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Somatic reversion of pathogenic DOCK8 variants alters lymphocyte differentiation and function to effectively cure DOCK8 deficiency
Bethany A. Pillay, … , Stuart G. Tangye, Cindy S. Ma
Bethany A. Pillay, … , Stuart G. Tangye, Cindy S. Ma
Published December 8, 2020
Citation Information: J Clin Invest. 2021;131(3):e142434. https://doi.org/10.1172/JCI142434.
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Research Article Immunology Infectious disease Article has an altmetric score of 92

Somatic reversion of pathogenic DOCK8 variants alters lymphocyte differentiation and function to effectively cure DOCK8 deficiency

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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.

Authors

Bethany A. Pillay, Mathieu Fusaro, Paul E. Gray, Aaron L. Statham, Leslie Burnett, Liliana Bezrodnik, Alisa Kane, Winnie Tong, Chrystelle Abdo, Sarah Winter, Samuel Chevalier, Romain Levy, Cécile Masson, Yohann Schmitt, Christine Bole, Marion Malphettes, Elizabeth Macintyre, Jean-Pierre De Villartay, John B. Ziegler, Joanne M. Smart, Jane Peake, Asghar Aghamohammadi, Lennart Hammarström, Hassan Abolhassani, Capucine Picard, Alain Fischer, Sylvain Latour, Benedicte Neven, Stuart G. Tangye, Cindy S. Ma

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Figure 4

Patient phenotype displays some aspects of DOCK8 deficiency due to DOCK8– cells.

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Patient phenotype displays some aspects of DOCK8 deficiency due to DOCK8...
PBMCs from healthy donors (n = 11), DOCK8-revertant patients (n = 3), and DOCK8-deficient patients (n = 7–9) were surface stained for CD3, CD4, CD8, CD20, CD56, CCR7, CD45RA, CD10, CD27, CD161, Vαβ, Vγδ, Vα7.2, Vα24, and Vβ11, fixed, permeabilized, and then intracellularly stained to detect DOCK8. Frequencies of (A) CD4+ T cells, CD8+ T cells, B cells (CD20+), and NK cells (CD3–CD56+); (B) αβ (CD3+ Vαβ+) and γδ (CD3+Vγδ+) T cells; (C) MAIT cells (CD3+CD161+Vα7.2+); (D) NKT cells (CD3+Vβ11+ Vα24+); (E) naive, Tcm and Tem CD4+ T cells; (F) naive, Tcm, Tem, and Temra CD8+ T cells; and (G) transitional, naive, and memory B cells were determined by flow cytometry. (H–N) The frequencies of the populations in A–G within the DOCK8– and DOCK8+ populations of the DOCK8-revertant patients. Circles, P1; squares, P2; triangles, P3. Error bars represent SEM.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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