Multimeric antibodies from antigen-specific human IgM+ memory B cells restrict Plasmodium parasites

Area of Science:

• Immunology
• Infectious Disease

Background:

• Multimeric immunoglobulin M (IgM) antibodies are crucial for early vertebrate immune responses.
• The specific roles of IgM in infection control remain unclear, partly due to challenges in differentiating it from IgG antibodies.

Purpose of the Study:

• To investigate the functional differences between IgM and IgG antibodies derived from Plasmodium falciparum-specific memory B cells.
• To explore the impact of antibody multimerization and avidity on immune responses against malaria.

Main Methods:

• Developed a pipeline to express B cell receptors (BCRs) from human memory B cells (MBCs) as both IgM and IgG.
• Analyzed somatic hypermutation and monomeric affinity of expressed BCRs.
• Determined the crystal structure of an IgM antibody-antigen complex.
• Assessed antigen binding and inhibitory activity against Plasmodium falciparum invasion.

Main Results:

• IgM and IgG antibodies from memory B cells exhibited comparable monomeric affinity.
• A multimeric IgM antibody showed significantly higher antigen binding and Plasmodium falciparum inhibitory activity than a monomeric IgG.
• Forced multimerization of IgG enhanced its antigen binding and parasite restriction capabilities.

Conclusions:

• High-avidity IgM demonstrates superior antigen binding and effector functions compared to monomeric IgG.
• Antibody avidity plays a critical role in modulating antibody efficacy.
• These findings underscore the therapeutic and vaccine potential of high-avidity IgM.