DOCK2 and a Recessive Immunodeficiency with Early-Onset Invasive Infections
Kerry Dobbs
(1)
,
Cecilia Domínguez Conde
(2)
,
Shen-Ying Zhang
(3, 4)
,
Silvia Parolini
(5)
,
Magali Audry
(3)
,
Janet Chou
(1)
,
Emma Haapaniemi
(6)
,
Sevgi Keles
(1, 7)
,
Ivan Bilic
(2)
,
Satoshi Okada
(3)
,
Michel Massaad
(8)
,
Samuli Rounioja
(9)
,
Adel Alwahadneh
,
Nina Serwas
(2)
,
Kelly Capuder
(8)
,
Ergin Çiftçi
(10)
,
Kerstin Felgentreff
(8)
,
Toshiro Ohsumi
(11)
,
Vincent Pedergnana
(4)
,
Bertrand Boisson
(3)
,
Şule Haskoloğlu
(10)
,
Arzu Ensari
(10)
,
Michael Schuster
(2)
,
Alessandro Moretta
(12)
,
Yuval Itan
(3)
,
Ornella Patrizi
(5)
,
Flore Rozenberg
(4)
,
Pierre Lebon
(4)
,
Janna Saarela
(13)
,
Mikael Knip
(14, 15, 9)
,
Slavé Petrovski
(16, 17)
,
David Goldstein
(16, 17)
,
Roberta Parrott
(17)
,
Berna Savas
(10)
,
Axel Schambach
(18)
,
Giovanna Tabellini
(5)
,
Christoph Bock
(2)
,
Talal Chatila
(1)
,
Anne Marie Comeau
(19)
,
Raif Geha
(1)
,
Laurent Abel
(3, 4)
,
Rebecca Buckley
(17)
,
Aydan İkincioğullari
(10)
,
Waleed Al-Herz
(20)
,
Merja Helminen
(9)
,
Figen Doğu
(10)
,
Jean-Laurent Casanova
(3, 4, 21, 22)
,
Kaan Boztuğ
(2, 23)
,
Luigi Notarangelo
(1, 24)
1
Boston Children's Hospital
2 CeMM - Research Center for Molecular Medicine of the Austrian Academy of Sciences [Vienna, Austria]
3 St. Giles Laboratory of Human Genetics of Infectious Diseases
4 IMAGINE - U1163 - Imagine - Institut des maladies génétiques
5 UniBs - Università degli Studi di Brescia = University of Brescia
6 Helsingin yliopisto = Helsingfors universitet = University of Helsinki
7 Necmettin Erbakan University [Konya, Turquie]
8 Boston Children's Hospital
9 Tampere University Hospital
10 Ankara University School of Medicine [Turkey]
11 Massachusetts General Hospital [Boston, MA, USA]
12 UniGe - Università degli studi di Genova = University of Genoa
13 FIMM - Institute for Molecular Medicine Finland [Helsinki]
14 Children's Hospital
15 Folkhälsan Research Center
16 Columbia University [New York]
17 Duke University [Durham]
18 MHH - Medizinische Hochschule Hannover = Hannover Medical School
19 UMASS - University of Massachusetts Medical School [Worcester]
20 Kuwait University
21 Hôpital Necker - Enfants Malades [AP-HP]
22 HHMI - Howard Hughes Medical Institute [Chevy Chase]
23 Medizinische Universität Wien = Medical University of Vienna
24 HSCI - Harvard Stem Cell Institute [Cambridge, USA]
2 CeMM - Research Center for Molecular Medicine of the Austrian Academy of Sciences [Vienna, Austria]
3 St. Giles Laboratory of Human Genetics of Infectious Diseases
4 IMAGINE - U1163 - Imagine - Institut des maladies génétiques
5 UniBs - Università degli Studi di Brescia = University of Brescia
6 Helsingin yliopisto = Helsingfors universitet = University of Helsinki
7 Necmettin Erbakan University [Konya, Turquie]
8 Boston Children's Hospital
9 Tampere University Hospital
10 Ankara University School of Medicine [Turkey]
11 Massachusetts General Hospital [Boston, MA, USA]
12 UniGe - Università degli studi di Genova = University of Genoa
13 FIMM - Institute for Molecular Medicine Finland [Helsinki]
14 Children's Hospital
15 Folkhälsan Research Center
16 Columbia University [New York]
17 Duke University [Durham]
18 MHH - Medizinische Hochschule Hannover = Hannover Medical School
