---
title: "Pathogenic NFKB2 p.Tyr867* Variant Causes Combined Immunodeficiency and Lymphoid Organ Defects in"
id: "biorxiv-2-a-pathogenic-nfkb2-variant-causes-combined-immunodeficiency-with-thymic-and"
canonical_url: "https://medichelpline.com/clinical-feed/biorxiv-2-a-pathogenic-nfkb2-variant-causes-combined-immunodeficiency-with-thymic-and"
content_type: "clinical_feed_article"
specialty: "General"
source_name: "bioRxiv (Biomedical Preprints)"
source_url: "https://www.biorxiv.org/content/10.64898/2026.10.02.756202v1?rss=1"
published_at: "2026-10-08T12:00:00.000Z"
evidence_level: "Verified Feed"
license: "CC-BY-NC-4.0 / Informational Use"
---
# Pathogenic NFKB2 p.Tyr867* Variant Causes Combined Immunodeficiency and Lymphoid Organ Defects in
## Provenance & Clinical Metadata
- **Canonical URL:** https://medichelpline.com/clinical-feed/biorxiv-2-a-pathogenic-nfkb2-variant-causes-combined-immunodeficiency-with-thymic-and
- **Specialty:** [General](https://medichelpline.com/clinical-feed/general.md)
- **Primary Source:** bioRxiv (Biomedical Preprints)
- **Source URL:** [Original Journal Publication](https://www.biorxiv.org/content/10.64898/2026.10.02.756202v1?rss=1)
- **Published At:** 2026-10-08T12:00:00.000Z
- **Evidence Rating:** Verified Feed
## Executive GIST (TL;DR)
- The study characterizes a novel rat model carrying a **Nfkb2** nonsense variant (c.2602T>A; p.Tyr867*, Nfkb2p.Tyr867*) that mirrors a human familial CVID-associated allele. - Mutant NFKB2 produced marked alterations of the **thymic** microenvironment, including reduced K5+ medullary thymic epithelial cells and decreased **AIRE** expression. - Thymocyte development was perturbed, with impaired thymic regulatory T-cell populations contributing to central tolerance defects. - Peripheral lymphoid architecture was severely disrupted: animals lacked lymph nodes and showed defects in the splenic marginal zone. - T-cell homeostasis was altered in both CD4+ and CD8+ compartments, with decreased regulatory T cells and reduced ICOS expression on CD4+ T cells. - The **B-cell** compartment exhibited impaired maturation, with accumulation of IgM+IgD- transitional cells and a strong reduction of IgD+ mature B cells. - Humoral immunity was profoundly compromised, including a complete absence of circulating immunoglobulins in the mutant rats. - Overall phenotype is a systemic combined immunodeficiency, highlighting the role of the non-canonical **NF-κB** pathway in thymic organization, peripheral lymphoid development, and adaptive immunity. - The rat model provides a tool to study mechanisms linking non-canonical NF-κB signaling to immune system organization and the pathogenesis of CVID-like syndromes.
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Anderson, Ignacio Anegon doi: https://doi.org/10.64898/2026.10.02.756202 This article is a preprint and has not been certified by peer review [[what does this mean?](https://www.biorxiv.org/about/FAQ#unrefereed)]. Severine Remy 1 CR2TI UMR 1064, INSERM; * [Find this author on Google Scholar](https://www.biorxiv.org/lookup/google-scholar?link_type=googlescholar&gs_type=author&author%5B0%5D=Severine%2BRemy%2B "Open in new tab") * [Find this author on PubMed](https://www.biorxiv.org/lookup/external-ref?access_num=Remy%20S&link_type=AUTHORSEARCH "Open in new tab") * [Search for this author on this site](https://www.biorxiv.org/search/author1%3ASeverine%2BRemy%2B) * [ORCID record for Severine Remy](http://orcid.org/0000-0002-5241-880X "Open in new tab") * For correspondence: severine.remy@univ-nantes.fr Laurent Tesson 2 Center for Research in Transplantation and Translational Immunology; * [Find this author on Google Scholar](https://www.biorxiv.org/lookup/google-scholar?link_type=googlescholar&gs_type=author&author%5B0%5D=Laurent%2BTesson%2B "Open in new tab") * [Find this author on PubMed](https://www.biorxiv.org/lookup/external-ref?access_num=Tesson%20L&link_type=AUTHORSEARCH "Open in new tab") * [Search for this author on this site](https://www.biorxiv.org/search/author1%3ALaurent%2BTesson%2B) Claire Usal 2 Center for Research in Transplantation and Translational Immunology; * [Find this author on Google Scholar](https://www.biorxiv.org/lookup/google-scholar?link_type=googlescholar&gs_type=author&author%5B0%5D=Claire%2BUsal%2B "Open in new tab") * [Find this author on