TY - JOUR
T1 - CD5L is a canonical component of circulatory IgM
AU - Oskam, Nienke
AU - den Boer, Maurits A.
AU - Lukassen, Marie V.
AU - Ooijevaar-De Heer, Pleuni
AU - Veth, Tim S.
AU - van Mierlo, Gerard
AU - Lai, Szu Hsueh
AU - Derksen, Ninotska I.L.
AU - Yin, Victor
AU - Streutker, Marij
AU - Franc, Vojtech
AU - Šiborová, Marta
AU - Damen, Mirjam J.A.
AU - Kos, Dorien
AU - Barendregt, Arjan
AU - Bondt, Albert
AU - van Goudoever, Johannes B.
AU - de Haas, Carla J.C.
AU - Aerts, Piet C.
AU - Muts, Remy M.
AU - Rooijakkers, Suzan H.M.
AU - Vidarsson, Gestur
AU - Rispens, Theo
AU - Heck, Albert J.R.
N1 - Publisher Copyright:
© 2023 National Academy of Sciences. All rights reserved.
PY - 2023/12/6
Y1 - 2023/12/6
N2 - 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 (36 kDa) protein CD5 antigen-like (CD5L, also called apoptosis inhibitor of macrophage). 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 FcαµR and the polymeric Immunoglobulin receptor. On the other hand, binding to FcµR 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.
AB - 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 (36 kDa) protein CD5 antigen-like (CD5L, also called apoptosis inhibitor of macrophage). 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 FcαµR and the polymeric Immunoglobulin receptor. On the other hand, binding to FcµR 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.
KW - IgM
KW - CD5L
KW - mass spectrometry
KW - immunoglobulin
KW - structure
UR - http://www.scopus.com/inward/record.url?scp=85179892950&partnerID=8YFLogxK
U2 - 10.1073/pnas.2311265120
DO - 10.1073/pnas.2311265120
M3 - Article
C2 - 38055740
AN - SCOPUS:85179892950
SN - 0027-8424
VL - 120
SP - 1
EP - 7
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 50
M1 - e2311265120
ER -