IgM antibodies and B cells are early responders during acute secondary viral infections and contribute to protection from severe disease 2255909

Abstract Introduction IgM antibodies comprise 5% of serum antibodies and are thought to be a primary (1°) and weak immune response. Yet, isolation of IgM monoclonal antibodies shows that IgM can potently neutralize viruses. Dengue viruses (DENV) cause >100 million infections per year. Secondary (2°) infections are a time of risk for severe disease because infection can be enhanced by pre-existing cross-reactive IgG antibodies. Methods Here we tested the role of polyclonal plasma IgM antibodies and IgM+ B cells in early 2° immunity to DENV infection. We conducted paired IgM- vs mock-depletions of acute and early convalescent (EC) sera from dengue patients to quantify the contribution of IgM to plasma neutralizing activity (Groups: 2° acute n = 32, 2° EC n = 19; 1° EC reference n = 18). Also, we used fluorescently labelled DENV to enumerate DENV-specific B cells by flow cytometry in 1° (n = 4) vs 2° (n = 4) dengue cases. Results Half of all 2° dengue cases demonstrated contribution of IgM to plasma neutralizing activity at both acute and EC phases; of these, IgM contributed, on average, to 41% of plasma neutralizing activity. In acute 2° DENV infection, a higher contribution of IgM to plasma neutralizing activity was associated with less severe disease, indicating a protective effect. IgM purified from 2° EC plasma demonstrated broad neutralizing activity against multiple DENV serotypes, unlike IgM from 1° EC, suggesting that 2° IgM may be recalled from memory. Notably, DENV-specific IgM+ B cells were significantly more expanded in acute 2° compared to 1° dengue immune responses. Conclusion IgM antibodies contribute to substantial plasma neutralizing activity in acute 2° DENV infection and confer broadly neutralizing specificities in early convalescence. In addition, IgM+ B cells expand rapidly in acute 2° dengue. Together, this indicates an underappreciated role for IgM antibodies and B cells as early responders in infection that may mitigate progression to severe disease. Funding Source HHMI Hanna H. Gray Fellowship to T.S. and P01 AI106695 to E.H. Topic Categories Viral Immunology (VIR)