Multiple immunologic abnormalities have been identified that might account for immune dysregulation in patients with WAS,5 including impaired function of regulatory T and regulatory B cells, defective apoptosis, abnormalities of the distribution and diversity of T and B lymphocytes, and defective function of T and natural killer cells, resulting in impaired clearance of pathogens and persistent inflammation. ...Wiskott-Aldrich syndrome protein (WASP)-deficient plasmacytoid dendritic cells are hyperresponsive to Toll-like receptor 9 stimulation and produce high amounts of type 1 interferon, which might also contribute to autoimmunity.6 More recently, we and others have identified B-cell autonomous effects of WASP deficiency that are likely to play a critical role in the autoimmunity of the disease.7-9 These include (1) hyperresponsiveness of WASP-deficient B cells to stimulation through the B-cell receptor and Toll-like receptors; (2) accumulation of B lymphocytes with a characteristic phenotype (CD21lowCD38low), which is indicative of a type 1 interferon signature and a marker of self-reactivity; (3) preferential use of immunoglobulin variable genes that are enriched in patients with autoimmune disease and decreased somatic hypermutation; (4) increased release of immature B cells from the bone marrow to the periphery; (5) increased levels of B cell-activating factor of the TNF family serum; and (6) decreased regulatory B-cell function. PL Table I Molecular, immunologic, and clinical characteristics of patients Values in boldface are outside of age-matched reference values (shown in parentheses).AIHA, Autoimmune hemolytic anemia; ANA, anti-nuclear antibodies; ANCA, anti-neutrophil cytosplasmic antibodies; ASMA, anti-smooth muscle antibodies; BAFF, B cell-activating factor of the TNF family; IBD, inflammatory bowel disease; NA, not available; ND, not done; PL, anti-phospholipid antibodies; Plt, anti-platelet antibodies; TPO, anti-thyroid peroxidase antibodies.