatory and follicular T helper cells, and dysregulated expression of several tumor necrosis factor family members. B cell differentiation in an ex vivo coculture system was intact, implying that the observed B cell defects were not intrinsic in nature and instead resulted from LTβR-dependent stromal cell interaction signaling critical for SLO formation. Collectively, we define a human inborn error of immunity caused primarily by a stromal defect affecting the development and function of SLOs.

Science ImmunologyVol. 9(101)
Ministry of Health (TR), Austrian Academy of Sciences (AT), University of Freiburg (DE), The University of Texas at San Antonio Health Science Center (US), Bilkent University (TR), University Medical Center Freiburg (DE), Humboldt-Universität zu Berlin (DE), Memorial Ankara Hospital (TR), Dr Lütfi Kırdar Kartal Eğitim ve Araştırma Hastanesi (TR), Vivantes Klinikum (DE), Istanbul University-Cerrahpaşa (TR), St Anna Children's Hospital (AT), CeMM Research Center for Molecular Medicine (AT), Başkent University Hospital (TR), Berlin Institute of Health at Charité - Universitätsmedizin Berlin (DE), Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases (AT), St. Anna Children's Cancer Research Institute, Hacettepe University (TR), Istanbul University (TR), Marmara University (TR), Freie Universität Berlin (DE), Medical University of Vienna (AT), Charité - Universitätsmedizin Berlin (DE)
Cancer Research Institute, Alex's Lemonade Stand Foundation for Childhood Cancer, Österreichischen Akademie der Wissenschaften, Austrian Science Fund, Türkiye Bilimsel ve Teknolojik Araştırma Kurumu, Österreichische Forschungsförderungsgesellschaft
Openalex Percentile: Top 13%
Immunodeficiency and Autoimmune Disorders
1.92
DOIOpen Access PDFOpenAlex
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