Critical role of WASp in germinal center tolerance through regulation of B cell apoptosis and diversification
Marc Descatoire,
Remi Fritzen,
Samuel Rotman,
Genevieve Kuntzelman,
Xavier Charles Leber,
Stephanie Droz-Georget,
Adrian J. Thrasher,
Elisabetta Traggiai,
Fabio Candotti
Affiliations
Marc Descatoire
Laboratory of Inherited Immune Disorders, Division of Immunology and Allergy, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland; Corresponding author
Remi Fritzen
University of St Andrews, St Andrews, UK
Samuel Rotman
Service of Clinical Pathology, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland
Genevieve Kuntzelman
Novartis Institutes for BioMedical Research, Basel, Switzerland
Xavier Charles Leber
Novartis Institutes for BioMedical Research, Basel, Switzerland
Stephanie Droz-Georget
Laboratory of Inherited Immune Disorders, Division of Immunology and Allergy, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland
Adrian J. Thrasher
University College of London, Great Ormond Street Institute of Child Health, London, UK
Elisabetta Traggiai
Novartis Institutes for BioMedical Research, Basel, Switzerland
Fabio Candotti
Laboratory of Inherited Immune Disorders, Division of Immunology and Allergy, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland
Summary: 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.
