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Hematopoietic stem cell transplant effectively rescues lymphocyte differentiation and function in DOCK8-deficient patients

Lookup NU author(s): Professor Andrew Cant

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Abstract

Copyright: © 2019 American Society for Clinical InvestigationBiallelic inactivating mutations in DOCK8 cause a combined immunodeficiency characterized by severe pathogen infections, eczema, allergies, malignancy, and impaired humoral responses. These clinical features result from functional defects in most lymphocyte lineages. Thus, DOCK8 plays a key role in immune cell function. Hematopoietic stem cell transplant (HSCT) is curative for DOCK8 deficiency. While previous reports have described clinical outcomes for DOCK8 deficiency following HSCT, the effect on lymphocyte reconstitution and function has not been investigated. Our study determined whether defects in lymphocyte differentiation and function in DOCK8-deficient patients were restored following HSCT. DOCK8-deficient T and B lymphocytes exhibited aberrant activation and effector function in vivo and in vitro. Frequencies of αβ T and MAIT cells were reduced, while γδT cells were increased in DOCK8-deficient patients. HSCT improved abnormal lymphocyte function in DOCK8-deficient patients. Elevated total and allergen-specific IgE in DOCK8-deficient patients decreased over time following HSCT. Our results document the extensive catalog of cellular defects in DOCK8-deficient patients and the efficacy of HSCT in correcting these defects, concurrent with improvements in clinical phenotypes. Overall, our findings reveal mechanisms at a functional cellular level for improvements in clinical features of DOCK8

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Author(s): Pillay BA, Avery DT, Smart JM, Cole T, Choo S, Chan D, Gray PE, Frith K, Mitchell R, Phan TG, Wong M, Campbell DE, Hsu P, Ziegler JB, Peake J, Alvaro F, Picard C, Bustamante J, Neven B, Cant AJ, Uzel G, Arkwright PD, Casanova J-L, Su HC, Freeman AF, Shah N, Hickstein DD, Tangye SG, Ma CS

Publication type: Article

Publication status: Published

Journal: JCI Insight

Year: 2019

Volume: 4

Issue: 11

Print publication date: 06/06/2019

Online publication date: 25/04/2019

Acceptance date: 17/04/2019

Date deposited: 29/08/2019

ISSN (print): 2379-3708

Publisher: American Society for Clinical Investigation

URL: https://doi.org/10.1172/jci.insight.127527

DOI: 10.1172/jci.insight.127527

PubMed id: 31021819

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