Somatic Reversion of Pathogenic Dock8 Variants Alters Lymphocyte Differentiation and Function to Effectively Cure Dock8 Deficiency

Somatic Reversion of Pathogenic Dock8 Variants Alters Lymphocyte Differentiation and Function to Effectively Cure Dock8 Deficiency Publisher Pubmed

Pillay BA^{1, 2} ; Fusaro M^{3, 4, 5} ; Gray PE^{6, 7, 8} ; Statham AL¹ ; Burnett L^{1, 2, 8} ; Bezrodnik L⁹ ; Kane A^{1, 2, 8, 10, 11, 12} ; Tong W^{8, 11} ; Abdo C¹³ ; Winter S^{3, 5, 14} ; Chevalier S⁴ ; Levy R^{3, 14, 15} ; Masson C^{3, 16} ; Schmitt Y^{3, 17, 18} Show All Authors

Pillay BA^{1, 2}
Fusaro M^{3, 4, 5}
Gray PE^{6, 7, 8}
Statham AL¹
Burnett L^{1, 2, 8}
Bezrodnik L⁹
Kane A^{1, 2, 8, 10, 11, 12}
Tong W^{8, 11}
Abdo C¹³
Winter S^{3, 5, 14}
Chevalier S⁴
Levy R^{3, 14, 15}
Masson C^{3, 16}
Schmitt Y^{3, 17, 18}
Bole C¹⁷
Malphettes M¹⁹
Macintyre E¹³
De Villartay JP²⁰
Ziegler JB^{6, 7, 8}
Smart JM²¹
Peake J²²
Aghamohammadi A²³
Hammarstrom L²⁴
Abolhassani H^{23, 24}
Picard C^{3, 4, 5, 14}
Fischer A^{3, 14, 25, 26}
Latour S⁵
Neven B^{14, 27}
Tangye SG^{1, 2, 8}
Ma CS^{1, 2, 8}

Show Affiliations

1. Garvan Institute of Medical Research, Sydney, NSW, Australia
2. St Vincent's Clinical School, Faculty of Medicine, University of New South Wales (UNSW), Sydney, NSW, Australia
3. Paris University, Imagine Institute, Universite de Paris, Paris, France
4. Study Center for Primary Immunodeficiencies, Assistance Publique-Hopitaux de Paris (AP-HP), Paris, France
5. Laboratory of Lymphocyte Activation and Susceptibility to EBV infection, INSERM UMR 1163, Imagine Institut, Paris, France
6. Department of Immunology and Infectious Diseases, Sydney Children's Hospital, Sydney, Australia
7. School of Women's and Children's Health, UNSW, Sydney, NSW, Australia
8. Clinical Immunogenomics Research Consortia of Australasia, Sydney, NSW, Australia
9. Clinical Immunology Center and Immunology Unit, Ricardo Gutierrez Children Hospital, Ciudad Autonoma de Buenos, Aires, Argentina
10. South Western Sydney Clinical School, Faculty of Medicine, UNSW, Sydney, NSW, Australia
11. HIV and Immunology Unit, St Vincent's Hospital, Sydney, Australia
12. Department of Immunology, Allergy and HIV, Liverpool Hospital, Liverpool, Sydney, Australia
13. Biological Onco-hematology, Universite de Paris, AP-HP and INEM, Paris, France
14. Pediatric Hematology and Immunology Unit, AP-HP, Paris, France
15. Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM UMR 1163, Paris, France
16. Imagine Institute, Bioinformatics Platform, INSERM UMR 1163, Paris, France
17. Genomic Core Facility, INSERM UMR 1163, Imagine Institute, Paris, France
18. INSERM US24, CNRS UMS3633, Paris, France
19. Immuno-Pathologie Clinique, AP-HP, Hopital Saint-Louis, Paris, France
20. Laboratory of Genome Dynamics in The Immune System, INSERM UMR 1163, Paris, France
21. Royal Children's Hospital, Melbourne, Australia
22. Queensland Children's Hospital, University of Queensland, South Brisbane, Australia
23. Research Center for Immunodeficiencies, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran
24. Division of Clinical Immunology, Department of Laboratory Medicine, Karolinska University Hospital Huddinge, Karolinska Institute, Stockholm, Sweden
25. College de France, Paris, France
26. Imagine Institute, INSERM UMR 1163, Paris, France
27. Universite de Paris, Imagine Institute Laboratory of Immunogenetics of Pediatric Autoimmune Diseases, INSERM UMR 1163, Paris, France

Source: Journal of Clinical Investigation Published:2021

Abstract

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. Copyright: © 2021, American Society for Clinical Investigation.

