A combined immunodeficiency with severe infections, inflammation, and allergy caused by ARPC1B deficiency

Stefano Volpi¹, Maria Pia Cicalese², Paul Tuijnenburg³, Anton T J Tool⁴, Eloy Cuadrado⁵, Marwan Abu-Halaweh⁶, Hamid Ahanchian⁷, Raed Alzyoud⁸, Zeynep Coban Akdemir⁹, Federica Barzaghi², Alexander Blank¹⁰, Bertrand Boisson¹¹, Cristina Bottino¹², Immacolata Brigida², Roberta Caorsi¹³, Jean-Laurent Casanova¹⁴, Sabrina Chiesa¹³, Ivan Kingyue Chinn¹⁵, Gregor Dückers¹⁶, Anselm Enders¹⁷, Hans Christian Erichsen¹⁸, Lisa R Forbes¹⁵, Tomasz Gambin¹⁹, Marco Gattorno¹³, Ehsan Ghayoor Karimiani²⁰, Silvia Giliani²¹, Michael S Gold²², Eva-Maria Jacobsen¹⁰, Machiel H Jansen³, Jovanka R King²², Ronald M Laxer²³, James R Lupski²⁴, Emily Mace¹⁵, Stefania Marcenaro²⁵, Reza Maroofian²⁶, Alexander B Meijer²⁷, Tim Niehues¹⁶, Luigi D Notarangelo²⁸, Jordan Orange¹⁵, Ulrich Pannicke²⁹, Chris Pearson³⁰, Paolo Picco³¹, Patrick J Quinn²², Ansgar Schulz¹⁰, Filiz Seeborg¹⁵, Asbjørg Stray-Pedersen³², Hasan Tawamie³³, Ester M M van Leeuwen³⁴, Alessandro Aiuti², Rae Yeung³⁵, Klaus Schwarz³⁶, Taco W Kuijpers³⁷

