Alopecia areata is driven by cytotoxic T lymphocytes and is reversed by JAK inhibition
By Luzhou Xing, Z. Dai, A. Jabbari, J. Cerise, C. Higgins, Weijuan Gong, Annemieke de Jong, S. Harel, G. Destefano, Lisa Rothman and 5 more. Nature Medicine, 2014
899 citations recorded by the source corpus.
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.
Subfields: Immunology, Urology
View Paper: https://www.semanticscholar.org/paper/3f1f175dc1213fe471ec8b1b8b26d107fb62ac94
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Citations in the corpus
- The JAK-STAT Pathway: Impact on Human Disease and Therapeutic Intervention (2015, background): “1 Most recently, topical and oral Jakinibs, including tofacitinib, have shown efficacy in treating immune-mediated alopecia (71, 72).”
- CD49a Expression Defines Tissue-Resident CD8+ T Cells Poised for Cytotoxic Function in Human Skin (2017, neutral): “Mouse epidermis displays analogous spatial restric- tions to the number of Trm cells during homeostasis (Zaid et al., 2014).”
- JAK–STAT Signaling as a Target for Inflammatory and Autoimmune Diseases: Current and Future Prospects (2017, background): “Comparison of biopsy samples at baseline and after 12 weeks of treatment demonstrated decreased inflammation post-treatment [122].”