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Style	Citing Format
MLA	Pillay BA, et al.. "Somatic Reversion of Pathogenic Dock8 Variants Alters Lymphocyte Differentiation and Function to Effectively Cure Dock8 Deficiency." Journal of Clinical Investigation, vol. 131, no. 3, 2021, pp. -.
APA	Pillay BA, Fusaro M, Gray PE, Statham AL, Burnett L, Bezrodnik L, Kane A, Tong W, Abdo C, Winter S, Chevalier S, Levy R, Masson C, Schmitt Y, Bole C, Malphettes M, Macintyre E, De Villartay JP, Ziegler JB, ... Ma CS (2021). Somatic Reversion of Pathogenic Dock8 Variants Alters Lymphocyte Differentiation and Function to Effectively Cure Dock8 Deficiency. Journal of Clinical Investigation, 131(3), -.
Chicago	Pillay BA, Fusaro M, Gray PE, Statham AL, Burnett L, Bezrodnik L, Kane A, et al.. "Somatic Reversion of Pathogenic Dock8 Variants Alters Lymphocyte Differentiation and Function to Effectively Cure Dock8 Deficiency." Journal of Clinical Investigation 131, no. 3 (2021): -.
Harvard	Pillay BA et al. (2021) 'Somatic Reversion of Pathogenic Dock8 Variants Alters Lymphocyte Differentiation and Function to Effectively Cure Dock8 Deficiency', Journal of Clinical Investigation, 131(3), pp. -.
Vancouver	Pillay BA, Fusaro M, Gray PE, Statham AL, Burnett L, Bezrodnik L, et al.. Somatic Reversion of Pathogenic Dock8 Variants Alters Lymphocyte Differentiation and Function to Effectively Cure Dock8 Deficiency. Journal of Clinical Investigation. 2021;131(3):-.
BibTex	@article{ author = {Pillay BA and Fusaro M and Gray PE and Statham AL and Burnett L and Bezrodnik L and Kane A and Tong W and Abdo C and Winter S and Chevalier S and Levy R and Masson C and Schmitt Y and Bole C and Malphettes M and Macintyre E and De Villartay JP and Ziegler JB and Smart JM and Peake J and Aghamohammadi A and Hammarstrom L and Abolhassani H and Picard C and Fischer A and Latour S and Neven B and Tangye SG and Ma CS}, title = {Somatic Reversion of Pathogenic Dock8 Variants Alters Lymphocyte Differentiation and Function to Effectively Cure Dock8 Deficiency}, journal = {Journal of Clinical Investigation}, volume = {131}, number = {3}, pages = {-}, year = {2021} }
RIS	TY - JOUR AU - Pillay BA AU - Fusaro M AU - Gray PE AU - Statham AL AU - Burnett L AU - Bezrodnik L AU - Kane A AU - Tong W AU - Abdo C AU - Winter S AU - Chevalier S AU - Levy R AU - Masson C AU - Schmitt Y AU - Bole C AU - Malphettes M AU - Macintyre E AU - De Villartay JP AU - Ziegler JB AU - Smart JM AU - Peake J AU - Aghamohammadi A AU - Hammarstrom L AU - Abolhassani H AU - Picard C AU - Fischer A AU - Latour S AU - Neven B AU - Tangye SG AU - Ma CS TI - Somatic Reversion of Pathogenic Dock8 Variants Alters Lymphocyte Differentiation and Function to Effectively Cure Dock8 Deficiency JO - Journal of Clinical Investigation VL - 131 IS - 3 SP - EP - PY - 2021 ER -

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