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Cited by 43Immunodeficiency and Autoimmune DisordersHematopoietic Stem Cell TransplantationT-cell and B-cell Immunology

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

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Pillay, Bethany A., Avery, Danielle T., Smart, Joanne M., Cole, Theresa, Choo, Sharon, Chan, Damien, Gray, Paul E., Frith, Katie +21 more·2019·JCI Insight
DOI 10.1172/jci.insight.127527PMC PMC6629099
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Abstract

Biallelic 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 deficiency after HSCT, identify biomarkers that correlate with improved clinical outcomes, and inform the general dynamics of immune reconstitution in patients with monogenic immune disorders following HSCT.

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  • One investigation revealed increased exhaustion and senescence in HEM1-deficient patient CD4+ and CD8+ T cells, closely resembling the phenotype of DOCK8-deficient T cells.

    “One investigation revealed increased exhaustion and senescence in patient CD4+ and CD8+ T cells, closely resembling the phenotype of DOCK8-deficient T cell [10, 30].”

    From HEM1 Actin Immunodysregulatory Disorder: Genotypes, Phenotypes, and Future Directions (2022) · cites this paper as [30]

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Authors
Pillay, B. A., Avery, D. T., Smart, J. M., Cole, T., Choo, S., Chan, D., Gray, P. E., Frith, K., Mitchell, R., Phan, T. G., Wong, M., Campbell, D. E., Hsu, P., Ziegler, J. B., Peake, J., Alvaro, F., Picard, C., Bustamante, J., Neven, B., Cant, A. J., Uzel, G., Arkwright, P. D., Casanova, J.-L., Su, H. C., Freeman, A. F., Shah, N., Hickstein, D. D., Tangye, S. G., & Ma, C. S.
Affiliations
  • Garvan Institute of Medical Research (AU)
  • Royal Children's Hospital (AU)
  • Women's and Children's Hospital (AU)
  • UNSW Sydney (AU)
  • Children's Hospital at Westmead (AU)
  • Children's Health Queensland Hospital and Health Service (AU)
  • John Hunter Hospital (AU)
  • Laboratory of Lymphocyte Activation and Susceptibility to EBV Infection, INSERM UMR 1163, Imagine institut, Paris, France.
  • Inserm (FR)
  • Pediatric Hematology-Immunology Unit, Necker Hospital for Sick Children, AP-HP, Paris, France.
  • Newcastle upon Tyne Hospitals NHS Foundation Trust (GB)
  • Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, Maryland, USA.
  • University of Manchester (GB)
  • Hôpital Necker-Enfants Malades (FR)
  • National Institutes of Health (US)
  • Pediatric Oncology Branch,
Corresponding author
  • Tangye, Stuart G.
  • Ma, Cindy S.
ORCID
Venue
JCI Insight
Publisher
American Society for Clinical Investigation
Published
2019-06-06
Volume
4
Issue
11
ISSN
2379-3708 (ISSN-L)
DOI
10.1172/jci.insight.127527
PMC
PMC6629099
OpenAlex
W2937568612
Cited by
43
References
1
Citations by year
2026: 4 · 2025: 5 · 2024: 3 · 2023: 7 · 2022: 6 · 2021: 9 · 2020: 7 · 2019: 2
FWCI
2.36
Type
journal article
Language
en
Open access
Locations
  • JCI Insight (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • Research Explorer (The University of Manchester) (publishedVersion, other-oa)
  • Newcastle University ePrints (Newcastle Univesity) (cc-by)
Funders
  • National Health and Medical Research Council (1060303,1088215,1127157)
  • Jeffrey Modell Foundation (JMF2016-1)
Topics
  • Life Sciences › Immunology and Microbiology › Immunology › Immunodeficiency and Autoimmune Disorders
  • Health Sciences › Medicine › Hematology › Hematopoietic Stem Cell Transplantation
  • Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
Keywords
DOCK8 deficiency, hematopoietic stem cell transplantation, combined immunodeficiency, lymphocyte differentiation, T cell activation, B cell function, mucosal-associated invariant T cells, γδ T cells, IgE, immune reconstitution
MeSH terms
Adolescent, Adult, B-Lymphocytes, Cell Differentiation, Child, Child, Preschool, Humans, Immunoglobulin E, Job Syndrome, Lymphocyte Activation, T-Lymphocytes, Treatment Outcome, Hematopoietic Stem Cell Transplantation, Guanine Nucleotide Exchange Factors, Young Adult

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