Inborn errors of immunity to infection: the rule rather than the exception

Abstract

The immune system's function is to protect against microorganisms, but infection is nonetheless the most frequent cause of death in human history. Until the last century, life expectancy was only approximately 25 years. Recent increases in human life span primarily reflect the development of hygiene, vaccines, and anti-infectious drugs, rather than the adjustment of our immune system to coevolving microbes by natural selection. We argue here that most individuals retain a natural vulnerability to infectious diseases, reflecting a great diversity of inborn errors of immunity.

Figure 1.

Mortality curves at various periods of human history, from the Palaeolithic period (<10,000 BCE) to modern times (2000 CE). Contemporary data for the UK and Mozambique are available from the WHO site (www.who.int/topics/global_burden_of_disease). Older data were obtained from the book by John Cairns (2). Life tables for the Palaeolithic and Neolithic periods are based on skeleton examinations, assuming that 60% of newborn infants survived to the age of five, because few very young skeletons were found in the burial grounds. The gradual adjustment of the immune system by natural selection did not increase life expectancy until the end of the 19th century, due to the coevolution of microorganisms and the emergence of new infectious threats. Thus, the increase in life expectancy in the 20th century does not reflect the sudden and global natural selection of high-quality immune genes. The area between the four ancient curves and the curve for the UK in 2000 corresponds to ∼65% of individuals currently alive. Most of these individuals have retained specific immunodeficiencies masked by medical progress.

Figure 2.

Variations in protective immunity to infection can be described at the genetic, cellular, individual, and population levels. Typically, rare susceptibility alleles are loss-of-function or hypomorphic, and are associated with a complete or partial cellular defect and a Mendelian disorder. Common susceptibility alleles may be hypomorphic or even wild type and associated with a subtle or normal cellular phenotype and a complex disease. The effects of rare and common alleles on individuals are generally specified in terms of clinical penetrance and relative risk, respectively. Denoting d as the wild-type allele and D as the deleterious allele, there are three penetrances, f_dd, f_Dd, and f_DD, defined as the probability of clinical disease for individuals with dd, Dd, and DD genotypes, respectively. There are two relative risks (RR), defined as the variation in the risk of clinical disease for Dd and DD individuals, compared with dd individuals, that can be computed from penetrances as RR_Dd = f_Dd/f_dd and RR_DD = f_DD/f_dd. The impact of these alleles at the population level can be measured in terms of attributable risk, as defined by the proportion of observed cases with infectious disease that would have been avoided if no one in the population were carrying the genotype(s) at risk, and computed from RRs and genotype frequencies. Therefore, for a common infectious disease common susceptibility alleles may lead to high levels of attributable risk despite their moderate individual effect (RR ∼ 2–3), whereas rare alleles with strong individual effect (high clinical penetrance, e.g., RR > 100) show little impact at the population level. There is, however, a continuous spectrum between these two poles in terms of allele frequency and impact on cellular phenotype, clinical penetrance, relative risk, and attributable risk. There are many intermediate situations, such as that observed with major genes that may display substantial effects at all levels, at least in some populations.