CD5L is a canonical component of circulatory IgM

Oskam, N.; den Boer, M. A.; Lukassen, M. V.; Ooijevaar-de Heer, P.; Veth, T. S.; van Mierlo, G.; Lai, S.-H.; Derksen, N. I.; Yin, V. C.; Streutker, M.; Franc, V.; Siborova, M.; Damen, M.; Kos, D.; Barendregt, A.; Bondt, A.; van Goudoever, J. B.; Haas, C. J.; Aerts, P. C.; Muts, R. M.; Rooijakkers, S. H.; Vidarsson, G.; Rispens, T.; Heck, A. J.

doi:10.1101/2023.05.27.542462

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bioRxiv · 10.1101/2023.05.27.542462

CD5L is a canonical component of circulatory IgM

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Abstract

Immunoglobulin M (IgM) is an evolutionary conserved key component of humoral immunity, and the first antibody isotype to emerge during an immune response. IgM is a large (1 MDa), multimeric protein, for which both hexameric and pentameric structures have been described, the latter additionally containing a joining (J) chain. Using a combination of single-particle mass spectrometry and mass photometry, proteomics and immunochemical assays, we here demonstrate that circulatory (serum) IgM exclusively exists as a complex of J-chain-containing pentamers covalently bound to the small CD5 antigen-like (CD5L, 36 kDa) protein. In sharp contrast, secretory IgM in saliva and milk is principally devoid of CD5L. Unlike IgM itself, CD5L is not produced by B cells, implying that it associates with IgM in the extracellular space. We demonstrate that CD5L integration has functional implications, i.e., it diminishes IgM binding to two of its receptors, the Fc{micro}R and the polymeric Immunoglobulin receptor (pIgR). On the other hand, binding to Fc{micro}R as well as complement activation via C1q seem unaffected by CD5L integration. Taken together, we redefine the composition of circulatory IgM as a J-chain containing pentamer, always in complex with CD5L.

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Oskam, N., den Boer, M. A., Lukassen, M. V., Ooijevaar-de Heer, P., Veth, T. S., van Mierlo, G., Lai, S.-H., Derksen, N. I., Yin, V. C., Streutker, M., Franc, V., Siborova, M., Damen, M., Kos, D., Barendregt, A., Bondt, A., van Goudoever, J. B., Haas, C. J., Aerts, P. C., Muts, R. M., Rooijakkers, S. H., Vidarsson, G., Rispens, T., Heck, A. J.. 2023-05-27. CD5L is a canonical component of circulatory IgM. https://doi.org/10.1101/2023.05.27.542462

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