Biallelic human SHARPIN loss of function induces autoinflammation and immunodeficiency

Hirotsugu Oda; Kalpana Manthiram; Pallavi Pimpale Chavan; Eva Rieser; Önay Veli; Öykü Kaya; Charles Rauch; Shuichiro Nakabo; Hye Sun Kuehn; Mariël Swart; Yanli Wang; Nisa Ilgim Çelik; Anne Molitor; Vahid Ziaee; Nasim Movahedi; Mohammad Shahrooei; Nima Parvaneh; Nasrin Alipour-Olyei; Raphael Carapito; Qin Xu; Silvia Preite; David B Beck; Jae Jin Chae; Michele Nehrebecky; Amanda K Ombrello; Patrycja Hoffmann; Tina Romeo; Natalie T Deuitch; Brynja Matthíasardóttir; James Mullikin; Hirsh Komarow; Jennifer Stoddard; Julie Niemela; Kerry Dobbs; Colin L Sweeney; Holly Anderton; Kate E Lawlor; Hiroyuki Yoshitomi; Dan Yang; Manfred Boehm; Jeremy Davis; Pamela Mudd; Davide Randazzo; Wanxia Li Tsai; Massimo Gadina; Mariana J Kaplan; Junya Toguchida; Christian T Mayer; Sergio D Rosenzweig; Luigi D Notarangelo; Kazuhiro Iwai; John Silke; Pamela L Schwartzberg; Bertrand Boisson; Jean-Laurent Casanova; Seiamak Bahram; Anand Prahalad Rao; Nieves Peltzer; Henning Walczak; Najoua Lalaoui; Ivona Aksentijevich; Daniel L Kastner

doi:10.1038/s41590-024-01817-w

Biallelic human SHARPIN loss of function induces autoinflammation and immunodeficiency

Nat Immunol. 2024 May;25(5):764-777. doi: 10.1038/s41590-024-01817-w. Epub 2024 Apr 12.

Authors

Hirotsugu Oda^#^{1

2

3}, Kalpana Manthiram^#^{4

5}, Pallavi Pimpale Chavan⁴, Eva Rieser^{6

7}, Önay Veli⁶, Öykü Kaya⁶, Charles Rauch^{6

7}, Shuichiro Nakabo⁸, Hye Sun Kuehn⁹, Mariël Swart⁶, Yanli Wang⁶, Nisa Ilgim Çelik⁶, Anne Molitor^{10

11}, Vahid Ziaee^{12

13

14

15}, Nasim Movahedi^{13

14

16}, Mohammad Shahrooei^{17

18}, Nima Parvaneh^{13

19}, Nasrin Alipour-Olyei^{10

11}, Raphael Carapito^{10

11

20}, Qin Xu⁵, Silvia Preite⁵, David B Beck^{4

21

22}, Jae Jin Chae⁴, Michele Nehrebecky⁴, Amanda K Ombrello⁴, Patrycja Hoffmann⁴, Tina Romeo⁴, Natalie T Deuitch⁴, Brynja Matthíasardóttir⁴, James Mullikin⁴, Hirsh Komarow⁵, Jennifer Stoddard⁹, Julie Niemela⁹, Kerry Dobbs⁵, Colin L Sweeney⁵, Holly Anderton^{23

24}, Kate E Lawlor^{23

24

25

26}, Hiroyuki Yoshitomi^{27

28

29}, Dan Yang³⁰, Manfred Boehm³⁰, Jeremy Davis³¹, Pamela Mudd³², Davide Randazzo⁸, Wanxia Li Tsai⁸, Massimo Gadina⁸, Mariana J Kaplan⁸, Junya Toguchida^{27

28}, Christian T Mayer³¹, Sergio D Rosenzweig⁹, Luigi D Notarangelo⁵, Kazuhiro Iwai²⁹, John Silke^{23

