Autoimmunity and immunodeficiency associated with monoallelic LIG4 mutations via haploinsufficiency - 03/08/23

Doi : 10.1016/j.jaci.2023.03.022

Annaïse J. Jauch, MD, PhD ^a, Olivier Bignucolo, PhD ^b, Sayuri Seki, DVM, PhD ^c, Marie Ghraichy, PhD ^d, Ottavia M. Delmonte, MD ^e, Valentin von Niederhäusern, MSc ^d, Rebecca Higgins, PhD ^f, Adhideb Ghosh, PhD ^f,^g, Masako Nishizawa, PhD ^c, Mariko Tanaka, MD, PhD ^h, Adrian Baldrich, MSc ^a, Julius Köppen, MD ^a, Julia R. Hirsiger, MSc ⁱ, Robin Hupfer, MSc ^a, Stephan Ehl, MD ^j, Anne Rensing-Ehl, MD ^j, Helmut Hopfer, MD ^k, Spasenija Savic Prince, MD ^k, Stephen R. Daley, PhD ^l, Florian A. Marquardsen, PhD ^a, Benedikt J. Meyer, MD, PhD ^a, Michael Tamm, MD ^m, Thomas D. Daikeler, MD ^n,^o, Tamara Diesch, MD ^p, Thomas Kühne, MD ^p, Arthur Helbling, MD ^q, Caroline Berkemeier, MD, PhD ^r, Ingmar Heijnen, PhD ^r, Alexander A. Navarini, MD, PhD ^f,^o, Johannes Trück, MD, PhD ^d, Jean-Pierre de Villartay, PhD ^s, Annette Oxenius, PhD ^t, Christoph T. Berger, MD ^i,^o, Christoph Hess, MD, PhD ^o,^u,^v, Luigi D. Notarangelo, MD ^e, Hiroyuki Yamamoto, MD, PhD ^a,^c,^{^{∗
Hiroyuki Yamamoto and Mike Recher are joint senior authors.},}^⁎ , Mike Recher, MD ^a,^o,^{^{∗
Hiroyuki Yamamoto and Mike Recher are joint senior authors.},}^⁎
^a Immunodeficiency Laboratory, Department of Biomedicine, University of Basel and University Hospital of Basel, Basel, Switzerland
^f Division of Dermatology and Dermatology Laboratory, Department of Biomedicine, University of Basel and University Hospital of Basel, Basel, Switzerland
ⁱ Translational Immunology, Department of Biomedicine, University of Basel and University Hospital of Basel, Basel, Switzerland
^u Immunobiology Laboratory, Department of Biomedicine, University of Basel and University Hospital of Basel, Basel, Switzerland
^r Division Medical Immunology, Laboratory Medicine, University of Basel and University Hospital of Basel, Basel, Switzerland
^k Institute for Pathology, University Hospital Basel, Basel, Switzerland
^m Department of Pneumology, University Hospital Basel, Basel, Switzerland
ⁿ Department of Rheumatology, University Hospital Basel, Basel, Switzerland
^o University Center for Immunology, University Hospital Basel, Basel, Switzerland
^p Division of Pediatric Oncology/Hematology, University Children’s Hospital Basel, Basel, Switzerland
^b Swiss Institute of Bioinformatics, Basel, Switzerland
^c AIDS Research Center, National Institute of Infectious Diseases, Tokyo, Japan
^h Department of Pathology, The University of Tokyo, Tokyo, Japan
^d Division of Immunology and Children's Research Center, University Children's Hospital Zurich, University of Zurich, Zurich, Switzerland
^g Competence Center for Personalized Medicine, University of Zürich/Eidgenössische Technische Hochschule, Zurich, Switzerland
^t Institute of Microbiology, Eidgenössische Technische Hochschule, Zurich, Switzerland
^e Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md
^j Institute for Immunodeficiency, Center for Chronic Immunodeficiency, Medical Center, Faculty for Medicine, University of Freiburg, Freiburg, Germany
^l Centre for Immunology and Infection Control, School of Biomedical Sciences, Faculty of Health, Queensland University of Technology, Brisbane, Queensland
^q Division of Allergology and clinical Immunology, Department of Pneumology and Allergology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
^s Laboratory of Genome Dynamics in the Immune System, Institut National de la Santé et de la Recherche Médicale Unité Mixte de Recherché 1163, Université Paris Descartes Sorbonne Paris Cité, Institut Imagine, Paris, France
^v Cambridge Institute of Therapeutic Immunology and Infectious Disease, Department of Medicine, University of Cambridge, Cambridge, United Kingdom

