Faculty Opinions recommendation of Tuberculosis and impaired IL-23-dependent IFN-γ immunity in humans homozygous for a common TYK2 missense variant.

Inherited IL-12Rβ1 and TYK2 deficiencies impair both IL-12-and IL-23-dependent IFN-γ immunity and are rare monogenic causes of tuberculosis, each found in about 1/100,000 individuals.We show that homozygosity for the common TYK2 P1104A allele, which is found in about 1/600 Europeans and 1/2,500 other individuals, is much more frequent in patients with tuberculosis than in ethnicity-adjusted controls (p = 8.37×10 -8 , odds ratio = 89.31[95%CI: 14.7-1,725]).We also show that the frequency of P1104A in Europeans has decreased significantly, from about 9% to 4.2%, over the last 4,000 years, consistent with purging of this variant by endemic tuberculosis.Moreover, we show that catalytically inactive P1104A impairs cellular responses to IL-23, but not to IFN-α, IL-10, or even IL-12, which, like IL-23, induces IFN-γ via activation of TYK2 and JAK2.Finally, we show that catalytically competent TYK2 is critical for IL-23 but not IL-12 responses, whereas catalytically competent JAK2 is redundant for both.Homozygosity for the P1104A missense variant of TYK2 selectively disrupts the induction of IFN-γ by IL-23 and is a common monogenic etiology of tuberculosis.