B cell-Intrinsic Defects of Wiskott-Aldrich Syndrome Protein-Deficiency in generating humoral memory responses

Abstract

Abstract Patients with Wiskott-Aldrich syndrome protein (WASP)-deficiency exhibit severe immunodeficiency, including a lack of long-lasting humoral protection. Our published data reveal that T follicular helper cells in both WAS patients and WASP-deficient mice are impaired. This study demonstrates a B cell-intrinsic role of WASP in generating antigen-specific memory B cells and humoral recall responses. While the serum IgG levels in patients with WAS are equivalent to those in age-matched healthy controls, the number and percentage of isotype-switched CD27+ memory B cells and the serum level of tetanus toxin-specific IgG post immunization in the patients are significantly lower than those in controls. Furthermore, the peripheral blood of the patients exhibits a substantial increase in atypical memory B cells that resemble B cells expanded in persistent viral and parasite infections. In immunized WASP knockout mice, the percentages of antigen-specific germinal center, isotype-switched memory B cells, and plasmablasts in the spleen all are decreased, while the percentages of total germinal center B cells and plasmablasts are unchanged, compared to wild-type mice. In bone marrow chimera mice, where only B cells lack WASP expression, WASP-deficient B cells show reductions in the antigen-specific germinal center and memory subsets similar to those seen in WASP knockout mice. However, the percentages of total germinal center and isotype-switched B cells in the WASP knockout chimera mice are equivalent to or higher than those in the wild-type chimera. These results indicate that WASP-deficient B cells play a critical and cell-intrinsic role in developing the humoral immune deficiency in WAS.