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


Bi-allelic inactivating mutations in DOCK8 cause a combined immunodeficiency characterised 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 transplantation (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 alphabeta T and MAIT cells were reduced while gammadeltaT 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 catalogue of cellular defects in DOCK8-deficient patients, and the efficacy of HSCT to correct these defects, concurrent with improvements in clinical phenotypes. Overall, our findings provide mechanisms at a functional cellular level for improvements in clinical features of DOCK8 deficiency post-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.

Type Journal
ISBN 2379-3708 (Electronic) 2379-3708 (Linking)
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.
Responsible Garvan Author A/Prof Cindy Ma
Publisher Name Journal of Clinical Investigation Insight
Published Date 2019-04-25
Published Volume 5
Published Issue 11
Status Always Electronic
DOI 10.1172/jci.insight.127527
URL link to publisher's version