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

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.

携带罕见表达缺失型（loss-of-expression, LOE）酪氨酸激酶2（TYK2）等位基因的人类纯合子细胞，其细胞应答存在受损但并未完全丧失；其中，对干扰素-α/β（IFN-α/β）的应答受损可导致患者罹患病毒性疾病，对白细胞介素-12（IL-12）与白细胞介素-23（IL-23）的应答受损则可导致患者罹患分枝杆菌病。携带常见P1104A TYK2等位基因的纯合子细胞，其对IL-23的应答存在选择性受损，仅会引发孤立性分枝杆菌病。本研究报道了来自5个家庭的6例患者的3种新型TYK2缺陷亚型，这些患者要么为罕见TYK2等位基因（R864C、G996R、G634E或G1010D）的纯合子，要么为P1104A与罕见等位基因（A928V）的复合杂合子。所有上述错义等位基因均可编码可检测到的蛋白质产物。其中，R864C与G1010D等位基因在各信号通路中分别属于功能减退型与功能丧失型（loss-of-function, LOF）。相较而言，G996R、G634E与A928V突变与P1104A类似，均为功能减退型突变，仅选择性损害IL-23相关的细胞应答。IL-23依赖性干扰素-γ（IFN-γ）诱导作用受损，是伴或不伴TYK2表达的完全性TYK2缺陷、各信号通路受累的部分性TYK2缺陷，以及仅IL-23信号通路受累的罕见或常见型部分性TYK2缺陷患者共有的分枝杆菌病发病的唯一机制。