Diversity against adversity: How adaptive immunity evolves potent antibodies

TL;DR

This paper presents a microscopic, sequence-based model of immune response that explains how potent antibodies evolve rapidly through affinity maturation, highlighting an optimal mutation rate balancing diversity and deleterious effects.

Contribution

It introduces a novel sequence-level model of immune evolution and provides an analytical theory explaining the optimal hypermutation rate and its impact on antibody potency.

Findings

Optimal hypermutation rate close to 10^-3 per nucleotide per replication.

Analytical theory links mutation effects to B cell fate and affinity ceilings.

Model predicts immune response variability based on molecular factors.

Abstract

How does immune system evolve functional proteins - potent antibodies - in such a short time? We address this question using a microscopic, protein-level, sequence-based model of humoral immune response with explicitly defined interactions between Immunoglobulins, host and pathogen proteins. Potent Immunoglobulins are discovered in this model via clonal selection and affinity maturation. Possible outcomes of an infection (extinction of cells, survival with complete elimination of viruses, or persistent infection) crucially depend on mutation rates of viral and Immunoglobulin proteins. The model predicts that there is an optimal Somatic Hypermutation (SHM) rate close to experimentally observed 10-3 per nucleotide per replication. Further, we developed an analytical theory which explains the physical reason for an optimal SHM program as a compromise between deleterious effects of random mutations on nascent maturing Immunoglobulins (adversity) and the need to generate diverse pool of mutated antibodies from which highly potent ones can be drawn (diversity). The theory explains such effects as dependence of B cell fate on affinity for an incoming antigen, ceiling in affinity of mature antibodies, Germinal Center sizes and maturation times. The theory reveals the molecular factors which determine the efficiency of affinity maturation, providing insight into variability of immune response to cytopathic (direct response by germline antibodies) and poorly cytopathic viruses (crucial role of SHM in response). These results demonstrate the feasibility and promise of microscopic sequence-based models of immune system, where population dynamics of evolving Immunoglobulins is explicitly tied to their molecular properties.