HEM1 Actin Immunodysregulatory Disorder: Genotypes, Phenotypes, and Future Directions

Abstract

Cells of the innate and adaptive immune systems depend on proper actin dynamics to control cell behavior for effective immune responses. Dysregulated actin networks are known to play a pathogenic role in an increasing number of inborn errors of immunity. The WAVE regulatory complex (WRC) mediates branched actin polymerization, a process required for key cellular functions including migration, phagocytosis, vesicular transport, and immune synapse formation. Recent reports of pathogenic variants in NCKAP1L, a hematopoietically restricted gene encoding the HEM1 protein component of the WRC, defined a novel disease involving recurrent bacterial and viral infections, autoimmunity, and excessive inflammation (OMIM 141180). This review summarizes the diverse clinical presentations and immunological phenotypes observed in HEM1-deficient patients. In addition, we integrate the pathophysiological mechanisms described in current literature and highlight the outstanding questions for diagnosis and management of the HEM1 actin immunodysregulatory disorder.

Keywords: Actinopathy; Autoimmunity; Autoinflammation; HLH; NCKAP1L; SLE; WRC.

Fig. 1

Critical functions of branched actin in immune cells. (a) Sheets of branched actin protrude to form lamellipodia at the leading edge of migrating cells, guiding transport through extracellular matrices (ECM). (b) While the extracellular domains of integrin proteins bind to ligands in the ECM during migration or on neighboring cells during adhesion, their intracellular domains recruit components of focal adhesion complexes that bind to the cytoskeleton. Retrograde actin flow, where newly assembled actin pushes against the membrane and filaments elongate toward the cell center, generates tensile strength for integrin activation, focal adhesion maturation, and cell migration. (c) A ring of cortical branched actin below the cell membrane mechanically inhibits vesicle fusion and allows for coordinated exocytosis. (d) Branched actin is required for extracellular pathogen phagocytosis by innate immune cells. (e) At immune synapses between lymphocytes and antigen presenting cells, a ring of peripheral branched actin drives cell spreading across the activating surface

Fig. 2

Exon map of NCKAP1L gene with locations of all reported pathogenic variants

Fig. 3

Schematic of cellular defects associated with HEM1 deficiency and their associated clinical manifestations