Tuberculosis and impaired IL-23-dependent IFN-γ immunity in humans homozygous for a common missense variant.

TitleTuberculosis and impaired IL-23-dependent IFN-γ immunity in humans homozygous for a common missense variant.
Publication TypeJournal Article
Year of Publication2018
AuthorsBoisson-Dupuis, S, Ramirez-Alejo, N, Li, Z, Patin, E, Rao, G, Kerner, G, Lim, CKang, Krementsov, DN, Hernandez, N, Ma, CS, Zhang, Q, Markle, J, Martinez-Barricarte, R, Payne, K, Fisch, R, Deswarte, C, Halpern, J, Bouaziz, M, Mulwa, J, Sivanesan, D, Lazarov, T, Naves, R, Garcia, P, Itan, Y, Boisson, B, Checchi, A, Jabot-Hanin, F, Cobat, A, Guennoun, A, Jackson, CC, Pekcan, S, Caliskaner, Z, Inostroza, J, Costa-Carvalho, BTavares, de Albuquerque, JAntonio Ta, Garcia-Ortiz, H, Orozco, L, Ozcelik, T, Abid, A, Rhorfi, IAbderahman, Souhi, H, Amrani, HNaji, Zegmout, A, Geissmann, F, Michnick, SW, Muller-Fleckenstein, I, Fleckenstein, B, Puel, A, Ciancanelli, MJ, Marr, N, Abolhassani, H, Balcells, MElvira, Condino-Neto, A, Strickler, A, Abarca, K, Teuscher, C, Ochs, HD, Reisli, I, Sayar, EH, El-Baghdadi, J, Bustamante, J, Hammarström, L, Tangye, SG, Pellegrini, S, Quintana-Murci, L, Abel, L, Casanova, J-L
JournalSci Immunol
Date Published2018 Dec 21

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 less than 1/600,000 individuals. We show that homozygosity for the common P1104A allele, which is found in about 1/600 Europeans and between 1/1000 and 1/10,000 individuals in regions other than East Asia, is more frequent in a cohort of patients with tuberculosis from endemic areas than in ethnicity-adjusted controls ( = 8.37 × 10; odds ratio, 89.31; 95% CI, 14.7 to 1725). Moreover, the frequency of P1104A in Europeans has decreased, from about 9% to 4.2%, over the past 4000 years, consistent with purging of this variant by endemic tuberculosis. Surprisingly, we also show that TYK2 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. Moreover, TYK2 P1104A is properly docked on cytokine receptors and can be phosphorylated by the proximal JAK, but lacks catalytic activity. Last, we show that the catalytic activity of TYK2 is essential for IL-23, but not IL-12, responses in cells expressing wild-type JAK2. In contrast, the catalytic activity of JAK2 is redundant for both IL-12 and IL-23 responses, because the catalytically inactive P1057A JAK2, which is also docked and phosphorylated, rescues signaling in cells expressing wild-type TYK2. In conclusion, homozygosity for the catalytically inactive P1104A missense variant of selectively disrupts the induction of IFN-γ by IL-23 and is a common monogenic etiology of tuberculosis.

Alternate JournalSci Immunol
PubMed ID30578352
PubMed Central IDPMC6341984
Grant ListU19 AI111143 / AI / NIAID NIH HHS / United States
UM1 HG006504 / HG / NHGRI NIH HHS / United States
U01 AI088685 / AI / NIAID NIH HHS / United States
UL1 TR001866 / TR / NCATS NIH HHS / United States
/ / Howard Hughes Medical Institute / United States
R37 AI095983 / AI / NIAID NIH HHS / United States
K99 AI127932 / AI / NIAID NIH HHS / United States
R01 AI089970 / AI / NIAID NIH HHS / United States
T32 GM007739 / GM / NIGMS NIH HHS / United States
U24 HG008956 / HG / NHGRI NIH HHS / United States