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Autor(en) / Beteiligte

Titel

Impaired IL-23-dependent induction of IFN-γ underlies mycobacterial disease in patients with inherited TYK2 deficiency

Ist Teil von

Ort / Verlag

United States: Rockefeller University Press

Erscheinungsjahr

2022

Link zum Volltext

Quelle

MEDLINE

Beschreibungen/Notizen

Human cells homozygous for rare loss-of-expression (LOE) TYK2 alleles have impaired, but not abolished, cellular responses to IFN-α/β (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-γ 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.

Sprache: Englisch
Identifikatoren: ISSN: 0022-1007, 1540-9538
eISSN: 1540-9538
DOI: 10.1084/jem.20220094
Titel-ID: cdi_swepub_primary_oai_prod_swepub_kib_ki_se_151324838

Format: –
Schlagworte: Humans, Immunodeficiency, Interferon-gamma - metabolism, Interleukin-23, Job Syndrome - genetics, Medicin och hälsovetenskap, TYK2 Kinase - deficiency, TYK2 Kinase - genetics, TYK2 Kinase - metabolism

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