^∗∗Corresponding author: Mike Recher, MD, University Immunology Center, University Hospital, Petersgraben 4, 4031 Basel, Switzerland and Immunodeficiency Laboratory, Department Biomedicine, Hebelstrasse 20, 4031 Basel, University of Basel, Switzerland.University Immunology CenterUniversity Hospital, Petersgraben 4, 4031 Basel, Switzerland and Immunodeficiency Laboratory, Department BiomedicineUniversity of BaselHebelstrasse 20Basel4031Switzerland^∗∗∗Hiroyuki Yamamoto, MD, PhD, AIDS Research Center, National Institute of Infectious Diseases, 4-7-1 Gakuen, Musashi-Murayama City, 208-0011 Tokyo, Japan.AIDS Research CenterNational Institute of Infectious Diseases4-7-1 GakuenMusashi-Murayama CityTokyo208-0011Japan

Abstract

Background

Biallelic mutations in LIG4 encoding DNA-ligase 4 cause a rare immunodeficiency syndrome manifesting as infant-onset life-threatening and/or opportunistic infections, skeletal malformations, radiosensitivity and neoplasia. LIG4 is pivotal during DNA repair and during V(D)J recombination as it performs the final DNA-break sealing step.

Objectives

This study explored whether monoallelic LIG4 missense mutations may underlie immunodeficiency and autoimmunity with autosomal dominant inheritance.

Methods

Extensive flow-cytometric immune-phenotyping was performed. Rare variants of immune system genes were analyzed by whole exome sequencing. DNA repair functionality and T-cell–intrinsic DNA damage tolerance was tested with an ensemble of in vitro and in silico tools. Antigen-receptor diversity and autoimmune features were characterized by high-throughput sequencing and autoantibody arrays. Reconstitution of wild-type versus mutant LIG4 were performed in LIG4 knockout Jurkat T cells, and DNA damage tolerance was subsequently assessed.

Results

A novel heterozygous LIG4 loss-of-function mutation (p.R580Q), associated with a dominantly inherited familial immune-dysregulation consisting of autoimmune cytopenias, and in the index patient with lymphoproliferation, agammaglobulinemia, and adaptive immune cell infiltration into nonlymphoid organs. Immunophenotyping revealed reduced naive CD4⁺ T cells and low TCR-Vα7.2⁺ T cells, while T-/B-cell receptor repertoires showed only mild alterations. Cohort screening identified 2 other nonrelated patients with the monoallelic LIG4 mutation p.A842D recapitulating clinical and immune-phenotypic dysregulations observed in the index family and displaying T-cell–intrinsic DNA damage intolerance. Reconstitution experiments and molecular dynamics simulations categorize both missense mutations as loss-of-function and haploinsufficient.

Conclusions

This study provides evidence that certain monoallelic LIG4 mutations may cause human immune dysregulation via haploinsufficiency.

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Key words : DNA ligase 4, DNA damage–autoimmunity, haploinsufficiency, autosomal dominant, inborn errors of immunity, immunodeficiency, primary immunodeficiency

Abbreviations used : BCR, BRCT2, DSB, HD, IGH, IGHA, IGHG, IR, KO, MD, MD memory, NHEJ, P1, TCR, TCRA, V(D)J, WT

Plan

Methods

Ethics approval and human subjects

Genetic analysis

Cell isolation and immunophenotyping

Results

Dominantly inherited immune-dysregulation

Preserved TCR/BCR repertoires

Novel heterozygous LIG4 missense variant

The R580Q variant reduces DSB ligation and DNA binding

Dysregulated DSB repair response in heterozygous LIG4 mutated primary T cells

The monoallelic LIG4 mutation p.A842D recapitulates impaired T-cell intrinsic DNA damage response and is linked with combined immunodeficiency

LIG4 R580Q and A842D mutations are functionally haploinsufficient

Discussion

M.R. was supported by the Swiss National Science Foundation (grants PP00P3_181038 and 310030_192652). A.J. was supported by the Swiss Cancer League (grant SNF 323630_151483) and Novartis Foundation for Medical-Biological Research. This work was supported by grants from the Swiss National Supercomputing Center (CSCS) to O.B. under the project IDs sm09 and s1099. J.T. was supported by the Swiss National Science Foundation (grants PZ00P3_161147 and PZ00P3_1837777). S.E. was supported by the BMBF GAIN consortium (grants TP6; 01GM1910A). This work was partially supported by the Japan Agency for Medical Research and Development (AMED) (grants JP19fm0208017 and JP22wm0325006) and the Takeda Science Foundation to H.Y. H.Y. was supported by the Swiss National Science Foundation (grant 310030_192652). S.S. was supported by the Ministry of Education, Culture, Sports, Science and Technology (MEXT) in Japan (JSPS) Grant-in-Aid for Early-Career Scientists [22K15480]. L.D.N. is supported by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health.

Disclosure of potential conflict of interest: The authors declare that they have no relevant conflicts of interest.

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Vol 152 - N° 2

P. 500-516 - août 2023 Retour au numéro

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Autoimmunity and immunodeficiency associated with monoallelic LIG4 mutations via haploinsufficiency - 03/08/23

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Results

Conclusions

Plan

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