IgE drives osteoclastogenesis via binding with FcεRII in sparganosis-induced bone destruction

Abstract Progressive multi-vertebral osteolysis, frequently misdiagnosed as malignancy or tuberculosis, can also be driven by a previously unrecognized infectious trigger. Here we demonstrate that sparganosis induces pronounced IgE-dependent osteoclastogenesis and severe bone destruction. Single-cell RNA analysis of peripheral blood mononuclear cells identified the immune cell landscape of spinal sparganosis (SS) and the immunoglobulin-related pathways upregulated in naïve B cells derived from SS. Notably, the sparganosis triggers osteoclast activation and subsequent bone destruction. IgE was found at a dramatically high level in SS and played a critical driver of osteoclast activity and osteolysis. Notably, >90% of this IgE proved non-plerocercoid-specific, indicating that infection triggers an IgE hyper-response which sustains osteoclast activation. Mechanistically, IgE binding to the low-affinity Fc epsilon receptor II (FcεRII) using its Fc part, followed by upregulating the expression and nuclear translocation of NFATc1 via activating the AKT/ERK signaling pathway, promotes osteoclast precursor cells differentiation and bone resorption. Importantly, Omalizumab, the only marketed drug of monoclonal anti-IgE antibodies, could compromise the osteoclastogenesis induced by IgE and SS plasma. These findings provide novel insights into the immunopathological mechanisms of IgE in promoting osteolytic destruction in SS, and Omalizumab is a candidate for a potential therapeutic strategy to alleviate osteolysis in SS patients.