19 UMASS - University of Massachusetts Medical School [Worcester]
20 Kuwait University
21 Hôpital Necker - Enfants Malades [AP-HP]
22 HHMI - Howard Hughes Medical Institute [Chevy Chase]
23 Medizinische Universität Wien = Medical University of Vienna
24 HSCI - Harvard Stem Cell Institute [Cambridge, USA]
Kerry Dobbs
- Fonction : Auteur
- PersonId : 774144
- ORCID : 0000-0002-3432-3137
Shen-Ying Zhang
- Fonction : Auteur
- PersonId : 760020
- ORCID : 0000-0002-9449-3672
- IdRef : 144474549
Sevgi Keles
- Fonction : Auteur
- PersonId : 779159
- ORCID : 0000-0001-7344-8947
Satoshi Okada
- Fonction : Auteur
- PersonId : 769679
- ORCID : 0000-0002-4622-5657
Adel Alwahadneh
- Fonction : Auteur
Vincent Pedergnana
- Fonction : Auteur
- PersonId : 174866
- IdHAL : vincent-pedergnana
- ORCID : 0000-0002-7852-5339
- IdRef : 175475547
Bertrand Boisson
- Fonction : Auteur
- PersonId : 757762
- ORCID : 0000-0001-5240-3555
- IdRef : 08188317X
Flore Rozenberg
- Fonction : Auteur
- PersonId : 759620
- ORCID : 0000-0003-0991-7774
- IdRef : 089425561
Mikael Knip
- Fonction : Auteur
Slavé Petrovski
- Fonction : Auteur
- PersonId : 785619
- ORCID : 0000-0002-1527-961X
Laurent Abel
- Fonction : Auteur
- PersonId : 756191
- ORCID : 0000-0001-7016-6493
- IdRef : 07779432X
Luigi Notarangelo
- Fonction : Auteur
- PersonId : 758298
- ORCID : 0000-0002-8335-0262
Résumé
Background Combined immunodeficiencies are marked by inborn errors of T-cell immunity in which the T cells that are present are quantitatively or functionally deficient. Impaired humoral immunity is also common. Patients have severe infections, autoimmunity, or both. The specific molecular, cellular, and clinical features of many types of combined immunodeficiencies remain unknown. Methods We performed genetic and cellular immunologic studies involving five unrelated children with early-onset invasive bacterial and viral infections, lymphopenia, and defective T-cell, B-cell, and natural killer (NK)-cell responses. Two patients died early in childhood; after allogeneic hematopoietic stem-cell transplantation, the other three had normalization of T-cell function and clinical improvement. Results We identified biallelic mutations in the dedicator of cytokinesis 2 gene (DOCK2) in these five patients. RAC1 activation was impaired in the T cells. Chemokine-induced migration and actin polymerization were defective in the T cells, B cells, and NK cells. NK-cell degranulation was also affected. Interferon-α and interferon-λ production by peripheral-blood mononuclear cells was diminished after viral infection. Moreover, in DOCK2-deficient fibroblasts, viral replication was increased and virus-induced cell death was enhanced; these conditions were normalized by treatment with interferon alfa-2b or after expression of wild-type DOCK2. Conclusions Autosomal recessive DOCK2 deficiency is a new mendelian disorder with pleiotropic defects of hematopoietic and nonhematopoietic immunity. Children with clinical features of combined immunodeficiencies, especially with early-onset, invasive infections, may have this condition. (Supported by the National Institutes of Health and others.).
Domaines
Sciences du Vivant [q-bio]Origine | Fichiers produits par l'(les) auteur(s) |
---|