title: Alopecia areata is driven by cytotoxic T lymphocytes and is reversed by JAK inhibition.
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. 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.
authors.affiliation: 1] Department of Pathology, Columbia University, New York, New York, USA. [2].
authors.forename: Luzhou
authors.initials: L
authors.lastname: Xing
authors.affiliation: 1] Department of Dermatology, Columbia University, New York, New York, USA. [2].
authors.forename: Zhenpeng
authors.initials: Z
authors.lastname: Dai
authors.affiliation: 1] Department of Dermatology, Columbia University, New York, New York, USA. [2].
authors.forename: Ali
authors.initials: A
authors.lastname: Jabbari
authors.affiliation: 1] Department of Dermatology, Columbia University, New York, New York, USA. [2] Department of Psychiatry, Columbia University, New York, New York, USA.
authors.forename: Jane E
authors.initials: JE
authors.lastname: Cerise
authors.affiliation: Department of Dermatology, Columbia University, New York, New York, USA.
authors.forename: Claire A
authors.initials: CA
authors.lastname: Higgins
authors.affiliation: Department of Dermatology, Columbia University, New York, New York, USA.
authors.forename: Weijuan
authors.initials: W
authors.lastname: Gong
authors.affiliation: Department of Dermatology, Columbia University, New York, New York, USA.
authors.forename: Annemieke
authors.initials: A
authors.lastname: de Jong
authors.affiliation: Department of Dermatology, Columbia University, New York, New York, USA.
authors.forename: Sivan
authors.initials: S
authors.lastname: Harel
authors.affiliation: 1] Department of Dermatology, Columbia University, New York, New York, USA. [2] Department of Epidemiology, Columbia University, New York, New York, USA.
authors.forename: Gina M
authors.initials: GM
authors.lastname: DeStefano
authors.affiliation: Department of Dermatology, Columbia University, New York, New York, USA.
authors.forename: Lisa
authors.initials: L
authors.lastname: Rothman
authors.affiliation: Department of Dermatology, Columbia University, New York, New York, USA.
authors.forename: Pallavi
authors.initials: P
authors.lastname: Singh
authors.affiliation: Department of Dermatology, Columbia University, New York, New York, USA.
authors.forename: Lynn
authors.initials: L
authors.lastname: Petukhova
authors.affiliation: Department of Dermatology, Columbia University, New York, New York, USA.
authors.forename: Julian
authors.initials: J
authors.lastname: Mackay-Wiggan
authors.affiliation: 1] Department of Dermatology, Columbia University, New York, New York, USA. [2] Department of Genetics and Development, Columbia University, New York, New York, USA. [3].
authors.forename: Angela M
authors.initials: AM
authors.lastname: Christiano
authors.affiliation: 1] Department of Pathology, Columbia University, New York, New York, USA. [2] Department of Dermatology, Columbia University, New York, New York, USA. [3] Department of Medicine, Columbia University, New York, New York, USA. [4].
authors.forename: Raphael
authors.initials: R
authors.lastname: Clynes
mesh_terms: D000506:Alopecia Areata / Q000188:drug therapy / Q000276:immunology*; D000818:Animals; D020869:Gene Expression Profiling; D006801:Humans; D053612:Janus Kinases / Q000037:antagonists & inhibitors*; D051379:Mice; D008809:Mice, Inbred C3H; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D012867:Skin / Q000378:metabolism; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*
chemical_list: D047428:Protein Kinase Inhibitors; D053612:Janus Kinases