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

Abstract

DOCK8 immunodeficiency syndrome (DIDS) is a progressive combined immunodeficiency that can be distinguished from other combined immunodeficiencies or hyperimmunoglobulinemia E syndromes in featuring (a) profound susceptibility to virus infections of the skin, with associated skin cancers, and (b) severe food allergies. The DOCK8 locus has many repetitive sequence elements that predispose to the generation of large germline deletions as well as recombination-mediated somatic DNA repair. Residual DOCK8 protein contributes to the variable disease phenotype. The severe virus infections of the skin, and probably also VZV-associated vasculopathy, reflect an important function of DOCK8, which is normally required to maintain lymphocyte shape integrity as the cells migrate through dense tissues. Loss of DOCK8 also causes immune deficits through other mechanisms including a milder generalized cell survival defect and skewing of T helper cell subsets. Recent work has uncovered the roles for DOCK8 in dendritic cell responses that can also help explain the virus susceptibility, as well as in regulatory T cells that might help explain autoimmunity in a minority of patients. Fortunately, hematopoietic stem cell transplantation cures the eczema and infection susceptibility of DIDS, but not necessarily the other disease manifestations including food allergies.

Keywords: DOCK8; atopic dermatitis; cancer; combined immunodeficiency; food allergy; hyperimmunoglobulinemia E syndrome; virus infections.

Figure 1

A. Stylized illustration of a patient showing clinical features of DIDS. B. Cellular pathogenesis of DIDS contributes to virus susceptibility and other skin manifestations of disease. Following virus infection of the skin (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. In DIDS, (2) and hence (3) are defective; additionally, T_H1-differentiated cells are decreased, T_H2-differentiated cells are increased, and T_H17-differentiated cells are decreased (4). Differentiated T cells extravasate into the skin where the cytokine imbalances contribute to increased virus replication (5), atopic dermatitis (6), and mucocutaneous candidiasis (7), respectively. In parallel, tissue resident memory T cells (T_RM) or NK cells normally kill virus-infected cells as they migrate continuously within the epidermis (7). In DIDS, these migrating cells undergo a form of cell death called cytothripsis, which compromises local antiviral immunity, also leading to increased virus replication (5).