Serum IgM crosslinks hepatitis B subviral particles into supramolecular immune complexes

Hepatitis B virus (HBV)-infected cells release hepatitis B surface antigen (HBsAg)-rich subviral particles (SVPs) in large excess over infectious virions. SVPs bind antibodies against HBsAg (anti-HBs), including neutralizing antibodies, but the physical products of antibody capture in human blood are uncharacterized. Here we used cryo-electron tomography (cryo-ET) to image HBsAg-enriched serum from a patient with severe acute Hepatitis B and observed three-dimensional assemblies of intact IgM-SVP immune complexes. These associations persisted at a lower particle density and were validated by a spatial-randomization null model. Subtomogram averaging and single-particle cryo-electron microscopy (cryo-EM) identified three serum IgM Fc-core assemblies, IgM-J-CD5L, IgM-J and IgM-J-SC, with cryo-EM maps reaching 2.8 angstrom resolution. Mapping these Fc core assemblies into tomograms revealed full-length IgM engaging individual SVPs through several Fab arms and bridging neighboring particles into immune complex networks containing multiple IgM molecules and SVPs. Thus, serum IgM uses multivalent Fab interactions to crosslink HBsAg-rich SVPs into supramolecular immune complexes. This observation extends the SVP decoy model from passive antibody sequestration to higher-order particle organization.