Primary immunodeficiencies suggest redundancy within the human immune system

Pathogen-driven evolution has shaped the complexity of the human immune system. Our genome contains at least 1854 gene products involved in immune responses. However, the redundancy and robustness of the immune system need further characterization. One way to examine this redundancy is through the study of monogenic primary immunodeficiencies (PIDs) associated with infections. Causal mutations affecting innate immunity genes are, in relative terms, close to seven times less frequent than those affecting adaptive immunity genes in PIDs. Loss-of-function mutations of innate immunity genes encoding pattern-recognition receptors (PRRs) and associated pathways rarely cause susceptibility to infections, which suggests that PRR pathways are partially redundant in the immune responses to infection. This dispensability has also been observed for constitutive products of the immune system, such as secretory immunoglobulin A, and for innate immune cells, such as natural killer and innate lymphoid cell subsets, which are not essential for viability. This Review discusses these findings in the context of their implications for the identification of previously unknown classes of PIDs and assessment of the susceptibility to infection associated with various targeted immunotherapies.