The line graph depicts the annual mortality rate of infections across various age classes. The horizontal axis represents age classes in years, ranging from less than 1 year to over 80 years. The vertical axis represents the annual mortality rate. The graph shows a U-shaped curve, with higher mortality rates in very young and very old age groups. The left side of the curve, representing younger ages, is labeled monogenic infections, indicating that deaths in this age group may be due to monogenic lesions impairing components of protective immunity. The right side of the curve, representing older ages, is labeled autoimmune infections, suggesting that deaths in this age group may be due to monogenic lesions impairing tolerance to self, leading to the production of auto-Abs that disrupt host defense. The curve indicates that the mortality rate decreases to a minimum in middle age groups and increases again in the elderly.
Model of the human genetic architecture of endemic infections. The prevalence of human death from most endemic infections follows a U-shaped curve (6). In the model illustrated in this figure, a revised version of a published figure (6), I propose that deaths during childhood may be due to monogenic lesions impairing components of protective immunity to primary infection (monogenic infections), whereas deaths of elderly individuals may be due to monogenic lesions impairing tolerance to self, thereby underlying the production of auto-Abs that disrupt host defense (autoimmune infections) possibly, but not necessarily, and perhaps rarely, targeting the same components as the single-gene lesions affecting childhood immunity. Indeed, while death in childhood often strikes children without acquired, adaptive immunity to the invading microbe, or displaying only cross-reactivity to related microbes, most elderly individuals are likely to have acquired adaptive immunity to the pathogen, even if this immunity is declining because of age, or at least immunity to similar serotypes. The example of inborn errors of type I IFNs in the young and auto-Abs against type I IFNs in the elderly corresponds to another epidemiological pattern, the J-shaped curve of pandemic infections, during which all infected individuals, young and old alike, are naive to infection, as observed for SARS-CoV-2 in 2020 (6). Our model does not exclude the contribution of other etiologies of death from infection in aging humans, including a polygenic component or somatic mutations or epigenetic changes in leukocytes or perhaps even in nonleukocytic cells.