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IgM functions through two distinct pathways: engagement of the IgM Fc receptor (Fc\u00b5R) and activation of the classical complement pathway. However, the extent of redundancy between these pathways and their roles at different stages of B cell differentiation remains unclear. To address this, we utilized Fc\u00b5R\u2010deficient mice and C\u00b513 mice, which express mutant IgM incapable of activating complement. Both strains exhibited impaired T\u2010dependent immune responses to low\u2010dose 4\u2010hydroxy\u20103\u2010nitrophenyl\u2010chicken \u03b3 globulin. Remarkably,\n                    <jats:italic>Fc\u00b5R<\/jats:italic>\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    C\u00b513 double\u2010mutant mice showed profound defects in antigen\u2010specific IgG production compared with either single mutant, revealing nonredundant, synergistic roles for Fc\u00b5R and complement. Mechanistically, both pathways are required for early B cell activation and expansion, promoting efficient class switch recombination, germinal center (GC) formation, and plasma cell differentiation. During the GC response, IgM BCR\u2010mediated complement activation, but not Fc\u00b5R, is required for GC B\u2010cell proliferation, survival, and affinity maturation. In contrast, Fc\u00b5R primarily enhances BCR signaling in na\u00efve B cells through downstream PI3K\u2010AKT and MAPK pathways. These findings define two cooperative yet distinct IgM\u2010mediated mechanisms that promote humoral immunity and regulate B cell differentiation in vivo.\n                  <\/jats:p>","DOI":"10.1002\/eji.70111","type":"journal-article","created":{"date-parts":[[2025,12,19]],"date-time":"2025-12-19T14:43:39Z","timestamp":1766155419000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Fc\u00b5R and IgM\u2010Mediated Complement Activation Cooperate to Enhance Humoral Immunity"],"prefix":"10.1002","volume":"55","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-2868-9379","authenticated-orcid":false,"given":"Zichao","family":"Wen","sequence":"first","affiliation":[{"name":"Department of Immunology School of Basic Medical Sciences Fudan University  Shanghai China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lulu","family":"Dong","sequence":"additional","affiliation":[{"name":"Department of Immunology School of Basic Medical Sciences Fudan University  Shanghai China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jun","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Immunology School of Basic Medical Sciences Fudan University  Shanghai China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qing","family":"Min","sequence":"additional","affiliation":[{"name":"Shanghai Sci\u2010Tech Inno Center for Infection &amp; 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