Alopecia areata is driven by cytotoxic T lymphocytes and is reversed by JAK inhibition.
Alopecia areata is driven by cytotoxic T lymphocytes and is reversed by JAK inhibition.
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斑秃（AA）是一种常见的自身免疫性疾病，由T细胞破坏毛囊引起。AA中自身反应性T细胞活化所需的免疫途径尚未确定，限制了合理靶向治疗的临床开发。全基因组关联研究（GWAS）表明，NKG 2D受体（KLRK 1基因的产物）的配体参与了疾病的发病机制。在这里，我们表明，细胞毒性CD 8 + NKG 2D + T细胞是必要的和足够的诱导AA在小鼠模型的疾病。小鼠和人AA皮肤的全局转录谱分析显示了指示细胞毒性T细胞浸润、干扰素-γ（IFN-γ）应答和已知可促进产生IFN-γ的CD 8 + NKG 2D+效应T细胞活化和存活的几种γ链（γc）细胞因子上调的基因表达特征。在治疗方面，抗体介导的IFN-γ、白细胞介素-2（IL-2）或白细胞介素-15受体β（IL-15 R β）阻断可预防疾病发展，减少AA小鼠模型中皮肤中CD 8 + NKG 2D + T细胞的蓄积和真皮IFN应答。全身给予Janus激酶（JAK）家族蛋白酪氨酸激酶（IFN-γ和γc细胞因子受体的下游效应物）的药理学抑制剂，可消除IFN特征并预防AA的发生，而局部给药可促进毛发再生并逆转已建立的疾病。值得注意的是，三名接受口服ruxolitinib（JAK 1和JAK 2的抑制剂）治疗的患者在治疗5个月内实现了几乎完全的毛发再生，这表明JAK抑制在人类AA中的潜在临床效用。
Alopecia areata (AA) is a common autoimmune disease resulting from damage of the hair follicle by T cells. The immune pathways required for autoreactive T cell activation in AA are not defined limiting clinical development of rational targeted therapies. Genome-wide association studies (GWAS) implicated ligands for the NKG2D receptor (product of the KLRK1 gene) in disease pathogenesis. Here, we show that cytotoxic CD8+NKG2D+ T cells are both necessary and sufficient for the induction of AA in mouse models of disease. Global transcriptional profiling of mouse and human AA skin revealed gene expression signatures indicative of cytotoxic T cell infiltration, an interferon-γ (IFN-γ) response and upregulation of several γ-chain (γc) cytokines known to promote the activation and survival of IFN-γ–producing CD8+NKG2D+ effector T cells. Therapeutically, antibody-mediated blockade of IFN-γ, interleukin-2 (IL-2) or interleukin-15 receptor β (IL-15Rβ) prevented disease development, reducing the accumulation of CD8+NKG2D+ T cells in the skin and the dermal IFN response in a mouse model of AA. Systemically administered pharmacological inhibitors of Janus kinase (JAK) family protein tyrosine kinases, downstream effectors of the IFN-γ and γc cytokine receptors, eliminated the IFN signature and prevented the development of AA, while topical administration promoted hair regrowth and reversed established disease. Notably, three patients treated with oral ruxolitinib, an inhibitor of JAK1 and JAK2, achieved near-complete hair regrowth within 5 months of treatment, suggesting the potential clinical utility of JAK inhibition in human AA.
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