Wiskott-Aldrich syndrome (WAS), an X-linked congenital immunodeficiency disorder, is characterized by three main symptoms—various immunodeficiencies, thrombocytopenia, and eczema—but it is also a diverse disease that can be complicated by autoimmune diseases, inflammatory bowel disease, and malignant tumors. Tohoku University Pediatrics has learned a lot from 13 WAS cases to date and has conducted basic research based on questions arising from clinical practice. We have also provided systemic management and hematopoietic stem cell transplant treatments in our own department, with long-term follow-up.
The WAS gene product, WASP, is expressed in all hematopoietic cell lineages, including hematopoietic stem cells. It functions as a signaling molecule regulating the actin cytoskeleton in the cell membrane and cytoplasm, as a transcription factor regulating various gene expressions in the cell nucleus, and as a tumor suppressor gene. Our department has previously conducted research on rapid diagnostic systems using flow cytometry, the function of WASP in T cells and natural killer (NK) cells, which are the mainstay of immunodeficiency, and the regulation of gene expression in the cell nucleus. While studying in the United States, I had the opportunity to study WASP-interacting protein (WIP), revealing that WIP forms a complex with the N-terminus of WASP and plays an essential role in stabilizing the WASP protein, the formation of an immunological synapse via the TCR receptor signaling pathway, the mechanism of WASP proteolysis, and the reason why missense variants in the N-terminus of WASP are common in clinical cases of WAS. The discovery of WIP deficiency, an autosomal recessive inheritance pattern, provided insights that clearly explained its molecular mechanism. Subsequently, WAS has expanded to three disease types, including ARPC1B deficiency (autosomal recessive inheritance pattern), which binds to the C-terminus of WASP.
Thrombocytopenia in WAS is characterized by both suppressed production and increased destruction. To apply our WAS research platform to clarify the pathogenesis of related pediatric diseases, we collected cases of congenital thrombocytopenia, which is important for differentiating it from immune thrombocytopenia (ITP), from across Japan for genetic analysis. We reported various genetic variants and novel congenital thrombocytopenia cases. Because autoimmune diseases in patients with WAS are primarily characterized by abnormalities in the innate immune system and abnormal B cell differentiation, our department has reported cases in which rituximab was effective as an antibody therapy in situations where steroid use is difficult. Inflammatory bowel disease (IBD), associated with bloody stools as the first symptom in infancy with WAS, is primarily caused by abnormalities in regulatory T cells and the IL-10 signaling pathway. Hoping to find a solution for cases of very early-onset inflammatory bowel disease (VEO-IBD) that are difficult to treat, we began genetic analysis by collecting domestic cases. In recent years, domestic collaborative research has accumulated knowledge about IL-10 signaling abnormalities and other conditions. WAS is a disease that is prone to be complicated with malignant tumors such as malignant lymphoma in older children, and we have clarified its characteristics, such as decreased tumor immune surveillance function by T/NK cells, and additional genetic abnormalities in the tumor.
The concept of so-called X-linked thrombocytopenia (XLT) is disappearing from the analysis of long-term prognosis of cases. I would like to summarize the research themes that spontaneously emerged from the clinical perspective of WAS and the research results that have been applied to the clinical practice of pediatric diseases, transcending the boundaries of immunodeficiency disorders and other medical fields, and discuss future challenges.
Finally, I would like to express my deepest gratitude to the senior professors who have guided me along the way, my co-researchers, the colleagues and graduate students who have worked with me in this research, and everyone in this society for their guidance and cooperation.
