Combination of High-Resolution Structures for the B Cell Receptor and Co-Receptors Provides an Understanding of Their Interactions with Therapeutic Antibodies

B cells are central to the adaptive immune response, providing long lasting immunity after infection. B cell activation is mediated by a cell surface B cell receptor (BCR) following recognition of an antigen. BCR signaling is modulated by several co-receptors including CD22 and a complex that contains CD19 and CD81. Aberrant signaling through the BCR and co-receptors promotes the pathogenesis of several B cell malignancies and autoimmune diseases. Treatment of these diseases has been revolutionized by the development of monoclonal antibodies that bind to B cell surface antigens, including the BCR and its co-receptors. However, malignant B cells can escape targeting by several mechanisms and until recently, rational design of antibodies has been limited by the lack of high-resolution structures of the BCR and its co-receptors. Herein we review recently determined cryo-electron microscopy (cryo-EM) and crystal structures of the BCR, CD22, CD19 and CD81 molecules. These structures provide further understanding of the mechanisms of current antibody therapies and provide scaffolds for development of engineered antibodies for treatment of B cell malignancies and autoimmune diseases.

Automated summary

B cells are key players in adaptive immunity, providing long-lasting immune protection after infection. The activation of B cells is mediated by a cell surface receptor called B cell receptor (BCR) upon recognition of an antigen. Abnormal signaling of the BCR and its co-receptors, such as CD22, CD19, and CD81, contributes to the development of B cell malignancies and autoimmune diseases. Recent advancements in cryo-electron microscopy (cryo-EM) and crystallography have provided high-resolution structures of the BCR and its co-receptors, which enhance our understanding of current antibody therapies and facilitate the development of engineered antibodies for the treatment of B cell malignancies and autoimmune diseases.