Recent Advances in DOCK8 Immunodeficiency Syndrome

Abstract

Since the discovery of the genetic basis of DOCK8 immunodeficiency syndrome (DIDS) in 2009, several hundred patients worldwide have been reported, validating and extending the initial clinical descriptions. Importantly, the beneficial role of hematopoietic stem cell transplantation for this disease has emerged, providing impetus for improved diagnosis. Additionally, several groups have further elucidated the biological functions of DOCK8 in the immune system that help explain disease pathogenesis. Here, we summarize these recent developments.

Keywords: DOCK8; combined immunodeficiency; cutaneous virus infection; cytothripsis; eczema; food allergy; genetics; hematopoietic stem cell transplantation; hyperimmunoglobulinemia E syndrome; somatic reversion; tissue resident memory T cells (TRM).

Fig. 1. Possible combinations of germline mutations in DIDS

Actual mutations with sequencing interpretations below. Yellow, DOCK8 allele. Red, deletion. X, point mutation (missense, nonsense, splicing mutation, small indel). Gray hatches, sequence that appears to be deleted.

Fig. 2. Somatic reversions can obscure a molecular diagnosis of DIDS

(a) During replication of DOCK8 alleles, either gene conversion or intragenic single crossover can occur to generate somatic reversions. (b) An example of DIDS patient with somatic reversion. Notice the small peaks in the dashed frame showed abnormal sequence that was barely detectable in Sanger sequencing of PBMC DNA as opposed to neutrophil DNA. (c) Intracellular flow cytometic detection of DOCK8 in the same patient. A distinctive double peak (black) indicates this was a DIDS patient with somatic reversion in T cells. The level of reversion was exceptionally high in this patient, which resulted in the apparently normal Sanger sequencing result in (b).

Fig. 3. A critical role for DOCK8 during cytoskeletal rearrangement

(a) A DOCK8-CDC42-PAK pathway regulates cytoskeletal proteins such as F-actin to keep the cell body and nuclei intact during 3D migration of lymphocytes. The coordination of migration, not the mobility per se, is impaired when DOCK8 is absent and leads to cytothripsis. (b) DOCK8 regulates CDC42 and WASp to rearrange cytoskeletal proteins such as F-actin and microtubules in the immunological synapse. This contributes to NK cell killing of target cells.