PubMed](https://www.biorxiv.org/lookup/external-ref?access_num=Usal%20C&link_type=AUTHORSEARCH "Open in new tab") * [Search for this author on this site](https://www.biorxiv.org/search/author1%3AClaire%2BUsal%2B) Marie Massoda 2 Center for Research in Transplantation and Translational Immunology; * [Find this author on Google Scholar](https://www.biorxiv.org/lookup/google-scholar?link_type=googlescholar&gs_type=author&author%5B0%5D=Marie%2BMassoda%2B "Open in new tab") * [Find this author on PubMed](https://www.biorxiv.org/lookup/external-ref?access_num=Massoda%20M&link_type=AUTHORSEARCH "Open in new tab") * [Search for this author on this site](https://www.biorxiv.org/search/author1%3AMarie%2BMassoda%2B) Severine Menoret 3 CRTI; * [Find this author on Google Scholar](https://www.biorxiv.org/lookup/google-scholar?link_type=googlescholar&gs_type=author&author%5B0%5D=Severine%2BMenoret%2B "Open in new tab") * [Find this author on PubMed](https://www.biorxiv.org/lookup/external-ref?access_num=Menoret%20S&link_type=AUTHORSEARCH "Open in new tab") * [Search for this author on this site](https://www.biorxiv.org/search/author1%3ASeverine%2BMenoret%2B) Irina Proekt 4 UCSF Diabetes Center; * [Find this author on Google Scholar](https://www.biorxiv.org/lookup/google-scholar?link_type=googlescholar&gs_type=author&author%5B0%5D=Irina%2BProekt%2B "Open in new tab") * [Find this author on PubMed](https://www.biorxiv.org/lookup/external-ref?access_num=Proekt%20I&link_type=AUTHORSEARCH "Open in new tab") * [Search for this author on this site](https://www.biorxiv.org/search/author1%3AIrina%2BProekt%2B) * [ORCID record for Irina Proekt](http://orcid.org/0000-0003-3818-1102 "Open in new tab") David Yu 4 UCSF Diabetes Center; * [Find this author on Google Scholar](https://www.biorxiv.org/lookup/google-scholar?link_type=googlescholar&gs_type=author&author%5B0%5D=David%2BYu%2B "Open in new tab") * [Find this author on PubMed](https://www.biorxiv.org/lookup/external-ref?access_num=Yu%20D&link_type=AUTHORSEARCH "Open in new tab") * [Search for this author on this site](https://www.biorxiv.org/search/author1%3ADavid%2BYu%2B) Axel You 2 Center for Research in Transplantation and Translational Immunology; * [Find this author on Google Scholar](https://www.biorxiv.org/lookup/google-scholar?link_type=googlescholar&gs_type=author&author%5B0%5D=Axel%2BYou%2B "Open in new tab") * [Find this author on PubMed](https://www.biorxiv.org/lookup/external-ref?access_num=You%20A&link_type=AUTHORSEARCH "Open in new tab") * [Search for this author on this site](https://www.biorxiv.org/search/author1%3AAxel%2BYou%2B) Matthieu Giraud 5 Centre de Recherche en Transplantation et Immunologie, INSERM U1064; * [Find this author on Google Scholar](https://www.biorxiv.org/lookup/google-scholar?link_type=googlescholar&gs_type=author&author%5B0%5D=Matthieu%2BGiraud%2B "Open in new tab") * [Find this author on PubMed](https://www.biorxiv.org/lookup/external-ref?access_num=Giraud%20M&link_type=AUTHORSEARCH "Open in new tab") * [Search for this author on this site](https://www.biorxiv.org/search/author1%3AMatthieu%2BGiraud%2B) * [ORCID record for Matthieu Giraud](http://orcid.org/0000-0002-1208-9677 "Open in new tab") Mark S. Anderson 4 UCSF Diabetes Center; * [Find this author on Google Scholar](https://www.biorxiv.org/lookup/google-scholar?link_type=googlescholar&gs_type=author&author%5B0%5D=Mark%2BS.%2BAnderson%2B "Open in new tab") * [Find this author on PubMed](https://www.biorxiv.org/lookup/external-ref?access_num=Anderson%20MS&link_type=AUTHORSEARCH "Open in new tab") * [Search for this author on this site](https://www.biorxiv.org/search/author1%3AMark%2BS.%2BAnderson%2B) Ignacio Anegon 6 INSERM * [Find this author on Google Scholar](https://www.biorxiv.org/lookup/google-scholar?link_type=googlescholar&gs_type=author&author%5B0%5D=Ignacio%2BAnegon%2B "Open in new tab") * [Find this author on PubMed](https://www.biorxiv.org/lookup/external-ref?access_num=Anegon%20I&link_type=AUTHORSEARCH "Open in new tab") * [Search for this author on this site](https://www.biorxiv.org/search/author1%3AIgnacio%2BAnegon%2B) * [Abstract](https://www.biorxiv.org/content/10.64898/2026.10.02.756202v1)[](https://www.biorxiv.org/panels_ajax_tab/biorxiv_tab_art/node:5852660/1) * [Info/History](https://www.biorxiv.org/content/10.64898/2026.10.02.756202v1.article-info)[](https://www.biorxiv.org/panels_ajax_tab/biorxiv_tab_info/node:5852660/1) * [Metrics](https://www.biorxiv.org/content/10.64898/2026.10.02.756202v1.article-metrics)[](https://www.biorxiv.org/panels_ajax_tab/article_tab_metrics/node:5852660/1) * [Supplementary