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

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

Higher Incidence of B Cell Malignancies in Primary Immunodeficiencies: A Combination of Intrinsic Genomic Instability and Exocytosis Defects at the Immunological Synapse

“…Therefore, among all the treatments options currently available for PID patients, hematopoietic stem cell transplantation (HSCT) is the most curative and reliable one. Multiple studies have reported significant efficacy of HSCT in different PID associated with synaptic defects (92, 201,[298][299][300][301][302][303][304][305]. However, HSCT is a heavy surgical procedure that requires prior immunosuppressive conditioning.…”

Flow Cytometric-Based Analysis of Defects in Lymphocyte Differentiation and Function Due to Inborn Errors of Immunity

“…The age range of the healthy donors is from birth (cord blood) to ~65 years old. These data are compiled from findings previously reported in the following publications: (29–37, 39–44).…”

“…Assessing respiratory burst in phagocytes using oxidation of fluorescent probes such as dihydrorhodamine 123 (DHR) following leukocyte activation in vitro is the gold standard for diagnosing individuals with either X-linked or AR forms of chronic granulomatous disease (70), as well as females carriers of the X-linked form of this condition (59). Lastly, the use of cell permeable fluorescent dyes such as carboxyfluorescein succinimidyl ester (CFSE), Cell trace violet and Cell trace yellow, to label intracellular molecules and then track the dilution and concomitant reduction in fluorescence intensity of these dyes with each cell division (71, 72) has enabled detailed analysis of the role of cell division in lymphocyte differentiation and how these events can be uncoupled or compromised in various PIDs (29–31, 33, 35–37, 40, 58, 60, 73–76).…”

“…Expression of DOCK8 in lymphocytes was then determined. These data are compiled from findings previously reported in the following publications: (37, 57, 58).…”

“…This disorder is characterized by recurrent cutaneous viral, bacterial and fungal infections, increased serum IgE levels, and severe atopic disease, including food-induced anaphylaxis (97). Similar to SAP expression in XLP, the use of mAbs to detect DOCK8 expression has been crucial for the diagnosis of DOCK8-deficient patients (37, 53, 97) (Figure 2). Intracellular flow cytometry for DOCK8 expression has also detected somatic reversion in these patients (54).…”