An expanding network of cytoskeletal defects

Since the discovery of the molecular cause of Wiskott-Aldrich syndrome, the importance of cytoskeletal function to immunity has been well-recognized. Beyond enabling cellular migration, the actin network is essential for many facets of innate and adaptive immunity, including phagocytosis, leukocyte activation, and immune synapse formation.²  Recent studies have demonstrated that self-tolerance including maintenance of T-regulatory cells and B-cell tolerance checkpoints also depend on regulators of actin polymerization,³  demonstrating the complex role that the cytoskeleton plays in cell activation and survival.

In this issue, Brigida et al describe T-cell defects in 6 patients with autosomal recessive deficiency of ARPC1B, a member of the ARP2/3 complex, which is an essential mediator of actin polymerization.¹  Defects in ARPC1B have been recently been associated with combined immunodeficiency and platelet abnormalities in several children.^4,-6  Clinical findings were very similar to other known defects of actin organization, including infections, atopy, and autoimmunity. Brigida et al expanded on previous reports by demonstrating the degree of T-cell dysfunction in these patients, including abnormalities in proliferation, activation, and immune synapse formation. Transduction of affected T cells with wild-type ARPC1B corrected the T-cell proliferative defects in vitro, suggesting that condition would be amenable to hematopoietic stem cell transplantation (HSCT). Similarly, 2 of the patients had minor populations of memory CD8⁺ T cells that expressed ARPC1B resulting from reversion mutations. V-β expression demonstrated oligoclonality in these revertant cell populations, suggesting that these populations rose from antigen-exposed T cells or from homeostatic proliferation.

ARPC1P joins a growing group of genes of actin regulatory that are proven causes of primary immunodeficiency disorders.²  These pathways share many commonalities, including susceptibility to a wide range of infections, atopy, and immunodysregulation. Lymphocyte abnormalities are a consistent feature, whereas platelet and neutrophil abnormalities are variably present in these disorders. Presence of revertant cell populations has also been described in patients with Wiskott-Aldrich syndrome and DOCK8 deficiency,^7,8  reflecting selective pressure and the survival advantage gained by revertant lymphocytes. Identification of DOCK8 deficiency via testing of T-cell receptor excision circles in whole blood has been reported,⁹  and with the described decreased in naïve T cells in these patients, it is possible that ARPC1B-deficient patients may similarly be detected by this method in newborn screening for severe combined immunodeficiency. Given the severity of these disorders, HSCT from a well-matched donor is considered the standard of care. Two of the patients described in this study underwent successful HSCT. Gene therapy for Wiskott-Aldrich syndrome has also been successful in previous trials,¹⁰  and because ARPC1B expression is limited to hematopoietic cells, this disease should similarly be amenable to a gene therapy approach.

As next-generation sequencing is applied to more patients with undefined forms of primary immunodeficiency, it is likely that ARPC1B will not be the last cytoskeletal disorder to be associated with human disease. Further study of the clinical spectrum and mechanistic biology of ARPC1B deficiency may identify new therapeutic targets and methods for early diagnosis and definitive treatment.