The Keio Journal of Medicine

Peripheral B lymphocyte tolerance
Amanda Gavin, Djemel AÏt-Azzouzene, Annica Mårtensson, Bao Duong, Laurent Verkoczy, José Luis Skog, Patrick Skog and David Nemazee

This lecture discusses two interrelated topics, B cell tolerance in the peripheral immunesystem and BAFF. Using the 3-83 antibody transgenic mouse bred to mice carrying cognate antigenin the liver, we previously found that clonal elimination drastically reduced the precursor frequencyof autoreactive cells. The consensus model to explain this tolerance is the 2-signal hypothesis, whichproposes that in the absence of T cell help BCR stimulation is a negative signal for B cells. However,this model fails to explain how these same B cells can respond to T-independent type II (TI-2) antigens,raising the question of how they distinguish TI-2 antigens from multimeric self determinants. Wepropose that B cells use NK-like missing self recognition to provide the needed specificity, as foreignantigens are unlikely to carry self markers. The model has implications for the evolution of the immunesystem, B lymphocyte signaling, tissue specificity of autoimmunity, and microbial subversion of theimmune system. Overexpression of the critical B cell survival cytokine BAFF/BLyS has been associatedwith autoimmunity. We have discovered a novel splice isoform that regulates BAFF activity andmay play a role in limiting B cell activity. The novel form, called DBAFF, is able to heteromultimerizewith normal BAFF and can suppress receptor binding and proteolytic release from the cell surface.Preliminary studies from transgenic mice overexpressing wild type or DBAFF are consistent with apossible regulatory role for DBAFF, raising the possibility that the relative expression levels of BAFFand DBAFF regulates tolerance.