| First Author | Becker-Herman S | Year | 2011 |
| Journal | J Exp Med | Volume | 208 |
| Issue | 10 | Pages | 2033-42 |
| PubMed ID | 21875954 | Mgi Jnum | J:177574 |
| Mgi Id | MGI:5295510 | Doi | 10.1084/jem.20110200 |
| Citation | Becker-Herman S, et al. (2011) WASp-deficient B cells play a critical, cell-intrinsic role in triggering autoimmunity. J Exp Med 208(10):2033-42 |
| abstractText | Patients with the immunodeficiency Wiskott-Aldrich syndrome (WAS) frequently develop systemic autoimmunity. Here, we demonstrate that mutation of the WAS gene results in B cells that are hyperresponsive to B cell receptor and Toll-like receptor (TLR) signals in vitro, thereby promoting a B cell-intrinsic break in tolerance. Whereas this defect leads to autoantibody production in WAS protein-deficient (WASp(-/-)) mice without overt disease, chimeric mice in which only the B cell lineage lacks WASp exhibit severe autoimmunity characterized by spontaneous germinal center formation, class-switched autoantibodies, renal histopathology, and early mortality. Both T cell help and B cell-intrinsic TLR engagement play important roles in promoting disease in this model, as depletion with anti-CD4 antibodies or generation of chimeric mice with B cells deficient in both WASp and MyD88 prevented development of autoimmune disease. These data highlight the potentially harmful role for cell-intrinsic loss of B cell tolerance in the setting of normal T cell function, and may explain why WAS patients with mixed chimerism after stem cell transplantation often develop severe humoral autoimmunity. |
