The age-specific microbiome of children with milk, egg, and peanut allergy.

BACKGROUND: Immune regulation by gut microbiota is affected by dysbiosis and may precede food allergy onset. Prior studies lacked comparisons stratified by age and clinical phenotype. OBJECTIVE: To assess the microbiome of children with food allergy (<3 years, 3-18 years) compared with similar aged children without food allergy. METHODS: A real-world prospective cross-sectional study performed from 2014 to 2019 recruited children highly likely to have milk, egg, or peanut allergy defined by history and serum IgE or confirmed by food challenge. 16S ribosomal RNA sequencing identified stool microbial DNA. Alpha and beta diversity was compared between groups with food allergy and healthy controls stratified by age. Differential abundance for non a priori taxa was accepted at absolute fold-change greater than 2 and q value less than 0.05. RESULTS: A total of 70 patients were included (56 with food allergy and 14 healthy controls). Groups were not significantly different in age, gender at birth, race, mode of delivery, breastfeeding duration, or antibiotic exposure. Younger children with food allergy had similar alpha diversity compared with controls. Beta diversity was significantly different by age (P = .001). There was differential abundance of several a priori (P < .05) taxa (including Clostridia) only in younger children. Both a priori (including Coprococcus and Clostridia) and non a priori (q < 0.05) Acidobacteria_Gp15, Aestuariispira, Tindallia, and Desulfitispora were significant in older children with food allergy, especially with peanut allergy. CONCLUSION: Dysbiosis associates with food allergy, most prominent in older children with peanut allergy. Younger children with and without food allergy have fewer differences in gut microbiota. This correlates with clinical observations of persistence of peanut allergy and improved efficacy and safety of oral immunotherapy in younger children. Age younger than 3 years should be considered when initiating therapeutic interventions.

Fetal echocardiographic features associated with bicuspid aortic valve.

BACKGROUND: Prenatal diagnosis of bicuspid aortic valve is challenging. Bicuspid aortic valve is often associated with aortic dilation. METHODS: Fetuses with postnatally confirmed bicuspid aortic valve were gestational age-matched with normal controls. Complex lesions were excluded. Aortic valve and arch measurements by two blinded investigators were compared. RESULTS: We identified 27 cases and 27 controls. Estimated fetal weight percentile was lower in cases than controls. Seven cases had one or more significant lesions including perimembranous ventricular septal defects (n = 2), isolated annular hypoplasia (n = 2), and/or arch hypoplasia/coarctation (n = 4). Fetuses with bicuspid aortic valves had significantly smaller median z-scores of the aortic annulus (-1.60 versus -0.53, p < 0.001) and root (-1.10 versus -0.53, p = 0.040), and larger ratios of root to annulus (1.32 versus 1.21, p < 0.001), sinotubular junction to annulus (1.07 versus 0.99, p < 0.001), ascending aorta to annulus (1.29 versus 1.18, p < 0.001), and transverse aorta to annulus (1.04 versus 0.96, p = 0.023). Leaflets were "doming" in 11 cases (41%) and 0 controls (p = 0.010), "thickened" in 10 cases (37%) and 0 controls (p = 0.002). We noted similar findings in the subgroup without significant additional cardiac defects. CONCLUSIONS: The appearance of doming or thickened aortic valve leaflets on fetal echocardiogram is associated with bicuspid aortic valve. Compared to controls, fetuses with bicuspid aortic valve had smaller aortic annulus sizes (possibly related to smaller fetal size) without proportionally smaller aortic measurements, resulting in larger aortic dimension to annulus ratios. Despite inherent challenges of diagnosing bicuspid aortic valve prenatally, these findings may increase suspicion and prompt appropriate postnatal follow-up.

Barriers to Receiving Follow-up Care Among Childhood Cancer Survivors.

