HHMI Hanna H. Gray Postdoctoral Fellow University of California, Berkeley, United States
Disclosure(s):
Tulika Singh, PhD, MPH: No financial relationships to disclose
Introduction/Rationale: 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.
