B cell-intrinsic deficiency of the Wiskott-Aldrich syndrome protein (WASp) causes severe abnormalities of the peripheral B-cell compartment in mice.

Abstract

Wiskott Aldrich syndrome (WAS) is caused by mutations in the WAS gene that encodes for a protein (WASp) involved in cytoskeleton organization in hematopoietic cells. Several distinctive abnormalities of T, B, and natural killer lymphocytes; dendritic cells; and phagocytes have been found in WASp-deficient patients and mice; however, the in vivo consequence of WASp deficiency within individual blood cell lineages has not been definitively evaluated. By conditional gene deletion we have generated mice with selective deficiency of WASp in the B-cell lineage (B/WcKO mice). We show that this is sufficient to cause a severe reduction of marginal zone B cells and inability to respond to type II T-independent Ags, thereby recapitulating phenotypic features of complete WASp deficiency. In addition, B/WcKO mice showed prominent signs of B-cell dysregulation, as indicated by an increase in serum IgM levels, expansion of germinal center B cells and plasma cells, and elevated autoantibody production. These findings are accompanied by hyperproliferation of WASp-deficient follicular and germinal center B cells in heterozygous B/WcKO mice in vivo and excessive differentiation of WASp-deficient B cells into class-switched plasmablasts in vitro, suggesting that WASp-dependent B cell-intrinsic mechanisms critically contribute to WAS-associated autoimmunity.

• Authors: Mike Recher, Siobhan O Burns, Miguel A de la Fuente, Stefano Volpi, Carin Dahlberg, Jolan E Walter, Kristin Moffitt, Divij Mathew, Nadine Honke, Philipp A Lang, Laura Patrizi, Hervé Falet, Marton Keszei, Masayuki Mizui, Eva Csizmadia, Fabio Candotti, Kari Nadeau, Gerben Bouma, Ottavia M Delmonte, Francesco Frugoni, Angela B Ferraz Fomin, David Buchbinder, Emma Maria Lundequist, Michel J Massaad, George C Tsokos, John Hartwig, John Manis, Cox Terhorst, Raif S Geha, Scott Snapper, Karl S Lang, Richard Malley, Lisa Westerberg, Adrian J Thrasher, Luigi D Notarangelo
• Journal: Blood (Blood) Vol. 119 Issue 12 Pg. 2819-28 (Mar 22 2012) ISSN: 1528-0020 [Electronic] United States
• PMID: 22302739 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Autoantibodies
• Autoantigens
• Was protein, mouse
• Wiskott-Aldrich Syndrome Protein

Topics

• Animals
• Autoantibodies (blood, immunology)
• Autoantigens (immunology)
• B-Lymphocytes (cytology, immunology)
• Cell Count
• Disease Models, Animal
• Flow Cytometry
• Fluorescent Antibody Technique
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Wiskott-Aldrich Syndrome Protein (deficiency, genetics, immunology)