Immunoglobulin M (IgM) are oligomeric antibodies that constitute the first line of immune defense, linking antigen recognition to the activation of inflammation. In their full-length form, activation of the complement system though binding of the initiating molecule C1q requires prior antigen engagement via Fab domains. In contrast, the contribution of their core, the constant fragment (Fc), remained poorly defined.
In a study published in FEBS Journal, IBS researchers evaluated the ability of the IgM Fc core to interact with C1q and to modulate its activity. Recombinant oligomeric constructs mimicking the native organization were produced, and their biophysical characterization (ISBG platforms) enabled the isolation of homogeneous pentameric and hexameric assemblies. Functional analyses by BLI and ELISA revealed an unexpected activation of complement in vitro via interaction with C1q. However, under conditions closer to the cellular context, these fragments did not induce complement-dependent cytotoxicity and instead exerted an inhibitory effect on antibody-mediated cell lysis, consistent with a mechanism of competition for C1q in solution.
These results reveal a dual role for the IgM core, acting as either an activator or a modulator depending on the molecular context, and open perspectives for the development of antiviral or antibacterial biomolecules, as well as for targeting complement-driven autoimmune or cancer-related pathologies.
The Fc fragment of IgMs binds C1q to activate the first step of the classical complement pathway, while inhibiting complement-dependent cytotoxicity. Pinto AJ, Chouquet A, Bally I, Rossi V, Thielens NM, Dumestre-Perard C, Kunert R, Gaboriaud C, Ling WL, Reiser JB. FEBS J. (2025) http://doi.org/10.1111/febs.70309
Contact : Jean-Baptiste Reiser, IBS/Complement, antibodies and infectious disease Group