DOCK8 deficiency: Insights into pathophysiology, clinical features and management

Abstract

Dedicator of Cytokinesis 8 (DOCK8) deficiency is a combined immunodeficiency that exemplifies the broad clinical features of primary immunodeficiencies (PIDs), extending beyond recurrent infections to include atopy, autoimmunity and cancer. It is caused by loss of function mutations in DOCK8, encoding a guanine nucleotide exchange factor highly expressed in lymphocytes that regulates the actin cytoskeleton. Additional roles of DOCK8 have also emerged, including regulating MyD88-dependent Toll-like receptor signaling and the activation of the transcription factor STAT3. DOCK8 deficiency impairs immune cell migration, function and survival, and it impacts both innate and adaptive immune responses. Clinically, DOCK8 deficiency is characterized by allergic inflammation as well as susceptibility towards infections, autoimmunity and malignancy. This review details the pathophysiology, clinical features and management of DOCK8 deficiency. It also surveys the recently discovered combined immunodeficiency due to DOCK2 deficiency, highlighting in the process the emerging spectrum of PIDs resulting from DOCK protein family abnormalities.

Insights into immunity from clinical and basic science studies of DOCK8 immunodeficiency syndrome

“…12 Around the same time, other groups used homozygosity mapping with sequencing of shared regions to identify autosomal recessive mutations in DOCK8 in different cohorts of AR-HIES patients. 13 (1), dendritic cells normally take up antigen and travel through the afferent lymphatics (2) to the lymph node where they prime T cells (3). Responding T cells differentiate and travel through efferent lymphatics to the blood, where they exit through venules into various tissues including the dermis of the skin.…”

“…DOCK8 immunodeficiency syndrome (DIDS), sometimes termed DOCK8 deficiency, has been previously reviewed elsewhere. [1][2][3] DIDS is a combined immunodeficiency that has several unusual clinical features (see pictorial summary in Figure 1A). Most but not all cases of DIDS are associated with elevated serum IgE.…”

DOCK8 Deficiency Presenting as an IPEX-Like Disorder

“…Whereas DOCK8 deficiency typically manifests as a combined immunodeficiency, with recurrent viral, bacterial and fungal infections, it also presents with several features of immune dysregulation, including allergic dysregulation, lymphoproliferation and autoimmunity, which may dominate the clinical picture (13, 17, 18). The clinical findings in our index case, patient P1, were skewed towards immune dysregulation, with prominence of enteropathy and colitis as clinical features in the absence of an obvious infectious agent, in addition to the other features such allergic dysregulation and autoimmunity (21, 24).…”

“…There are several mechanisms by which DOCK8 deficiency may impact T reg cell function (13). DOCK8 regulates the actin cytoskeleton by virtue of its activation of CDC42, which in turn activates Wiskott-Aldrich protein (WASP) (6).…”

“…In B cells, DOCK8 enables a TLR9-PYK2-STAT3 cascade that promotes B cell proliferation and memory B cell formation (10). DOCK8 deficiency gives rise to an autosomal recessive form of the hyper IgE (AR-HIES) syndrome that overlaps in its features with autosomal dominant hyper IgE (AD-HIES) syndrome caused by loss of function mutations in STAT3 (11–13). Patients with DOCK8 deficiency suffer from recurrent infections, including candidiasis, cutaneous viral infections (molluscum contagiosum, herpes simplex viruses, human papilloma viruses), as well as cutaneous and invasive bacterial infections.…”