Affiliations

¹ Clinica Pediatrica e Reumatologia, Centro per le malattie Autoinfiammatorie e Immunodeficienze, Istituto Giannina Gaslini, Genova, Italy; DINOGMI, Università degli Studi di Genova, Genova, Italy. Electronic address: stefanovolpi@gaslini.org.
² Pediatric Immunohematology, San Raffaele Hospital and San Raffaele Telethon Institute for Gene Therapy (SR-TIGET), Milan, Italy.
³ Department of Pediatric Immunology, Rheumatology and Infectious Diseases, Emma Children's Hospital, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands; Department of Experimental Immunology, Amsterdam Infection & Immunity Institute, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands.
⁴ Department of Blood Cell Research, Sanquin Research and Landsteiner Laboratory AMC, University of Amsterdam, Amsterdam, the Netherlands.
⁵ Department of Immunopathology, Sanquin Research and Landsteiner Laboratory AMC, University of Amsterdam, Amsterdam, the Netherlands.
⁶ Department of Biotechnology and Genetics Engineering in Philadelphia University, Amman, Jordan.
⁷ Department of Allergy and Immunology, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.
⁸ Queen Rania Children's Hospital, Immunology, Allergy and Rheumatology Section, Bone Marrow Transplantation for Primary Immunodeficiency Disorders, Amman, Jordan.
⁹ Baylor-Hopkins Center for Mendelian Genomics of the Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas.
¹⁰ Department of Pediatrics, University Medical Center Ulm, Ulm, Germany.
¹¹ St Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY; Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Paris, France; Imagine Institute, Paris Descartes University, Paris, France.
¹² Department of Experimental Medicine (DIMES), University of Genoa, Genova, Italy; Istituto Giannina Gaslini, Genova, Italy.
¹³ Clinica Pediatrica e Reumatologia, Centro per le malattie Autoinfiammatorie e Immunodeficienze, Istituto Giannina Gaslini, Genova, Italy.
¹⁴ St Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY; Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Paris, France; Imagine Institute, Paris Descartes University, Paris, France; Pediatric Hematology-Immunology and Rheumatology Unit, Necker Hospital for Sick Children, APHP, Paris, France; Howard Hughes Medical Institute, New York, NY.
¹⁵ Department of Pediatrics, Section of Allergy, Immunology, and Rheumatology & Center for Human Immunobiology, Texas Children's Hospital, Houston, Texas.
¹⁶ Center for Child and Adolescent Medicine, Helios-Clinic, Krefeld, Germany.
¹⁷ Department of Immunology and Infectious Disease, John Curtin School of Medical Research and Centre for Personalised Immunology, Australian National University, Canberra, ACT, Australia.
¹⁸ Section of Paediatric Medicine and Transplantation, Division of Paediatric and Adolescent Medicine, Oslo University Hospital, Oslo, Norway.
¹⁹ Baylor-Hopkins Center for Mendelian Genomics of the Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas; Institute of Computer Science, Warsaw University of Technology, Warsaw, Poland.
²⁰ Molecular and Clinical Sciences Institute, St George's, University of London, Cranmer Terrace, London, United Kingdom; Innovative Medical Research Center, Mashhad Branch, Islamic Azad University, Mashhad, Iran.
²¹ Medical Genetics Unit and "A. Nocivelli" Institute for Molecular Medicine, Spedali Civili Hospital, Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy.
²² Discipline of Pediatrics, School of Medicine, University of Adelaide and Department of Allergy and Clinical Immunology, Women's and Children's Health Network, Adelaide, South Australia, Australia.
²³ Division of Rheumatology, Department of Paediatrics and Department of Medicine, University of Toronto, The Hospital for Sick Children, Toronto, Ontario, Canada.
²⁴ Baylor-Hopkins Center for Mendelian Genomics of the Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas; Department of Pediatrics, Baylor College of Medicine, Houston, Texas; Texas Children's Hospital, Houston, Texas.
²⁵ Istituto Giannina Gaslini, Genova, Italy.
²⁶ Medical Research, RILD Welcome Wolfson Centre, Exeter Medical School, Royal Devon and Exeter NHS Foundation Trust, Exeter and Genetics and Molecular Cell Sciences Research Centre, St George's University of London, London, United Kingdom.
²⁷ Department of Plasma Proteins, Sanquin Research and Landsteiner Laboratory AMC, University of Amsterdam, Amsterdam, the Netherlands.
²⁸ Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, Md.
²⁹ Institute for Transfusion Medicine, University Ulm, Ulm, Germany.
³⁰ Department of General Medicine, Women's and Children's Health Network, Adelaide, South Australia, Australia.
³¹ Clinica Pediatrica e Reumatologia, Istituto Giannina Gaslini, Genova, Italy.
³² Norwegian National Unit for Newborn Screening, Division of Pediatric and Adolescent Medicine, Oslo University Hospital, Oslo, Norway.
³³ Institute of Human Genetics of Leipzig, Leipzig, Germany.
³⁴ Department of Experimental Immunology, Amsterdam Infection & Immunity Institute, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands.
³⁵ Division of Rheumatology, Department of Paediatrics and Department of Medicine, University of Toronto, The Hospital for Sick Children, Toronto, Ontario, Canada; Department of Paediatrics, Institute of Medical Science, University of Toronto, Cell Biology Program, The Hospital for Sick Children, Toronto, Ontario, Canada; Department of Immunology, Institute of Medical Science, University of Toronto, Cell Biology Program, The Hospital for Sick Children, Toronto, Ontario, Canada.
³⁶ Institute for Transfusion Medicine, University Ulm, Ulm, Germany; the Institute for Clinical Transfusion Medicine and Immunogenetics Ulm, German Red Cross Blood Service Baden-Wuerttemberg - Hessen, Ulm, Germany.
³⁷ Department of Pediatric Immunology, Rheumatology and Infectious Diseases, Emma Children's Hospital, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands; Department of Blood Cell Research, Sanquin Research and Landsteiner Laboratory AMC, University of Amsterdam, Amsterdam, the Netherlands. Electronic address: t.w.kuijpers@amc.nl.

PMID: 30771411
PMCID: PMC6677392
DOI: 10.1016/j.jaci.2019.02.003

Case Reports

A combined immunodeficiency with severe infections, inflammation, and allergy caused by ARPC1B deficiency

Stefano Volpi et al. J Allergy Clin Immunol. 2019 Jun.

. 2019 Jun;143(6):2296-2299.

doi: 10.1016/j.jaci.2019.02.003. Epub 2019 Feb 13.

