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Dr. Junyu Xiao’s group provided critical insights into the assembly and secretion of human IgM and IgA

 

Immunoglobulins play pivotal roles in the immune system. Five classes of immunoglobulins exist in human, each containing a characteristic type of heavy chain. IgM is the first class of antibody produced after B cell activation. Secretory IgM, together with IgA, also plays a critical role in the mucosal immune system. IgM and IgA form oligomers, and the presence of multivalent antigen-binding sites in the IgM and IgA oligomers is a key factor in their ability to agglutinate pathogens. In the presence of the joining chain (J-chain), IgM forms a stable pentamer, whereas IgA mainly forms a dimer. The overall structural organization of these polymeric immunoglobulins, and the function of J-chain in regulating their assembly processes, are not completely understood. Furthermore, to function at the mucosal surface, IgM and IgA secreted by the plasma cells have to be transcytosed through the mucosal epithelial cells. This process critically depends on the polymeric immunoglobulin receptor (pIgR). How pIgR/SC specifically facilitates the secretion of IgM and IgA also remains elusive.

In a paper published in Science, Dr. Junyu Xiao’s group at Peking University reported a cryo-electron microscopy structure of the Fc region of human IgM in complex with the J-chain and pIgR ectodomain (also known as the secretory component, or SC). They showed that the IgM-Fc pentamer is formed asymmetrically, resembling a hexagon with a missing triangle. This is in contrast to the widely documented symmetric IgM pentamer model in textbooks. The tailpieces of IgM-Fc pack into an amyloid-like structure to stabilize the pentamer. The J-chain caps the tailpiece assembly and bridges the interaction between IgM-Fc and pIgR, which undergoes a large conformational change to engage the IgM–J complex. These results provide a structural basis for the function of IgM.

Dr. Junyu Xiao’s group further investigated the structure of secretory IgA. In another paper published in Cell Research, they reported a cryo-electron microscopy structure of the Fc region of human IgA1 in complex with the J-chain and SC, which reveals a more complete structure of the J-chain and distinctive features for the interactions between IgA, J-chain, and SC. They also studied the interaction between SIgA and S. pneumoniae adhesin SpsA, and determined a cryo-EM structure of human IgA-Fc–J–SC in complex with the N-terminal domain of SpsA, which shows how human pIgR/SC is specifically recognized by SpsA. These results advance the molecular understanding of secretory IgA and shed light on S. pneumoniae pathogenesis.

Dr. Junyu Xiao is the corresponding author of these articles. These projects were supported by the National Key Research and Development Program of China, the National Science Foundation of China, the Qidong-SLS Innovation Fund, and the Clinical Medicine Plus X Project of Peking University.

Links:
https://science.sciencemag.org/content/367/6481/1014
https://www.nature.com/articles/s41422-020-0336-3