Little is known on why adherence to follow-up care in childhood cancer survivors (CCS) is lacking. This study characterized barriers to adherence to follow-up care among CCS, identified sociodemographic correlates of barriers, and examined whether barriers to follow-up care relate to health-related quality of life. Adult CCS (N=84) were anonymously surveyed via REDCap using the Barriers to Care Questionnaire (BCQ) and the Quality of Life Scale-Cancer Survivor (QOL-CS). Both descriptive and correlation analyses were conducted. The median BCQ total score was 88.5 (interquartile ranges:78.4 to 95.7), with the greatest barriers reported in the Skills (eg, ease of navigating the healthcare system) and Pragmatism subscales (eg, cost). There was a statistically significant correlation between the BCQ total score and the QOL-CS total score (rs=0.47, P <0.0001) and the physical, psychological, and social QOL-CS subscales (all P 's<0.05). The results found that barriers to follow-up care for CCS are mostly related to cost and appointment logistics, and that more barriers to care is associated with lower health-related quality of life among CCS. Identifying barriers to follow-up care is the first step in improving adherence, which would allow for earlier detection of late effects of cancer therapy and thereby result in reductions in morbidity and mortality.

Pre-hospital caloric deficits in surgical patients.

BACKGROUND: The timing, route, and amount of nutrition for surgical patients with substantial caloric deficits remain active areas of study. Current guidelines are based on in-hospital days NPO after admission to the hospital. This historic process neglects the multiple days of caloric deficit patients experience prior to hospital admission. AIM: To determine the impact of pre-hospital caloric deficit (PHCD) for surgical patients on their outcomes. METHODS: 313 patients admitted with a diagnosis of small bowel obstruction, pancreatitis, or diverticulitis were analyzed for their PHCD's. PHCD's were estimated using patient-reported days with significant emesis, and absent oral intake. Patients with PHCD's were compared to patients with no PHCD for length of stay, status on discharge, disposition, and 30-day readmission rate. RESULTS: There were 313 patients and 42% of the patients were male. The median age was 65 years. Median number of days sick prior to hospital admission was 1 (IQR: 1 to 2). Median PHCD was 1882 kcal (IQR: 1355 to 3650). Median number of days NPO while in-hospital was 3 (IQR: 2 to 5). Median in-hospital caloric deficit was 4268 kcal (IQR: 2825 to 6610). No significant association was observed between discharge disposition, complication rate, ambulatory status, 30-day readmission rate and PHCD. In-hospital caloric deficit was associated with complications after surgery (p < 0.0001). CONCLUSION: Small PHCD's in patients with SBO's, pancreatitis, or diverticulitis do not negatively affect their outcomes. Further research of patients with large PHCD's is needed to best treat surgical patients at risk for malnutrition.

Integrative analysis of rare copy number variants and gene expression data in alopecia areata implicates an aetiological role for autophagy.

Alopecia areata (AA) is a highly prevalent autoimmune disease that attacks the hair follicle and leads to hair loss that can range from small patches to complete loss of scalp and body hair. Our previous linkage and genome-wide association studies (GWAS) generated strong evidence for aetiological contributions from inherited genetic variants at different population frequencies, including both rare mutations and common polymorphisms. Additionally, we conducted gene expression (GE) studies on scalp biopsies of 96 patients and controls to establish signatures of active disease. In this study, we performed an integrative analysis on these two datasets to test the hypothesis that rare CNVs in patients with AA could be leveraged to identify drivers of disease in our AA GE signatures. We analysed copy number variants (CNVs) in a case-control cohort of 673 patients with AA and 16 311 controls independent of the case-control cohort of 96 research participants used in our GE study. Using an integrative computational analysis, we identified 14 genes whose expression levels were altered by CNVs in a consistent direction of effect, corresponding to gene expression changes in lesional skin of patients. Four of these genes were affected by CNVs in three or more unrelated patients with AA, including ATG4B and SMARCA2, which are involved in autophagy and chromatin remodelling, respectively. Our findings identified new classes of genes with potential contributions to AA pathogenesis.

Microenvironmental reprogramming by three-dimensional culture enables dermal papilla cells to induce de novo human hair-follicle growth.

De novo organ regeneration has been observed in several lower organisms, as well as rodents; however, demonstrating these regenerative properties in human cells and tissues has been challenging. In the hair follicle, rodent hair follicle-derived dermal cells can interact with local epithelia and induce de novo hair follicles in a variety of hairless recipient skin sites. However, multiple attempts to recapitulate this process in humans using human dermal papilla cells in human skin have failed, suggesting that human dermal papilla cells lose key inductive properties upon culture. Here, we performed global gene expression analysis of human dermal papilla cells in culture and discovered very rapid and profound molecular signature changes linking their transition from a 3D to a 2D environment with early loss of their hair-inducing capacity. We demonstrate that the intact dermal papilla transcriptional signature can be partially restored by growth of papilla cells in 3D spheroid cultures. This signature change translates to a partial restoration of inductive capability, and we show that human dermal papilla cells, when grown as spheroids, are capable of inducing de novo hair follicles in human skin.