material](https://www.biorxiv.org/content/10.64898/2026.10.02.756202v1.supplementary-material)[](https://www.biorxiv.org/panels_ajax_tab/biorxiv_tab_data/node:5852660/1) * [ Preview PDF](https://www.biorxiv.org/content/10.64898/2026.10.02.756202v1.full.pdf+html)[](https://www.biorxiv.org/panels_ajax_tab/biorxiv_tab_pdf/node:5852660/1) ![Loading](https://www.biorxiv.org/sites/all/modules/contrib/panels_ajax_tab/images/loading.gif) ## Abstract The non-canonical NF-kappa B pathway, in which NFKB2 plays a central role, is critical for lymphoid organ development and immune homeostasis. Pathogenic NFKB2 variants have been strongly associated with a broad spectrum of human pathologies, notably immunodysregulation syndromes, characterized by recurrent infections, autoantibody production and endocrine abnormalities. The mechanisms underlying the resulting immune defects remain incompletely understood. In the present study, we characterized the immune phenotype of a novel rat model harboring a Nfkb2 non-sense mutation located in the c-terminal region of the gene (c.2602T>A; p.Tyr867*, Nfkb2p.Tyr867*). This variant has been identified in patients with a familial form of common variable immunodeficiency (CVID) presenting with autoimmunity manifestations. Using this model, we demonstrate that mutated NFKB2 resulted in profound alterations of the thymic microenvironment, including reduced K5+ medullary thymic epithelial cells and decreased AIRE expression, accompanied by altered thymocyte development and impaired thymic regulatory T populations. Peripheral lymphoid organization was also profoundly affected, with absence of lymph nodes, defects in the splenic marginal zone, and alterations of CD4+ and CD8+ T-cell homeostasis, including impaired Treg populations and reduced ICOS expression on CD4+ T cells. The B-cell compartment was markedly altered, with impaired B-cell maturation, characterized by accumulation of IgM+IgD- transitional cells and a marked reduction of IgD+ mature B cells. These abnormalities were associated with impaired humoral immunity and complete absence of circulating immunoglobulins. Collectively, our findings define a systemic combined immunodeficiency phenotype in the Nfkb2-mutated rat, highlighting its utility for studying the role of non-canonical NF-kB signaling in immune system organization and adaptative immunity. ### Competing Interest Statement The authors have declared no competing interest. ## Funder Information Declared Fondation Maladies Rares, https://ror.org/03jpxze54, Grant#13131 University of California San Francisco Medical Center, Purchasing Agreement #167872754 Copyright The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a [CC-BY-NC-ND 4.0 International license](http://creativecommons.org/licenses/by-nc-nd/4.0/). bioRxiv and medRxiv thank the following for their generous financial support: > The Chan Zuckerberg Initiative, Cold Spring Harbor Laboratory, the Sergey Brin Family Foundation, California Institute of Technology, Centre National de la Recherche Scientifique, Fred Hutchinson Cancer Center, Imperial College London, Massachusetts Institute of Technology, Stanford University, The University of Edinburgh, University of Washington, and Vrije Universiteit Amsterdam. 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[ Download PDF](https://www.biorxiv.org/content/10.64898/2026.10.02.756202v1.full.pdf) Print/Save Options [Download PDF](https://www.biorxiv.org/content/biorxiv/early/2026/10/08/2026.10.02.756202.full.pdf)Full Text & In-line FiguresXML [More Info](https://www.biorxiv.org/about/FAQ#PrintOptions "More Information on Print/Save Options") [Supplementary Material ](https://www.biorxiv.org/content/10.64898/2026.10.02.756202v1.supplementary-material) [ Email](https://www.biorxiv.org/ "Email this Article") [ Share](https://www.biorxiv.org/) A PATHOGENIC NFKB2 VARIANT CAUSES COMBINED IMMUNODEFICIENCY WITH THYMIC AND PERIPHERAL LYMPHOID DEFECTS IN RATS Severine Remy, Laurent Tesson, Claire Usal, Marie Massoda, Severine Menoret, Irina Proekt,
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