Somatic reversion of pathogenic DOCK8 variants alters lymphocyte differentiation and function to effectively cure DOCK8 deficiency
Bethany Pillay
(1, 2)
,
Mathieu Fusaro
(3)
,
Paul Gray
(4, 5)
,
Aaron Statham
(1)
,
Leslie Burnett
(1, 2)
,
Liliana Bezrodnik
(6)
,
Alisa Kane
(1, 2, 7, 8, 9)
,
Winnie Tong
(8)
,
Chrystelle Abdo
(10)
,
Sarah Winter
(3, 11)
,
Samuel Chevalier
,
Romain Levy
(3, 11)
,
Cécile Masson
(3)
,
Yohann Schmitt
(3, 12)
,
Christine Bole
(3)
,
Marion Malphettes
(13)
,
Elizabeth Macintyre
(10)
,
Jean-Pierre de Villartay
(3)
,
John Ziegler
(4, 5)
,
Joanne Smart
(14)
,
Jane Peake
(15)
,
Asghar Aghamohammadi
(16)
,
Lennart Hammarström
(17)
,
Hassan Abolhassani
(16, 17)
,
Capucine Picard
(3, 11)
,
Alain Fischer
(3, 11, 18)
,
Sylvain Latour
(3)
,
Benedicte Neven
(11, 3)
,
Stuart Tangye
(1, 2)
,
Cindy Ma
(1, 2)
1
Garvan Institute of medical research
2 UNSW - University of New South Wales [Sydney]
3 Imagine - U1163 - Imagine - Institut des maladies génétiques (IHU)
4 Sydney Children's hospital
5 School of Women's and Children's Health
6 Ricardo Gutierrez Children's Hospital
7 Faculty of Medicine - South Western Sydney Clinical School [Liverpool, Australia]
8 St. Vincent's Hospital, Sydney
9 Liverpool hospital Sydney
10 INEM - UM 111 (UMR 8253 / U1151) - Institut Necker Enfants-Malades
11 Hôpital Necker - Enfants Malades [AP-HP]
12 UAR 3633 / US24 - Structure Fédérative de Recherche Necker
13 AP-HP - Hopital Saint-Louis [AP-HP]
14 Royal Alexandra Children's Hospital
15 UQ [All campuses : Brisbane, Dutton Park Gatton, Herston, St Lucia and other locations] - The University of Queensland
16 TUMS - Tehran University of Medical Sciences
17 Karolinska Institutet [Stockholm]
18 CdF (institution) - Collège de France
2 UNSW - University of New South Wales [Sydney]
3 Imagine - U1163 - Imagine - Institut des maladies génétiques (IHU)
4 Sydney Children's hospital
5 School of Women's and Children's Health
6 Ricardo Gutierrez Children's Hospital
7 Faculty of Medicine - South Western Sydney Clinical School [Liverpool, Australia]
8 St. Vincent's Hospital, Sydney
9 Liverpool hospital Sydney
10 INEM - UM 111 (UMR 8253 / U1151) - Institut Necker Enfants-Malades
11 Hôpital Necker - Enfants Malades [AP-HP]
12 UAR 3633 / US24 - Structure Fédérative de Recherche Necker
13 AP-HP - Hopital Saint-Louis [AP-HP]
14 Royal Alexandra Children's Hospital
15 UQ [All campuses : Brisbane, Dutton Park Gatton, Herston, St Lucia and other locations] - The University of Queensland
16 TUMS - Tehran University of Medical Sciences
17 Karolinska Institutet [Stockholm]
18 CdF (institution) - Collège de France
Bethany Pillay
- Fonction : Auteur
- PersonId : 798778
- ORCID : 0000-0001-7964-544X
Mathieu Fusaro
- Fonction : Auteur
- PersonId : 800975
- ORCID : 0000-0002-5332-3626
Paul Gray
- Fonction : Auteur
- PersonId : 798776
- ORCID : 0000-0003-2057-3968
Sarah Winter
- Fonction : Auteur
- PersonId : 798767
- ORCID : 0000-0001-7985-3986
Samuel Chevalier
- Fonction : Auteur
Marion Malphettes
- Fonction : Auteur
- PersonId : 762206
- ORCID : 0000-0002-9888-2528
Elizabeth Macintyre
- Fonction : Auteur
- PersonId : 762165
- ORCID : 0000-0003-0520-0493
Jean-Pierre de Villartay
- Fonction : Auteur
- PersonId : 756189
- ORCID : 0000-0001-5987-0463
- IdRef : 070707820
John Ziegler
- Fonction : Auteur
- PersonId : 815760
- ORCID : 0000-0002-5257-3113
Jane Peake
- Fonction : Auteur
- PersonId : 756556
- ORCID : 0000-0001-9003-5861
Lennart Hammarström
- Fonction : Auteur
- PersonId : 794455
- ORCID : 0000-0002-8635-9609
Hassan Abolhassani
- Fonction : Auteur
- PersonId : 783429
- ORCID : 0000-0002-4838-0407
Capucine Picard
- Fonction : Auteur
- PersonId : 758297
- ORCID : 0000-0001-8788-5056
- IdRef : 091572363
Sylvain Latour
- Fonction : Auteur
- PersonId : 764611
- ORCID : 0000-0001-8238-4391
- IdRef : 117717886
Stuart Tangye
- Fonction : Auteur
- PersonId : 804753
- ORCID : 0000-0002-5360-5180
Cindy Ma
- Fonction : Auteur
- PersonId : 794453
- ORCID : 0000-0001-5387-8413
Résumé
Inborn errors of immunity cause monogenic immune dysregulatory conditions such as severe and recurrent pathogen infection, inflammation, allergy, and malignancy. Somatic reversion refers to the spontaneous repair of a pathogenic germline genetic variant and has been reported to occur in a number of inborn errors of immunity, with a range of impacts on clinical outcomes of these conditions. DOCK8 deficiency due to biallelic inactivating mutations in DOCK8 causes a combined immunodeficiency characterized by severe bacterial, viral, and fungal infections, as well as allergic disease and some cancers. Here, we describe the clinical, genetic, and cellular features of 3 patients with biallelic DOCK8 variants who, following somatic reversion in multiple lymphocyte subsets, exhibited improved clinical features, including complete resolution of infection and allergic disease, and cure over time. Acquisition of DOCK8 expression restored defective lymphocyte signalling, survival and proliferation, as well as CD8+ T cell cytotoxicity, CD4+ T cell cytokine production, and memory B cell generation compared with typical DOCK8-deficient patients. Our temporal analysis of DOCK8-revertant and DOCK8-deficient cells within the same individual established mechanisms of clinical improvement in these patients following somatic reversion and revealed further nonredundant functions of DOCK8 in human lymphocyte biology. Last, our findings have significant implications for future therapeutic options for the treatment of DOCK8 deficiency.