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Alopecia areata is driven by cytotoxic T lymphocytes and is reversed by JAK inhibition

Nature Medicine volume 20, pages 1043–1049 (2014)Cite this article

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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 therapies1. 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+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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Figure 1: CD8+NKG2D+ cytotoxic T lymphocytes accumulate in the skin and are necessary and sufficient to induce disease in AA mice.
Figure 2: Prevention of AA by blocking antibodies to IFN-γ, IL-2 or IL-15Rβ.
Figure 3: Systemic JAK1/2 or JAK3 inhibition prevents the onset of AA in grafted C3H/HeJ mice.
Figure 4: Reversal of established AA with topical small-molecule inhibitors of the downstream effector kinases JAK1/2 or JAK3, and clinical results of patients with AA.

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Acknowledgements

We thank the National Alopecia Areata Registry, as well as M. Duvic, V. Price, M. Hordinsky and D. Norris, and the National Alopecia Areata Foundation. We thank J. Sundberg, T. Behrens, D. Bickers, J. O'Shea, T. Waldmann, B. Jabri, D. Raulet, L. Lanier, T. Spies, M. Hayden, R. Paus, P. Green, B. Lebwohl, D. Accili and C. Jahoda for stimulating discussions. We are grateful for clinical support from M. Furniss, C. Clark and G. Ulerio and expert technical assistance from M. Zhang, E. Chang, H. Lam and J. Huang. This work was supported in part by US Public Health Service National Institutes of Health NIAMS grants R01AR056016 (to A.M.C.) and R21AR061881 (to A.M.C and R.C.), a Shared Instrumentation Grant for the LSR II Flow Cytometer (S10RR027050) to R.C. and the Columbia University Skin Disease Research Center (P30AR044535), as well as the Locks of Love Foundation and the Alopecia Areata Initiative. J.E.C. is supported by the T32GM082271 Medical Genetics Training Grant (issued to A.M.C.). A.J., C.A.H., S.H. and A.d.J. are recipients of Career Development Awards from the Dermatology Foundation, and A.J. is also supported by the Louis V. Gerstner Jr Scholars Program.

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Author notes

  1. Luzhou Xing, Zhenpeng Dai and Ali Jabbari: These authors contributed equally to this work.

  2. Angela M Christiano and Raphael Clynes: These authors jointly directed this work.

Authors and Affiliations

  1. Department of Pathology, Columbia University, New York, New York, USA

    Luzhou Xing & Raphael Clynes

  2. Department of Dermatology, Columbia University, New York, New York, USA

    Zhenpeng Dai, Ali Jabbari, Jane E Cerise, Claire A Higgins, Weijuan Gong, Annemieke de Jong, Sivan Harel, Gina M DeStefano, Lisa Rothman, Pallavi Singh, Lynn Petukhova, Julian Mackay-Wiggan, Angela M Christiano & Raphael Clynes

  3. Department of Psychiatry, Columbia University, New York, New York, USA

    Jane E Cerise

  4. Department of Epidemiology, Columbia University, New York, New York, USA

    Gina M DeStefano

  5. Department of Genetics and Development, Columbia University, New York, New York, USA

    Angela M Christiano

  6. Department of Medicine, Columbia University, New York, New York, USA

    Raphael Clynes

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Contributions

L.X., Z.D. and A.J. were responsible in large part for performing the studies reported herein and participated in the design, execution and interpretation of the data. C.A.H. was responsible for establishing the C3H/HeJ graft model. A.d.J., S.H., G.M.D., L.R. and P.S. were involved in additional molecular and cell biological experiments. W.G. performed immunofluorescence and morphometric studies. L.P. and J.E.C. performed biostatistical analysis of all data sets. J.M.-W. was instrumental in human sample acquisition and analysis. A.M.C. and R.C. were responsible for conception, design, oversight, execution and interpretation of data for this study. All authors contributed to drafts, writing, figure preparation and editing of the final manuscript.

Corresponding authors

Correspondence to Angela M Christiano or Raphael Clynes.

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Competing interests

Columbia University has filed for intellectual property protection on the treatment of AA with small-molecule JAK inhibitors (PCT/US2011/059029 and PCT/US2013/034688).

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Supplementary Figures 1–17, Supplementary Tables 1–5 and Supplementary Methods (PDF 26872 kb)

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Xing, L., Dai, Z., Jabbari, A. et al. Alopecia areata is driven by cytotoxic T lymphocytes and is reversed by JAK inhibition. Nat Med 20, 1043–1049 (2014). https://doi.org/10.1038/nm.3645

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