Structural basis of malaria RIFIN binding by LILRB1-containing antibodies

Area of Science:

• Immunology
• Structural Biology
• Parasitology

Background:

• Plasmodium falciparum repetitive interspersed families of polypeptides (RIFINs) are variant surface antigens expressed on infected erythrocytes.
• RIFINs bind to inhibitory receptors like LAIR1, and previous work showed that inserting LAIR1 DNA into immunoglobulin genes can create RIFIN-specific antibodies.

Purpose of the Study:

• To investigate the general relevance of receptor domain insertion for antibody generation by examining LILRB1, another inhibitory receptor that binds RIFINs.
• To identify and characterize antibodies that incorporate LILRB1 domains.

Main Methods:

• Screening plasma from Malian donors to identify individuals with LILRB1-containing antibodies.
• Isolating B cell clones and analyzing DNA insertions in the switch region.
• Employing mass spectrometry and binding assays to identify RIFINs binding to LILRB1.
• Determining crystal and cryo-electron microscopy structures of RIFIN-LILRB1 complexes and antibody fragments (Fabs).

Main Results:

• Individuals with LILRB1-containing antibodies were identified.
• B cell clones exhibited DNA insertions encoding LILRB1 extracellular domains (D3D4 or D3) in the VH-CH1 elbow.
• A set of RIFINs was found to bind LILRB1 domain 3 (D3).
• Structural analysis revealed a RIFIN-LILRB1 D3 interaction mode similar to RIFIN-LAIR1, with antibodies displaying an unconventional architecture.

Conclusions:

• RIFINs bind to LILRB1 via domain D3.
• This study provides a naturally occurring example of how inserting receptor domains into the VH-CH1 elbow can generate novel, RIFIN-specific antibodies.
• The findings illustrate a general principle for creating new antibodies through receptor domain insertion.