Abstract
AbstractThe immune response to an acute primary infection is a coupled process of antigen proliferation, molecular recognition by naive B-cells, and their subsequent proliferation and antibody shedding. Here we show B-cells can efficiently recognise new antigens by a tuned kinetic proofreading mechanism, where the number of proofreading steps and the characteristic rate of each step are set by the complexity of the immune repertoire. This process produces potent, specific and fast recognition of antigens, maintaining a spectrum of genetically distinct B-cell lineages as input for affinity maturation. We show that the proliferation-recognition dynamics of a primary infection can me mapped onto a generalised Luria-Delbrück process, akin to the dynamics of the classic fluctuation experiment. We derive the resulting statistics of the activated immune repertoire: antigen binding affinity, expected size, and frequency of active B-cell clones are related by power laws. Their exponents depend on the antigen and B-cell proliferation rate, the number of proofreading steps, and the lineage density of the naive repertoire. Empirical data of mouse immune repertoires are found to be consistent with activation involving at least three proofreading steps. Our model predicts key clinical characteristics of acute infections. The primary immune response to a given antigen is strongly heterogeneous across individuals; few elite responders are distinguished by early activation of high-affinity clones. Conversely, ageing of the immune system, by reducing the density of naive clones, degrades potency and speed of pathogen recognition.
Publisher
Cold Spring Harbor Laboratory