Allergen Immunotherapy Extract Shortages and Their Effects on Clinical Care: A Work Group Report of the AAAAI Immunotherapy, Allergen Standardization, and Allergy Diagnostics Committee.

Allergen immunotherapy (AIT) is the only disease-modifying therapy indicated for treatment of allergic asthma, rhinitis, conjunctivitis, and Hymenoptera hypersensitivity. Manufacturing of the extracts used in AIT involve multistep complex processes as well as regulatory oversight. Furthermore, some source materials are vulnerable to unexpected events of nature. Given these circumstances, allergen extract supply can be disrupted with a potential to adversely impact patient care. A group of members from the American Academy of Allergy, Asthma, and Immunology (AAAAI) Immunotherapy, Allergy Standardization and Allergy Diagnostic Committee formed a workgroup to assess the frequency and effects of allergen extract shortages and associated factors. This workgroup developed a survey that was distributed to a random 20% of the AAAAI membership. In addition, the group also performed a review of the scientific literature on allergen extract supply and shortage. Based on the findings of the survey study and literature review, the workgroup reports frequency and extent of shortages, potential ways to improve communication with suppliers, and need for further guidance in patient care during times of shortage.

Patients Diagnosed with Multisystem Inflammatory Syndrome in Children Have Persistent Neurologic, Sleep, and Psychiatric Symptoms After Hospitalization.

Background: Acute neurological complications from COVID-19 have been reported in both pediatric and adult populations. Chronic symptoms after recovery have been reported in adults and can include neuropsychiatric and sleep symptoms. Persistent symptoms in children with the multisystem inflammatory syndrome in children (MIS-C) have not been studied. Methods: We conducted a single-center retrospective chart review and cross-sectional survey of patients diagnosed with MIS-C. Patients and parents were surveyed on symptoms before the COVID-19 pandemic, upon admission, and 23 weeks (interquartile range 20-26 weeks) after discharge. Age and gender-matched patients requiring intensive care unit (ICU) care for status asthmaticus were surveyed as a control group. Results: In this cohort of 47 patients, 77% reported neurological, 60% psychiatric, and 77% sleep symptoms during hospitalization. Prior to hospitalization, 15% reported neurological, 0% psychiatric, and 7% sleep symptoms. Eighteen (50%) of the 36 patients who had neurological symptoms during hospitalization continued to have symptoms on follow-up (odds ratio [OR] = ∞, p = .003]). Similarly, 16 (57%) of 28 patients with psychiatric symptoms reported persistence at follow-up (OR = 5.00; p = .02). Fifteen (42%) of the 18 patients reporting sleep disturbance during hospitalization had persistence on follow-up (OR = 1.9; p = .49). The aggregate of neurological, psychiatric, and sleep symptoms during admission and at follow-up was significantly higher for MIS-C patients requiring ICU care when compared to the control group (p = .01). Conclusions: In this cohort of patients with MIS-C, a majority of patients reported new-onset neuropsychiatric and sleep symptoms. Almost half of these patients had persistent symptoms on a follow-up survey.

Continuous and intermittent administration of intravenous sildenafil in critically ill infants with pulmonary hypertension.

