Open Sesame: How B cells sense monovalent antigens
Dr. Jianying Yang, member of the FRIAS-USIAS Joint Research Group Freiburg/Strasbourg 2013-15 on “In Vivo Visualizing the Dynamics of Cytokine-Targeting Cells” and his colleagues have analysed this process and published their findings on B cell activation in the prestigious EMBO journal. In their article, the authors Christoph Volkmann, Naema Brings, Martin Becker, Elias Hobeika, Jianying Yang and Michael Reth explain how exactly the body recognizes the need to produce antibodies. In their research, they were able to prove that the B cell antigen receptor that activates the B cells forms a closed autoinhibited oligomer and that antigen binding then leads to the opening and activation of the B cell antigen receptor. Their findings allow for a better understanding of how this immune response is initiated, which is especially important for vaccinations to be successful.
Antigen receptors on B lymphocytes sense foreign molecules, such as pathogens or vaccines, and activate the B cells to produce antibodies that protect humans against many diseases.
Large amounts of antibodies are produced after an acute infection or a successful vaccination. This limits the duration of an infectious disease and protects us from re-infection. The production of antibodies during an immune response requires the activation of specific B lymphocytes (B cells). How these B cells sense and become activated upon contact with structurally diverse immunogenic molecules (also called antigens) is not completely understood. For a long time, it was thought that antigen-sensing by the B cell antigen receptor (BCR) requires the cross-linking of two BCR monomers. However, with this cross-linking model (CLM), it is difficult to explain how monovalent antigens, that per se cannot "cross-link” two BCR monomers, are able to activate the BCR. The dissociation-activation model (DAM) of BCR activation offers a simple solution to this problem. According to this model, the BCR is not a monomer but rather forms a closed autoinhibited oligomer on the surface of resting B cells. Antigen binding, be it mono- or polyvalent, disturbs this pre-ordered structure and leads to the opening and activation of the BCR. To gain acceptance for either model (CLM or DAM), it would be important to directly monitor conformational alterations (aggregation or dissociation) of the BCR upon binding to monovalent antigens. The work of Volkmann et al. did exactly this. Employing a Fab-based proximity ligation assay (Fab-PLA), which monitors alteration of the BCR conformation at 10-20 nanometer distances, they found that exposure of these B cells to a monovalent antigen results in the dissociation, rather than an aggregation of the BCR. Interestingly, this sensing and opening process requires the presence and activity of the Src family kinase Lyn.
Previous experiments showed that the exposure of B cells to full-length anti-BCR antibodies could activate the BCR, whereas monovalent Fab fragments failed to do so. This result was taken as evidence that "cross-linking” by divalent antibodies or polyvalent antigens is required for BCR activation. The authors showed that, indeed, monovalent Fab fragments of anti-BCR antibodies bind to the light chain or heavy chain of the BCR but were not able to open the BCR. However, a monovalent anti-idiotypic Fab fragment that directly interacts with the antigen-binding site could open the BCR. These findings support the DAM hypothesis and falsify the cross-linking hypothesis. In further studies, the authors found that binding of monovalent antigens opens both the IgM- and IgD-BCR but that receptor opening induces signaling only from the IgM-BCR, but not from the IgD-BCR. These findings give a new and more detailed view of the B cell activation process lying at the foundation of any successful vaccination leading to humoral immunity.
Volkmann, C., N. Brings, M. Becker, E. Hobeika, J. Yang, and M. Reth. 2016. Molecular requirements of the B-cell antigen receptor for sensing monovalent antigens. EMBO J