Tuberculosis and impaired IL-23–dependent IFN-γ immunity in humans homozygous for a common TYK2 missense variant
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Citations
Inborn errors of type I IFN immunity in patients with life-threatening COVID-19
The Immunobiology of the Interleukin-12 Family: Room for Discovery.
Human IFN-γ immunity to mycobacteria is governed by both IL-12 and IL-23
Autoimmune pathways in mice and humans are blocked by pharmacological stabilization of the TYK2 pseudokinase domain.
Human inborn errors of immunity: An expanding universe.
References
Clinical Features of Candidiasis in Patients With Inherited Interleukin 12 Receptor β1 Deficiency
A Restricted Role for TYK2 Catalytic Activity in Human Cytokine Responses Revealed by Novel TYK2-Selective Inhibitors
Interleukin-12 Receptor β1 Chain Deficiency in a Child with Disseminated Tuberculosis
Autosomal Recessive Cardiomyopathy Presenting as Acute Myocarditis.
The incubation period distribution of tuberculosis estimated with a molecular epidemiological approach
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Frequently Asked Questions (11)
Q2. What is the reason for the impairment of IFN production in P1104A homozygo?
T cells of P1104A homozygotes have impaired IFN- production, due to their very weak response to IL-23, accounting for the susceptibility to MSMD or primary tuberculosis.
Q3. What is the role of TYK2 in antimycobacterial immunity?
the TYK2-dependent response to IL-23 that is disrupted by P1104A is essential for antimycobacterial IFN- immunity, but seems to be redundant for anti-fungal IL-17 immunity, given the absence of Candida infection in the patients described here.
Q4. What is the effect of TYK2 variants on cellular responses to IL-12?
The impact of TYK2 variants on cellular responses to IL-12 and IL-23 is irrelevant in nonhematopoietic cells, because the receptors for these cytokines are expressed only on leukocytes.
Q5. What is the CI for the TYK2 P1104A homozygos?
Several genome-wide association studies have shown that homozygosity for TYK2 P1104A has a strong protective effect (ORs ranging from 0.1 to 0.3) against various autoinflammatory or autoimmune conditions (41).
Q6. What grants were awarded to the Laboratory of Human Genetics of Infectious Diseases?
Funding: The Laboratory of Human Genetics of Infectious Diseases was supported, in part, by grants from the French National Agency for Research (ANR) under the “Investissement d’avenir” program (grant no. ANR-10-IAHU-01), the TBPATHGEN project (grant no.
Q7. What is the effect of negative selection on TYK2 P1104A?
The stronger selection operating on MEFV M694V, and to a lesser extent HFE C282Y, than on TYK2 P1104A is consistent with the inevitability of MF and hemochromatosis in patients with these mutations, whereas tuberculosis development also requires exposure to M. tuberculosis.
Q8. How did the authors determine the frequency of TYK2 variants in Europeans?
The authors analyzed the occurrence of negative selection acting on the two TYK2 variants by testing whether their frequency in Europeans has decreased more than other variants that were in the same frequency range 4000 years ago.
Q9. What is the common etiology of tuberculosis in Europe?
Between 1/10,000 and 1/1000 individuals are homozygous in endemic regions of the world (other than East Asia), where P1104A TYK2 is likely to define a strictly recessive but relatively common etiology of severe primary tuberculosis (about 0.5% of cases).
Q10. What was the phenotype of TYK2 in P1104A homozy?
In P1104A homozygous cells, the response to IFN- was modestly reduced in terms of JAK1, TYK2, STAT3, and STAT1 phosphorylation (Fig. 3C and fig.
Q11. What is the level of enrichment in homozygosity?
P1104A homozygosity was more enriched among patients with MSMD than among controls [P = 3.27 × 10−3; OR, 23.53; 95% confidence interval (CI), 2.9 to 483], and an even higher level of enrichment was observed among patients with tuberculosis (P = 8.37 × 10−8; OR, 89.31; 95% CI, 14.7 to 1725).