24}, Pamela L Schwartzberg⁵, Bertrand Boisson^{33

34

35}, Jean-Laurent Casanova^{33

34

35

36

37}, Seiamak Bahram^{10

11

20}, Anand Prahalad Rao³⁸, Nieves Peltzer^{6

39

40}, Henning Walczak^{6

7

41}, Najoua Lalaoui^{42

43

44}, Ivona Aksentijevich⁴⁵, Daniel L Kastner⁴⁶

Affiliations

¹ National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA. [email protected].
² Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany. [email protected].
³ Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany. [email protected].
⁴ National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
⁵ National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
⁶ Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany.
⁷ Institute of Biochemistry I, Medical Faculty, University of Cologne, Cologne, Germany.
⁸ National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, USA.
⁹ Department of Laboratory Medicine, Clinical Center, National Institutes of Health, Bethesda, MD, USA.
¹⁰ Laboratoire d'ImmunoRhumatologie Moléculaire, INSERM UMR_S1109, Plateforme GENOMAX, Faculté de Médecine, Fédération Hospitalo-Universitaire OMICARE, Centre de Recherche d'Immunologie et d'Hématologie, CRBS, Fédération de Médecine Translationnelle de Strasbourg, Université de Strasbourg, Strasbourg, France.
¹¹ Institut Thématique Interdisciplinaire (ITI) de Médecine de Précision de Strasbourg, Strasbourg, France.
¹² Division of Rheumatology, Department of Pediatrics, Tehran University of Medical Sciences, Tehran, Iran.
¹³ Children's Medical Center, Pediatrics Center of Excellence, Tehran, Iran.
¹⁴ Pediatric Rheumatology Society of Iran, Tehran, Iran.
¹⁵ Pediatric Rheumatology Research Group, Rheumatology Research Center, Tehran, Iran.
¹⁶ School of Medicine, Golestan University of Medical Sciences, Gorgan, Iran.
¹⁷ Clinical and Diagnostic Immunology, Department of Microbiology, Immunology, and Transplantation, KU Leuven, Leuven, Belgium.
¹⁸ Dr. Shahrooei Lab, 22 Bahman St., Ashrafi Esfahani Blvd, Tehran, Iran.
¹⁹ Division of Allergy and Clinical Immunology, Department of Pediatrics, Tehran University of Medical Sciences, Tehran, Iran.
²⁰ Laboratoire d'Immunologie, Plateau Technique de Biologie, Pôle de Biologie, Nouvel Hôpital Civil, Strasbourg, France.
²¹ Center for Human Genetics and Genomics, New York University Grossman School of Medicine, New York, NY, USA.
²² Division of Rheumatology, Department of Medicine, New York University Grossman School of Medicine, New York, NY, USA.
²³ The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.
²⁴ Department of Medical Biology, University of Melbourne, Parkville, Victoria, Australia.
²⁵ Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, Victoria, Australia.
²⁶ Department of Molecular and Translational Science, Monash University, Clayton, Victoria, Australia.
²⁷ Institute for Life and Medical Sciences, Kyoto University, Kyoto, Japan.
²⁸ Center for iPS Cell Research and Application, Kyoto University, Kyoto, Japan.
²⁹ Graduate School of Medicine, Kyoto University, Kyoto, Japan.
³⁰ National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA.
³¹ National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
³² Division of Pediatric Otolaryngology, Children's National Hospital, Washington, DC, USA.
³³ St. Giles Laboratory of Human Genetics of Infectious Diseases, The Rockefeller University, New York, NY, USA.
³⁴ Laboratory of Human Genetics of Infectious Diseases, INSERM, Necker Hospital for Sick Children, Paris, France.
³⁵ Imagine Institute, Paris Cité University, Paris, France.
³⁶ Department of Pediatrics, Necker Hospital for Sick Children, Paris, France.
³⁷ Howard Hughes Medical Institute, The Rockefeller University, New York, NY, USA.
³⁸ Manipal Hospital, Bengaluru, India.
³⁹ Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany.
⁴⁰ Department of Translational Genomics, University of Cologne, Cologne, Germany.
⁴¹ Centre for Cell Death, Cancer, and Inflammation, UCL Cancer Institute, University College, London, UK.
⁴² The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia. [email protected].
⁴³ Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia. [email protected].
⁴⁴ Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria, Australia. [email protected].
⁴⁵ National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA. [email protected].
⁴⁶ National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA. [email protected].

^# Contributed equally.

PMID: 38609546
DOI: 10.1038/s41590-024-01817-w

Abstract

The linear ubiquitin assembly complex (LUBAC) consists of HOIP, HOIL-1 and SHARPIN and is essential for proper immune responses. Individuals with HOIP and HOIL-1 deficiencies present with severe immunodeficiency, autoinflammation and glycogen storage disease. In mice, the loss of Sharpin leads to severe dermatitis due to excessive keratinocyte cell death. Here, we report two individuals with SHARPIN deficiency who manifest autoinflammatory symptoms but unexpectedly no dermatological problems. Fibroblasts and B cells from these individuals showed attenuated canonical NF-κB responses and a propensity for cell death mediated by TNF superfamily members. Both SHARPIN-deficient and HOIP-deficient individuals showed a substantial reduction of secondary lymphoid germinal center B cell development. Treatment of one SHARPIN-deficient individual with anti-TNF therapies led to complete clinical and transcriptomic resolution of autoinflammation. These findings underscore the critical function of the LUBAC as a gatekeeper for cell death-mediated immune dysregulation in humans.

Publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural
Case Reports

MeSH terms

Alleles
Animals
B-Lymphocytes / immunology
Female
Fibroblasts / immunology
Fibroblasts / metabolism
Humans
Immunologic Deficiency Syndromes* / genetics
Immunologic Deficiency Syndromes* / immunology
Inflammation / genetics
Inflammation / immunology
Intracellular Signaling Peptides and Proteins / genetics
Intracellular Signaling Peptides and Proteins / metabolism
Loss of Function Mutation
Male
Mice
NF-kappa B / metabolism
Nerve Tissue Proteins*
Ubiquitin-Protein Ligases / genetics
Ubiquitins*

Substances

SHARPIN protein, human
NF-kappa B
Ubiquitin-Protein Ligases
Intracellular Signaling Peptides and Proteins
sharpin
Nerve Tissue Proteins
Ubiquitins

Abstract

Publication types

MeSH terms

Substances

Grants and funding