Intravenous (IV) sildenafil may be administered as a continuous infusion or intermittent bolus dosing in infants with pulmonary hypertension (PH). We aimed to compare these delivery methods. METHODS: We retrospectively evaluated subjects less than 12 months old treated with IV sildenafil for PH. Vital signs, oxygen requirement, vasoactive-inotropic score (VIS), and echocardiogram results before and after sildenafil initiation, and the need for discontinuation due to side effects, were noted. RESULTS: Forty-three subjects were identified (23 continuous, 20 intermittent). There were clinically significant differences in PH classifications between groups. The continuous group was significantly younger (p = 0.010) with higher baseline severity of illness suggested by higher inspired oxygen (FiO2 ) and VIS (p = 0.012). After sildenafil initiation, there were no significant differences in changes in blood pressure, oxygen saturation, FiO2 , or VIS between groups, and no difference in the number of subjects requiring discontinuation due to side effects (4 continuous, 1 intermittent, p = 0.351). Eight continuous group subjects (34.8%) and 3 intermittent group subjects (15.0%) died (p = 0.024), but echocardiographic improvement in PH degree was more common in the continuous group (77.8% vs. 33.3%, p = 0.007). CONCLUSION: In this small cohort of infants treated with continuous or intermittent IV sildenafil, in the setting of different baseline characteristics between groups, there were no significant differences in changes in vital signs, VIS, FiO2 , or need for discontinuation of therapy due to side effects. Higher continuous group mortality may be explained by greater baseline illness severity, but larger prospective, randomized studies are required to investigate these different delivery methods.

Validation of the 2019 European League Against Rheumatism/American College of Rheumatology Criteria Compared to the 1997 American College of Rheumatology Criteria and the 2012 Systemic Lupus International Collaborating Clinics Criteria in Pediatric Systemic Lupus Erythematosus.

OBJECTIVE: Different classification criteria for systemic lupus erythematosus (SLE) have been proposed for many years. The most widely used and accepted criteria has been the 1997 American College of Rheumatology (ACR) criteria. In 2012, the Systemic Lupus International Collaborating Clinics (SLICC) criteria were published in an attempt to improve the clinical relevance of SLE criteria. In 2017, weighted criteria were proposed that included entry criteria, something the 1997 ACR and the 2012 SLICC criteria did not identify. The aim of the present study was to validate the 2017 weighted criteria, the 1997 ACR criteria, and the 2012 SLICC criteria and compare the sensitivities and specificities in pediatric SLE. METHODS: For the past 15 years, retrospective chart review of patients diagnosed with SLE before age 19 years was conducted. The controls were patients referred for serologies positive for antinuclear antibodies but did not fulfill criteria for diagnosis of SLE at the initial visit or were diagnosed with another autoimmune disease. The 3 classification criteria sets were applied to these patients and compared against a gold standard of physician diagnosis. RESULTS: A total of 156 patients were diagnosed with SLE. The sensitivity for the 2017 weighted criteria was 0.974 (95% confidence interval [95% CI] 0.936-0.993) and the specificity was 0.984 (95% CI 0.966-0.994). The sensitivity for the 1997 ACR criteria was 0.872 (95% CI 0.809-0.920) and the specificity was 1.00 (95% CI 0.990-1.000). The sensitivity for the 2012 SLICC criteria was 0.974 (95% CI 0.936-0.993) and the specificity was 0.997 (95% CI 0.985-1.000). CONCLUSION: The 2017 weighted criteria and the 2012 SLICC criteria were more sensitive than the 1997 ACR criteria. There were no significant differences in sensitivity and specificity between the 2012 SLICC and the 2017 weighted criteria.

Application of t-SNE to human genetic data.

The t-distributed stochastic neighbor embedding t-SNE is a new dimension reduction and visualization technique for high-dimensional data. t-SNE is rarely applied to human genetic data, even though it is commonly used in other data-intensive biological fields, such as single-cell genomics. We explore the applicability of t-SNE to human genetic data and make these observations: (i) similar to previously used dimension reduction techniques such as principal component analysis (PCA), t-SNE is able to separate samples from different continents; (ii) unlike PCA, t-SNE is more robust with respect to the presence of outliers; (iii) t-SNE is able to display both continental and sub-continental patterns in a single plot. We conclude that the ability for t-SNE to reveal population stratification at different scales could be useful for human genetic association studies.

Molecular signatures define alopecia areata subtypes and transcriptional biomarkers.

Alopecia areata (AA) is an autoimmune disease typified by nonscarring hair loss with a variable clinical course. In this study, we conducted whole genome gene expression analysis of 96 human scalp skin biopsy specimens from AA or normal control subjects. Based on gene expression profiling, samples formed distinct clusters based on the presence or absence of disease as well as disease phenotype (patchy disease compared with alopecia totalis or universalis). Differential gene expression analysis allowed us to robustly demonstrate graded immune activity in samples of increasing phenotypic severity and generate a quantitative gene expression scoring system that classified samples based on interferon and cytotoxic T lymphocyte immune signatures critical for disease pathogenesis.

