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.

Alopecia areata (AA) is among the most highly prevalent human autoimmune diseases, leading to disfiguring hair loss due to the collapse of immune privilege of the hair follicle and subsequent autoimmune attack1,2. The genetic basis of AA is largely unknown. We undertook a genome-wide association study (GWAS) in a sample of 1,054 cases and 3,278 controls and identified 139 single nucleotide polymorphisms that are significantly associated with AA (P ≤ 5 × 10 −7 ). Here we show © 2010 Macmillan Publishers Limited. All rights reservedCorrespondence and requests for materials should be, addressed to A.M.C. (amc65@columbia.edu). Supplementary Information is linked to the online version of the paper at www.nature.com/nature.Author Contributions L.P. performed technical aspects in preparation of samples for genotyping, the statistical analysis and preparation of the manuscript. M.D., V.P., M.H. and D.N. participated in phenotyping, diagnosis, and access to patient samples from the National Alopecia Areata Registry. Y.S., P.S. and H.K. provided expertise in RT-PCR and immunofluorescence. K.C.M. and R.P. provided expertise in immunhistochemistry. A.L. and P.K.G. provided control samples and performed genotyping as well as insight into autoimmune diseases. W.V.C. and C.I.A. provided additional statistical analysis and control samples from a distinct cohort. C.A.B.J. performed hair follicle microdissection and provided indispensable scientific expertise on the dermal sheath. A.M.C. provided oversight and conceptual guidance to the project, input into the functional significance of candidate genes, supervision of laboratory personnel, management of collaborations, preparation of the manuscript and all reporting requirements for granting agencies.Reprints and permissions information is available at www.nature.com/reprints.The authors declare no competing financial interests.Readers are welcome to comment on the online version of this article at www.nature.com/nature. NIH Public Access Author ManuscriptNature. Author manuscript; available in PMC 2011 January 1. PRDX5 and STX17). A region of strong association resides within the ULBP (cytomegalovirus UL16-binding protein) gene cluster on chromosome 6q25.1, encoding activating ligands of the natural killer cell receptor NKG2D that have not previously been implicated in an autoimmune disease. By probing the role of ULBP3 in disease pathogenesis, we also show that its expression in lesional scalp from patients with AA is markedly upregulated in the hair follicle dermal sheath during active disease. This study provides evidence for the involvement of both innate and acquired immunity in the pathogenesis of AA. We have defined the genetic underpinnings of AA, placing it within the context of shared pathways among autoimmune diseases, and implicating a novel disease mechanism, the upregulation of ULBP ligands, in triggering autoimmunity.AA affects about 5.3 million people in the United States alone, including males and females across all ethnic groups, with a lifetime risk ...

Alopecia areata is an autoimmune disorder characterized by transient, non-scarring hair loss and preservation of the hair follicle. Hair loss can take many forms ranging from loss in well-defined patches to diffuse or total hair loss, which can affect all hair bearing sites. Patchy alopecia affecting the scalp is the most common type. Alopecia areata affects nearly 2% of the general population at some point during their lifetime. Skin biopsies of alopecia areata affected skin show a lymphocytic infiltrate in and around the bulb or the lower part of the hair follicle in anagen (hair growth) phase. A breakdown of immune privilege of the hair follicle is thought to be an important driver of alopecia areata. Genetic studies in patients and mouse models showed that alopecia areata is a complex, polygenic disease. Several genetic susceptibility loci were identified associated with signaling pathways that are important to hair follicle cycling and development. Alopecia areata is usually diagnosed based on clinical manifestations, but dermoscopy and histopathology can be helpful. Alopecia areata is difficult to manage medically, but recent advances in understanding the molecular mechanisms have revealed new treatments and the possibility of remission in the near future.

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