Critical role of WASp in germinal center tolerance through regulation of B cell apoptosis and diversification

• Published in: Cell reports (Cambridge) 2022-03, Vol.38 (10), p.110474-110474, Article 110474
• Main Authors: Descatoire, Marc, Fritzen, Remi, Rotman, Samuel, Kuntzelman, Genevieve, Leber, Xavier Charles, Droz-Georget, Stephanie, Thrasher, Adrian J., Traggiai, Elisabetta, Candotti, Fabio
• Format: Article
• Language: English
• Subjects: Animals; Apoptosis; Autoantibodies; autoimmunity; Germinal Center - pathology; germinal center B cells; Mice; Mice, Knockout; Wasps; Wiskott-Aldrich syndrome; Wiskott-Aldrich Syndrome - pathology
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2022.110474

A main feature of Wiskott-Aldrich syndrome (WAS) is increased susceptibility to autoimmunity. A key contribution of B cells to development of these complications has been demonstrated through studies of samples from affected individuals and mouse models of the disease, but the role of the WAS protein (WASp) in controlling peripheral tolerance has not been specifically explored. Here we show that B cell responses remain T cell dependent in constitutive WASp-deficient mice, whereas selective WASp deletion in germinal center B cells (GCBs) is sufficient to induce broad development of self-reactive antibodies and kidney pathology, pointing to loss of germinal center tolerance as a primary cause leading to autoimmunity. Mechanistically, we show that WASp is upregulated in GCBs and regulates apoptosis and plasma cell differentiation in the germinal center and that the somatic hypermutation-derived diversification is the basis of autoantibody development. [Display omitted] •WASp is highly expressed in germinal center B cells, suggesting its relevance in situ•WASp-defective mouse germinal center B cells are sufficient to induce autoimmunity•WASp-defective germinal center B cells show lower apoptosis rate•WASp-defective B cells acquire self-reactivity during the germinal center reaction Descatoire et al. show that deletion of Wiskott-Aldrich syndrome (WAS) protein from germinal center B cells leads to reduced B cell apoptosis and broad autoimmunity that is dependent on B cell diversification, pointing to a critical role of WASp in the tolerance mechanisms at play in the germinal center reaction.