Oral ruxolitinib induces hair regrowth in patients with moderate-to-severe alopecia areata.

BACKGROUND. Alopecia areata (AA) is a common autoimmune disease with a lifetime risk of 1.7%; there are no FDA-approved treatments for AA. We previously identified a dominant IFN-γ transcriptional signature in cytotoxic T lymphocytes (CTLs) in human and mouse AA skin and showed that treatment with JAK inhibitors induced durable hair regrowth in mice by targeting this pathway. Here, we investigated the use of the oral JAK1/2 inhibitor ruxolitinib in the treatment of patients with moderate-to-severe AA. METHODS. We initiated an open-label clinical trial of 12 patients with moderate-to-severe AA, using oral ruxolitinib, 20 mg twice per day, for 3-6 months of treatment followed by 3 months follow-up off drug. The primary endpoint was the proportion of subjects with 50% or greater hair regrowth from baseline to end of treatment. RESULTS. Nine of twelve patients (75%) demonstrated a remarkable response to treatment, with average hair regrowth of 92% at the end of treatment. Safety parameters remained largely within normal limits, and no serious adverse effects were reported. Gene expression profiling revealed treatment-related downregulation of inflammatory markers, including signatures for CTLs and IFN response genes and upregulation of hair-specific markers. CONCLUSION. In this pilot study, 9 of 12 patients (75%) treated with ruxolitinib showed significant scalp hair regrowth and improvement of AA. Larger randomized controlled trials are needed to further assess the safety and efficacy of ruxolitinib in the treatment of AA. TRIAL REGISTRATION. Clinicaltrials.gov NCT01950780. FUNDING. Locks of Love Foundation, the Alopecia Areata Initiative, NIH/National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), and the Irving Institute for Clinical and Translational Research/Columbia University Medical Center Clinical and Translational Science Award (CUMC CTSA).

Safety and efficacy of the JAK inhibitor tofacitinib citrate in patients with alopecia areata.

BACKGROUND: Alopecia areata (AA) is an autoimmune disease characterized by hair loss mediated by CD8+ T cells. There are no reliably effective therapies for AA. Based on recent developments in the understanding of the pathomechanism of AA, JAK inhibitors appear to be a therapeutic option; however, their efficacy for the treatment of AA has not been systematically examined. METHODS: This was a 2-center, open-label, single-arm trial using the pan-JAK inhibitor, tofacitinib citrate, for AA with >50% scalp hair loss, alopecia totalis (AT), and alopecia universalis (AU). Tofacitinib (5 mg) was given twice daily for 3 months. Endpoints included regrowth of scalp hair, as assessed by the severity of alopecia tool (SALT), duration of hair growth after completion of therapy, and disease transcriptome. RESULTS: Of 66 subjects treated, 32% experienced 50% or greater improvement in SALT score. AA and ophiasis subtypes were more responsive than AT and AU subtypes. Shorter duration of disease and histological peribulbar inflammation on pretreatment scalp biopsies were associated with improvement in SALT score. Drug cessation resulted in disease relapse in 8.5 weeks. Adverse events were limited to grade I and II infections. An AA responsiveness to JAK/STAT inhibitors score was developed to segregate responders and nonresponders, and the previously developed AA disease activity index score tracked response to treatment. CONCLUSIONS: At the dose and duration studied, tofacitinib is a safe and effective treatment for severe AA, though it does not result in a durable response. Transcriptome changes reveal unexpected molecular complexity within the disease. TRIAL REGISTRATION: ClinicalTrials.gov NCT02197455 and NCT02312882. FUNDING: This work was supported by the US Department of Veterans Affairs Office of Research and Development, National Institute of Arthritis and Musculoskeletal and Skin Diseases National Institutes of Health grant R01 AR47223 and U01 AR67173, the National Psoriasis Foundation, the Swedish Society of Medicine, the Fernström Foundation, the Locks of Love Foundation, the National Alopecia Areata Foundation, and the Ranjini and Ajay Poddar Resource Fund for Dermatologic Diseases Research.

