The timeline starts with the discovery in 1986 that a homozygous mutation of M x renders many inbred mice vulnerable to influenza virus. In 1993, a homozygous mutation of Nramp 1 was found to render mice vulnerable to B c g slash L s h slash I t y infections. Also in the early 1990s, the P t o gene was identified in resistance to Pseudomonas in plants. In 1996, the first monogenic infections in humans were identified with inborn errors of type 2 I F N immunity underlying Mendelian susceptibility to mycobacterial disease. In 2004, autoantibodies neutralizing type 2 I F N were reported in rare patients with mycobacterial disease. In 2006, inborn errors of the T L R 3–U N C 93 B 1–dependent type 1 I F N pathway in the brain were discovered to underlie herpes simplex encephalitis (H S E) in children. In 2018, homozygosity for T Y K 2 P 1104 A was found to underlie about one percent of cases of tuberculosis in populations of European descent. Since 2020, autoantibodies neutralizing type 1 I F N s have been shown to underlie severe COVID-19.
Timeline of monogenic infections in plants, mice, and humans at the molecular level. Monogenic defects underlying a specific infection were first characterized in mice, in 1986, with the discovery, by molecular complementation, that a homozygous mutation of Mx renders many inbred mice vulnerable to influenza virus (14). The first positional cloning study in mice led to the discovery in 1993 that a homozygous mutation of Nramp1 renders mice vulnerable to mycobacteria (Bcg locus), Salmonella (Ity), and Leishmania (Lsh) (15). In 1993 and 1995, superb studies unraveled the role of the Pto and RPM1 genes in resistance to Pseudomonas in tomato and Arabidopsis thaliana, respectively (11, 12, 13). The first monogenic infections were identified in humans in 1996, with the discovery that inborn errors of type II IFN immunity can underlie MSMD (24, 25). Primary immunodeficiencies and disorders of complement are not represented in this figure (see text, Table 1, and Fig. 4). Autoantibodies neutralizing type II IFN were first reported in 2004, in rare patients with mycobacterial disease (26, 27). MSMD is indicated in brackets because of the identification of autoantibodies and the exclusion of a genetic etiology of MSMD. The first monogenic non-Mendelian inborn errors underlying rare sporadic infections were characterized in 2006, with the discovery that inborn errors of the TLR3-UNC93B–dependent type I IFN pathway in the brain can underlie herpes simplex virus 1 encephalitis in children, a condition that is almost always sporadic (28, 29). The first monogenic etiology involving a common variant and therefore underlying a significant proportion of cases of a common infection was reported in 2018, with the discovery that homozygosity for TYK2 P1104A underlies about 1% of cases of tuberculosis in populations of European descent (30, 31, 32). Finally, autoantibodies neutralizing type I IFNs have, since 2020, been shown to underlie unprecedented proportions of cases of a growing number of severe viral diseases of the lungs, brain, and liver, and adverse reactions to live-attenuated viral vaccines (33, 34).