Germline-encoded specificities and the predictability of the B cell response

Area of Science:

• Immunology
• Evolutionary Biology
• Computational Biology

Background:

• Antibodies are crucial for fighting pathogens like HIV, influenza, and SARS-CoV-2.
• High-affinity antibodies often originate from B cells with specific immunoglobulin alleles.
• The role of germline alleles versus somatic mutation in shaping antibody response quality is debated.

Purpose of the Study:

• To investigate whether germline alleles or random mutations primarily determine high-affinity antibody production.
• To assess the predictability of immune responses based on genetic factors.

Main Methods:

• Computer simulations modeling B cell evolution under selection.
• Experimental infection of mice with influenza virus.
• Analysis of B cell receptor sequences and amino acid substitutions.

Main Results:

• Simulations showed that strong germline advantages lead to consistent allele usage across individuals.
• In contrast, weaker germline advantages resulted in divergent allele usage over time, mirroring experimental findings in mice.
• No evidence of convergent evolution towards specific amino acid motifs during affinity maturation was found.

Conclusions:

• Germline-encoded specificities can promote similar immune responses, but diverse evolutionary routes to high affinity exist.
• The genetic predictability of antibody responses to infection and vaccination is limited by these diverse evolutionary pathways.