Authors

Affiliations

¹ Clinica Pediatrica e Reumatologia, Centro per le malattie Autoinfiammatorie e Immunodeficienze, Istituto Giannina Gaslini, Genova, Italy; DINOGMI, Università degli Studi di Genova, Genova, Italy. Electronic address: stefanovolpi@gaslini.org.
² Pediatric Immunohematology, San Raffaele Hospital and San Raffaele Telethon Institute for Gene Therapy (SR-TIGET), Milan, Italy.
³ Department of Pediatric Immunology, Rheumatology and Infectious Diseases, Emma Children's Hospital, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands; Department of Experimental Immunology, Amsterdam Infection & Immunity Institute, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands.
⁴ Department of Blood Cell Research, Sanquin Research and Landsteiner Laboratory AMC, University of Amsterdam, Amsterdam, the Netherlands.
⁵ Department of Immunopathology, Sanquin Research and Landsteiner Laboratory AMC, University of Amsterdam, Amsterdam, the Netherlands.
⁶ Department of Biotechnology and Genetics Engineering in Philadelphia University, Amman, Jordan.
⁷ Department of Allergy and Immunology, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.
⁸ Queen Rania Children's Hospital, Immunology, Allergy and Rheumatology Section, Bone Marrow Transplantation for Primary Immunodeficiency Disorders, Amman, Jordan.
⁹ Baylor-Hopkins Center for Mendelian Genomics of the Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas.
¹⁰ Department of Pediatrics, University Medical Center Ulm, Ulm, Germany.
¹¹ St Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY; Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Paris, France; Imagine Institute, Paris Descartes University, Paris, France.
¹² Department of Experimental Medicine (DIMES), University of Genoa, Genova, Italy; Istituto Giannina Gaslini, Genova, Italy.
¹³ Clinica Pediatrica e Reumatologia, Centro per le malattie Autoinfiammatorie e Immunodeficienze, Istituto Giannina Gaslini, Genova, Italy.
¹⁴ St Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY; Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Paris, France; Imagine Institute, Paris Descartes University, Paris, France; Pediatric Hematology-Immunology and Rheumatology Unit, Necker Hospital for Sick Children, APHP, Paris, France; Howard Hughes Medical Institute, New York, NY.
¹⁵ Department of Pediatrics, Section of Allergy, Immunology, and Rheumatology & Center for Human Immunobiology, Texas Children's Hospital, Houston, Texas.
¹⁶ Center for Child and Adolescent Medicine, Helios-Clinic, Krefeld, Germany.
¹⁷ Department of Immunology and Infectious Disease, John Curtin School of Medical Research and Centre for Personalised Immunology, Australian National University, Canberra, ACT, Australia.
¹⁸ Section of Paediatric Medicine and Transplantation, Division of Paediatric and Adolescent Medicine, Oslo University Hospital, Oslo, Norway.
¹⁹ Baylor-Hopkins Center for Mendelian Genomics of the Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas; Institute of Computer Science, Warsaw University of Technology, Warsaw, Poland.
²⁰ Molecular and Clinical Sciences Institute, St George's, University of London, Cranmer Terrace, London, United Kingdom; Innovative Medical Research Center, Mashhad Branch, Islamic Azad University, Mashhad, Iran.
²¹ Medical Genetics Unit and "A. Nocivelli" Institute for Molecular Medicine, Spedali Civili Hospital, Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy.
²² Discipline of Pediatrics, School of Medicine, University of Adelaide and Department of Allergy and Clinical Immunology, Women's and Children's Health Network, Adelaide, South Australia, Australia.
²³ Division of Rheumatology, Department of Paediatrics and Department of Medicine, University of Toronto, The Hospital for Sick Children, Toronto, Ontario, Canada.
²⁴ Baylor-Hopkins Center for Mendelian Genomics of the Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas; Department of Pediatrics, Baylor College of Medicine, Houston, Texas; Texas Children's Hospital, Houston, Texas.
²⁵ Istituto Giannina Gaslini, Genova, Italy.
²⁶ Medical Research, RILD Welcome Wolfson Centre, Exeter Medical School, Royal Devon and Exeter NHS Foundation Trust, Exeter and Genetics and Molecular Cell Sciences Research Centre, St George's University of London, London, United Kingdom.
²⁷ Department of Plasma Proteins, Sanquin Research and Landsteiner Laboratory AMC, University of Amsterdam, Amsterdam, the Netherlands.
²⁸ Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, Md.
²⁹ Institute for Transfusion Medicine, University Ulm, Ulm, Germany.
³⁰ Department of General Medicine, Women's and Children's Health Network, Adelaide, South Australia, Australia.
³¹ Clinica Pediatrica e Reumatologia, Istituto Giannina Gaslini, Genova, Italy.
³² Norwegian National Unit for Newborn Screening, Division of Pediatric and Adolescent Medicine, Oslo University Hospital, Oslo, Norway.
³³ Institute of Human Genetics of Leipzig, Leipzig, Germany.
³⁴ Department of Experimental Immunology, Amsterdam Infection & Immunity Institute, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands.
³⁵ Division of Rheumatology, Department of Paediatrics and Department of Medicine, University of Toronto, The Hospital for Sick Children, Toronto, Ontario, Canada; Department of Paediatrics, Institute of Medical Science, University of Toronto, Cell Biology Program, The Hospital for Sick Children, Toronto, Ontario, Canada; Department of Immunology, Institute of Medical Science, University of Toronto, Cell Biology Program, The Hospital for Sick Children, Toronto, Ontario, Canada.
³⁶ Institute for Transfusion Medicine, University Ulm, Ulm, Germany; the Institute for Clinical Transfusion Medicine and Immunogenetics Ulm, German Red Cross Blood Service Baden-Wuerttemberg - Hessen, Ulm, Germany.
³⁷ Department of Pediatric Immunology, Rheumatology and Infectious Diseases, Emma Children's Hospital, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands; Department of Blood Cell Research, Sanquin Research and Landsteiner Laboratory AMC, University of Amsterdam, Amsterdam, the Netherlands. Electronic address: t.w.kuijpers@amc.nl.