Master regulators of infiltrate recruitment in autoimmune disease identified through network-based molecular deconvolution.

Network-based molecular modeling of physiological behaviors has proven invaluable in the study of complex diseases such as cancer, but these approaches remain largely untested in contexts involving interacting tissues such as autoimmunity. Here, using Alopecia Areata (AA) as a model, we have adapted regulatory network analysis to specifically isolate physiological behaviors in the skin that contribute to the recruitment of immune cells in autoimmune disease. We use context-specific regulatory networks to deconvolve and identify skin-specific regulatory modules with IKZF1 and DLX4 as master regulators (MRs). These MRs are sufficient to induce AA-like molecular states in vitro in three cultured cell lines, resulting in induced NKG2D-dependent cytotoxicity. This work demonstrates the feasibility of a network-based approach for compartmentalizing and targeting molecular behaviors contributing to interactions between tissues in autoimmune disease.

Pharmacologic inhibition of JAK-STAT signaling promotes hair growth.

Several forms of hair loss in humans are characterized by the inability of hair follicles to enter the growth phase (anagen) of the hair cycle after being arrested in the resting phase (telogen). Current pharmacologic therapies have been largely unsuccessful in targeting pathways that can be selectively modulated to induce entry into anagen. We show that topical treatment of mouse and human skin with small-molecule inhibitors of the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway results in rapid onset of anagen and subsequent hair growth. We show that JAK inhibition regulates the activation of key hair follicle populations such as the hair germ and improves the inductivity of cultured human dermal papilla cells by controlling a molecular signature enriched in intact, fully inductive dermal papillae. Our findings open new avenues for exploration of JAK-STAT inhibition for promotion of hair growth and highlight the role of this pathway in regulating the activation of hair follicle stem cells.

Reversal of Alopecia Areata Following Treatment With the JAK1/2 Inhibitor Baricitinib.

BACKGROUND: Alopecia areata (AA) is an autoimmune disease resulting in hair loss with devastating psychosocial consequences. Despite its high prevalence, there are no FDA-approved treatments for AA. Prior studies have identified a prominent interferon signature in AA, which signals through JAK molecules. METHODS: A patient with AA was enrolled in a clinical trial to examine the efficacy of baricitinib, a JAK1/2 inhibitor, to treat concomitant CANDLE syndrome. In vivo, preclinical studies were conducted using the C3H/HeJ AA mouse model to assess the mechanism of clinical improvement by baricitinib. FINDINGS: The patient exhibited a striking improvement of his AA on baricitinib over several months. In vivo studies using the C3H/HeJ mouse model demonstrated a strong correlation between resolution of the interferon signature and clinical improvement during baricitinib treatment. INTERPRETATION: Baricitinib may be an effective treatment for AA and warrants further investigation in clinical trials.

Induced pluripotent stem cells from human revertant keratinocytes for the treatment of epidermolysis bullosa.

Revertant mosaicism is a naturally occurring phenomenon involving spontaneous correction of a pathogenic gene mutation in a somatic cell. It has been observed in several genetic diseases, including epidermolysis bullosa (EB), a group of inherited skin disorders characterized by blistering and scarring. Induced pluripotent stem cells (iPSCs), generated from fibroblasts or keratinocytes, have been proposed as a treatment for EB. However, this requires genome editing to correct the mutations, and, in gene therapy, efficiency of targeted gene correction and deleterious genomic modifications are still limitations of translation. We demonstrate the generation of iPSCs from revertant keratinocytes of a junctional EB patient with compound heterozygous COL17A1 mutations. These revertant iPSCs were then differentiated into naturally genetically corrected keratinocytes that expressed type XVII collagen (Col17). Gene expression profiling showed a strong correlation between gene expression in revertant iPSC-derived keratinocytes and the original revertant keratinocytes, indicating the successful differentiation of iPSCs into the keratinocyte lineage. Revertant-iPSC keratinocytes were then used to create in vitro three-dimensional skin equivalents and reconstitute human skin in vivo in mice, both of which expressed Col17 in the basal layer. Therefore, revertant keratinocytes may be a viable source of spontaneously gene-corrected cells for developing iPSC-based therapeutic approaches in EB.

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

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 ß (IL-15Rß) 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.