Wiskott-Aldrich Syndrome at the nexus of autoimmune and primary immunodeficiency diseases

Abstract

Wiskott-Aldrich Syndrome (WAS) is a X-linked primary immunodeficiency disorder also marked by a very high (up to 70%) incidence of autoimmunity. Wiskott-Aldrich Syndrome arises from mutations in the Wiskott-Aldrich Syndrome protein (WASp), a cytoplasmic protein that links signaling by cell surface receptors such as the T-cell receptor and integrins to actin polymerization. WASp promotes the functions of multiple cell types that support immune responses, but also is important for the function of regulatory T cells and in TCR-induced apoptosis, two negative mechanisms of immune regulation that maintain peripheral immune tolerance. Here we review the nature of immune defects and autoimmunity in WAS and WASp deficient mice and discuss how this single gene defect can simultaneously impair immune responses to pathogens and promote autoimmunity. The myriad cellular immune defects found in WAS make this Mendelian syndrome an interesting model for the study of more complex immune diseases that arise from the interplay of environmental and multiple genetic risk factors.

Figure 1. Wiskott Aldrich Syndrome Protein domains and function

The indicated domains of WASp are shown schematically, with proteins and other molecules binding WASp shown below the schematic, and functions shown above. EVH1/WH1 domain: enabled VASP (vasodilator-stimulated protein) homology 1)/WH1 (WASP Homology 1). B: Basic Domain. GBD: GTPase Binding Domain. Proline Rich Domain (PRD). The PRD of WASp has been reported to bind numerous Src Homology 3 (SH3) domain containing proteins, including Btk, Hck, Fyn, Lyn, Itk, Nck, c-Src. Grb2, p85a, PI-3K, PLC-g, PSTPIP1, PTP-PEST, profilin and VASP [38, 39]. PSTPIP1 binding has been implicated in trafficking of WASp to the immune synapse [15], and binding of Fyn and PTP-PEST has been implicated in regulating tyrosine 291 phosphorylation and the function of WASp in T cell activation [21]. VCA domain: Verprolin, cofilin, acidic domain.

Figure 2. WASp affects multiple cellular processes in immunity

Green arrows represent processes with positive influence on immune responses and red arrows represent processes that reduce immune responses through cytotoxicity or other regulatory mechanisms. Immune processes influenced by WASp are numbered in the figure with green numbers denoting effects of WASp that enhance immune responses and red denoting effects of WASp which regulate immune responses. Specific functions of WASp are numbered as follows: 1) WASp promotes dendritic cell (DC) podosome formation and migration [40], presentation of particulate antigens [41] and T-DC contacts in the immune synapse in a DC intrinsic manner [42, 43] 2) WASp in T cells can enhance the efficiency of immune synapse formation which contributes to T cell activation [14, 15] 3) WASp also promotes cyokine secretion which also contributes to T cell activation and effector function [16] 4) WASp promotes restimulation-induced cell death and release of cytotoxic granules and FasL[24]. 5) WASp promotes B cell adhesion, migration, and germinal center formation [33] 6) WASp promotes T reg homeostasis, Treg control of effector T cell proliferation and Treg killing of B cells [25, 28, 35]. 7) WASp promotes cytotoxicity of NK cells [37] 8) WASp may also promote uptake of apoptotic blebs by macrophages [44], although we have not reproduced this defect in WASp deficient macrophages [24].