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    Impaired IL-23-dependent induction of IFN-? underlies mycobacterial disease in patients with inherited TYK2 deficiency
    (Rockefeller Univ Press, 2022) Ogishi, Masato; Augusto Arias, Andres; Yang, Rui; Han, Ji Eun; Zhang, Peng; Rinchai, Darawan; Halpern, Joshua
    Human cells homozygous for rare loss-of-expression (LOE) TYK2 alleles have impaired, but not abolished, cellular responses to IFN-alpha/beta (underlying viral diseases in the patients) and to IL-12 and IL-23 (underlying mycobacterial diseases). Cells homozygous for the common P1104A TYK2 allele have selectively impaired responses to IL-23 (underlying isolated mycobacterial disease). We report three new forms of TYK2 deficiency in six patients from five families homozygous for rare TYK2 alleles (R864C, G996R, G634E, or G1010D) or compound heterozygous for P1104A and a rare allele (A928V). All these missense alleles encode detectable proteins. The R864C and G1010D alleles are hypomorphic and loss-of-function (LOF), respectively, across signaling pathways. By contrast, hypomorphic G996R, G634E, and A928V mutations selectively impair responses to IL-23, like P1104A. Impairment of the IL-23-dependent induction of IFN-gamma is the only mechanism of mycobacterial disease common to patients with complete TYK2 deficiency with or without TYK2 expression, partial TYK2 deficiency across signaling pathways, or rare or common partial TYK2 deficiency specific for IL-23 signaling.
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    Inborn errors of OAS-RNase L in SARS-CoV-2-related multisystem inflammatory syndrome in children
    (Amer Assoc Advancement Science, 2023) Lee, Danyel; Le Pen, Jeremie; Yatim, Ahmad; Dong, Beihua; Aquino, Yann; Ogishi, Masato; Pescarmona, Remi
    Multisystem inflammatory syndrome in children (MIS-C) is a rare and severe condition that follows benign COVID-19. We report autosomal recessive deficiencies of OAS1, OAS2, or RNASEL in five unrelated children with MIS-C. The cytosolic double-stranded RNA (dsRNA)-sensing OAS1 and OAS2 generate 2'-5'-linked oligoadenylates (2-5A) that activate the single-stranded RNA-degrading ribonuclease L (RNase L). Monocytic cell lines and primary myeloid cells with OAS1, OAS2, or RNase L deficiencies produce excessive amounts of inflammatory cytokines upon dsRNA or severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) stimulation. Exogenous 2-5A suppresses cytokine production in OAS1-deficient but not RNase L-deficient cells. Cytokine production in RNase L-deficient cells is impaired by MDA5 or RIG-I deficiency and abolished by mitochondrial antiviral-signaling protein (MAVS) deficiency. Recessive OAS-RNase L deficiencies in these patients unleash the production of SARS-CoV-2-triggered, MAVS-mediated inflammatory cytokines by mononuclear phagocytes, thereby underlying MIS-C.
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    Inborn errors of type I IFN immunity in patients with life-threatening COVID-19
    (Amer Assoc Advancement Science, 2020) Zhang, Qian; Bastard, Paul; Liu, Zhiyong; Le Pen, Jeremie; Moncada-Velez, Marcela; Chen, Jie; Ogishi, Masato
    Clinical outcome upon infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ranges from silent infection to lethal coronavirus disease 2019 (COVID-19). We have found an enrichment in rare variants predicted to be loss-of-function (LOF) at the 13 human loci known to govern Toll-like receptor 3 (TLR3)- and interferon regulatory factor 7 (IRF7)-dependent type I interferon (IFN) immunity to influenza virus in 659 patients with life-threatening COVID-19 pneumonia relative to 534 subjects with asymptomatic or benign infection. By testing these and other rare variants at these 13 loci, we experimentally defined LOF variants underlying autosomal-recessive or autosomal-dominant deficiencies in 23 patients (3.5%) 17 to 77 years of age. We show that human fibroblasts with mutations affecting this circuit are vulnerable to SARS-CoV-2. Inborn errors of TLR3-and IRF7-dependent type I IFN immunity can underlie life-threatening COVID-19 pneumonia in patients with no prior severe infection.
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    Inherited human ITK deficiency impairs IFN-? immunity and underlies tuberculosis
    (Rockefeller Univ Press, 2022) Ogishi, Masato; Yang, Rui; Rodriguez, Remy; Golec, Dominic P.; Martin, Emmanuel; Philippot, Quentin; Bohlen, Jonathan
    Inborn errors of IFN-gamma immunity can underlie tuberculosis (TB). We report three patients from two kindreds without EBV viremia or disease but with severe TB and inherited complete ITK deficiency, a condition associated with severe EBV disease that renders immunological studies challenging. They have CD4(+) alpha beta T lymphocytopenia with a concomitant expansion of CD4(-)CD8(-) double-negative (DN) alpha beta and V delta 2(-) gamma delta T lymphocytes, both displaying a unique CD38(+)CD45RA(+)T-bet(+)EOMES(-) phenotype. Itk-deficient mice recapitulated an expansion of the gamma delta T and DN alpha beta T lymphocyte populations in the thymus and spleen, respectively. Moreover, the patients' T lymphocytes secrete small amounts of IFN-gamma in response to TCR crosslinking, mitogens, or forced synapse formation with autologous B lymphocytes. Finally, the patients' total lymphocytes secrete small amounts of IFN-gamma, and CD4(+), CD8(+), DN alpha beta T, V delta 2(+) gamma delta T, and MAIT cells display impaired IFN-gamma production in response to BCG. Inherited ITK deficiency undermines the development and function of various IFN-gamma-producing T cell subsets, thereby underlying TB.