The sting of WASP deficiency: autoimmunity exposed

In this issue of Blood, Volpi and colleagues have further dissected the role of B lymphocytes in autoimmune reactions using a murine model for Wiskott-Aldrich syndrome (WAS) and identified a novel potential therapeutic target, which may have implications not only for this disease but also other causes of autoimmunity.¹ 

Primary immunodeficiencies (PIDs) are rare inborn errors, predominantly inherited in a recessive fashion, in which persistent or recurrent infection, often due to opportunistic pathogens, is a major manifestation. As we understand more about normal immune function by studying the effects of these rare genetic mutations in patients, so our awareness of the potential presentations of such patients has evolved.²  Autoimmunity coexists with infectious manifestations in conventional PIDs (eg, Omenn syndrome, FOXP3 deficiency, AIRE deficiency),³  but increasingly autoimmune manifestations are recognized as the major symptom of newly described primary immunodeficiencies. Examples include patients with mutations in ITCH, CTLA4, and tripeptidyl-peptidase II, and autosomal dominantly inherited gain-of-function signal transducer and activator of transcription-1 and -3 (STAT-1 and STAT-3)⁴  diseases. Prevention and treatment of infections is achieved by appropriate judicious antimicrobial prophylaxis and early and aggressive treatment with targeted antimicrobials. Treatment of autoimmune manifestations of PID is more challenging: although there are numerous immunosuppressive agents, and an increasing choice of targeted monoclonal antibodies is available, their targets are often broad. Immunocytes providing functional antimicrobial defense are often bystander casualties in attempts to neutralize and eliminate the damaging effects of autoreactive cells, often leading to significant infectious sequelae, which, in a patient with a genetically inherited disposition of infection, may prove fatal.

WAS is a conventional X-linked PID, first described almost 80 years ago, and characterized by microplatelet thrombocytopenia, recurrent infections, eczema, lymphoid malignancies, and autoimmunity, of which the most common manifestations are autoimmune cytopenia, vasculitis, arthritis, inflammatory bowel disease, and immunoglobulin A (IgA) nephropathy. Major functions of the WAS protein (WASP) include polymerization of the actin cytoskeleton which is important for many hematopoietic and immune cell functions, including the cytoskeletal reorganization required for efficient cell movement, immune synapse formation, and intracellular signaling. Previous work in a murine model of WAS has shown that WASP plays a critical B-lymphocyte–specific role in immune homeostasis, development of the marginal zone, regulation of germinal center interactions, and prevention of autoimmunity by negative selection of autoreactive B-lymphocyte progenitors, although the models did not exclude the potential interaction of other WAS-deficient hematopoietic cells in these findings.^5,6 

Volpi and colleagues have extended these observations in a double knockout murine model in which B lymphocytes lack both WASP and neural WASP (N-WASP), another ubiquitously expressed member of the WASP family critical in actin cytoskeletal modification. They elegantly demonstrate that mice with WAS-deficient B lymphocytes (B/WcKO) display increased production of IgM and IgG autoantibodies (see figure, panel A) and had increased glomerular deposits of IgG leading to renal immunopathology, in contrast to mice with B/DcKO which lacked IgG autoantibodies and failed to develop renal disease (see figure, panels B-C). These findings suggest an important role for N-WASP in the development of autoimmune pathology in WAS patients, and thus identify an important potential therapeutic target. Although hematopoietic stem cell transplantation can effectively cure these patients, mixed donor chimerism increases the risk of autoimmune complications posttransplantation.⁷  Gene therapy offers an alternative curative pathway for these patients, but only partial function is restored in such patients, increasing the potential risk of late-occurring autoimmunity.⁸  Thus, identification of a novel and specifically directed therapeutic target may extend the treatment options available to this group of patients, before or after stem cell therapy. Given that autoantibody-driven autoimmune disease is commonly encountered among the general community, it may well be that such a target has widespread applicability in the general medical community.