1. Alopecia areata is driven by cytotoxic T lymphocytes and is reversed by jak inhibition
- Author
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Xing, Luzhou, Dai, Zhenpeng, Jabbari, Ali, Cerise, Jane E., Higgins, Claire A., Gong, Weijuan, de Jong, Annemieke, Harel, Sivan, DeStefano, Gina M., Rothman, Lisa, Singh, Pallavi, Petukhova, Lynn, Mackay-Wiggan, Julian, Christiano, Angela M., and Clynes, Raphael
- Subjects
T cells -- Research -- Analysis -- Physiological aspects ,Baldness -- Research -- Analysis -- Development and progression ,Alopecia -- Research -- Analysis -- Development and progression ,Biological sciences ,Health - Abstract
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 (1). Genome-wide association studies (GWAS) (2) implicated ligands for the NKG2D receptor (product of the KLRK1 gene) in disease pathogenesis. Here, we show that cytotoxic [CD8.sup.+][NKG2D.sup.+] 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.sup.+][NKG2D.sup.+] effector T cells. Therapeutically, antibody-mediated blockade of IFN-γ, interleukin-2 (IL-2) or interleukin-15 receptor β (IL-15Rb) prevented disease development, reducing the accumulation of [CD8.sup.+][NKG2D.sup.+] 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 [γ.sub.c] 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., Alopecia areata is a T cell-mediated autoimmune disease characterized phenotypically by hair loss and, histologically, by infiltrating T cells surrounding the hair follicle bulb (reviewed in ref. 1). Previous studies [...]
- Published
- 2014