PMID: 30771411
PMCID: PMC6677392
DOI: 10.1016/j.jaci.2019.02.003

No abstract available

PubMed Disclaimer

Conflict of interest statement

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

Figures

**FIG 1.**
Clinical features, imaging, and histology of relevant tissues in affected patients. A, Frequencies of clinical manifestations in ARPC1B-deficient patients (detailed in Table E8). **B-D**, Diffuse warts, eczema, and skin vasculitis in P7. E, Sialadenitis and lymph node enlargement in P3. *CMV*, cytomegalovirus; GH, growth hormone.

**FIG 2.**
Immune cell abnormalities. A, Representative plots of the altered B-lymphocyte staining (*left panel*), B-lymphocyte percentage (*middle panel*), and CD19 expression (geometric mean fluorescence intensity, *right panel*) in ARPC1B-deficient patients. For CD4⁺ and CD8⁺ T-cell subsets (naive, memory, and effector-memory populations), see Fig E1. B, Treg-cell subset analysis with a representative dot plot showing percentage of Treg cells (CD4⁺CD25RA^posCD127^neg), and Treg FOXP3 and Helios expression. C, FOXP3 and Helios expression of *In vitro* expanded Treg cells from patient and control (lines connect each patient with their own healthy relative used as control). D, FACS plots showing the proliferation of allogeneic T-responder cells (T_resp) measured by cell-trace violet (CTV) dilution. The stimulated and unstimulated T_resp without Treg cells are shown in blue. Treg cells from controls (in gray) and patients (in red) were cultured at different ratios with T_resp cells while stimulated with anti-CD3/CD28. E, Quantification of CD4 and CD8 T_resp-cell suppression by Treg cells. F, NK cells of patients were functionally evaluated against the K562 cell line by CD107A expression experiments. Resting NK cells (left panel) and IL-2–stimulated cells (right panel) were evaluated and compared with 10 healthy controls. All controls are represented by healthy adults. Bars indicate means ± SD, and a star indicates statistical significance as assessed by Mann-Whitney test (P < .05). Stim, Stimulated; unstim, unstimulated.

See this image and copyright information in PMC

References

1. Kuijpers TW, Tool ATJ, van der Bijl I, de Boer M, van Houdt M, de Cuyper IM, et al. Combined immunodeficiency with severe inflammation and allergy caused by ARPC1B deficiency. J Allergy Clin Immunol 2017;140:273–7.e10. - PubMed
1. Kahr WH, Pluthero FG, Elkadri A, Warner N, Drobac M, Chen CH, et al. Loss of the Arp2/3 complex component ARPC1B causes platelet abnormalities and predisposes to inflammatory disease. Nat Commun 2017;8:14816. - PMC - PubMed
1. Somech R, Lev A, Lee YN, Simon AJ, Barel O, Schiby G, et al. Disruption of thrombocyte and T lymphocyte development by a mutation in ARPC1B. J Immunol 2017;199:4036–45. - PMC - PubMed
1. Brigida I, Zoccolillo M, Cicalese MP, Pfajfer L, Barzaghi F, Scala S, et al. T cell defects in patients with ARPC1B germline mutations account for their combined immunodeficiency. Blood 2018;132:2362–74. - PMC - PubMed
1. Su HC, Jing H, Angelus P, Freeman AF. Insights into immunity from clinical and basic science studies of DOCK8 immunodeficiency syndrome. Immunol Rev 2019;287:9–19. - PMC - PubMed

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A combined immunodeficiency with severe infections, inflammation, and allergy caused by ARPC1B deficiency

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A combined immunodeficiency with severe infections, inflammation, and allergy caused by ARPC1B deficiency

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Conflict of interest statement

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