Alopecia areata profiling shows TH1, TH2, and IL-23 cytokine activation without parallel TH17/TH22 skewing

Background: Alopecia areata (AA) is a common T cell-mediated disorder with limited therapeutics. A molecular profile of cytokine pathways in AA tissues is lacking. Although studies have focused on T(H)1/IFN-gamma responses, several observations support a shared genetic background between AA and atopy. Objective: We sought to define the AA scalp transcriptome and associated biomarkers with comparisons with atopic dermatitis (AD) and psoriasis. Methods: We performed microarray and RT-PCR profiling of 27 lesional and 17 nonlesional scalp samples from patients with AA for comparison with normal scalp samples (n = 6). AA gene expression was also compared with samples from patients with lesional or nonlesional AD and those with psoriasis. A fold change of greater than 1.5 and a false discovery rate of less than 0.05 were used for differentially expressed genes (DEGs). Results: We established the AA transcriptomes (lesional vs nonlesional: 734 DEGs[297 upregulated and 437 downregulated]; lesional vs normal: 4230 DEGs [1980 upregulated and 2250 downregulated]), including many upregulated immune and downregulated hair keratin genes. Equally impressive as upregulation in T(H)1/interferon markers (IFNG and CXCL10/CXCL9) were those noted in T(H)2 (IL13, CCL18, CCL26, thymic stromal lymphopoietin, and periostin), T(H)9/IL-9, IL-23 (p40 and p19), and IL-16 mediators (all P < .05). There were no increases in T(H)17/T(H)22 markers. Hair keratin (KRT) expressions (ie, KRT86 and KRT85) were significantly suppressed in lesional skin. Greater scalp involvement (>25%) was associated with greater immune and keratin dysregulation and larger abnormalities in nonlesional scalp samples (ie, CXCL10 and KRT85). Conclusions: Our data associate the AA signature with T(H)2, T(H)1, IL-23, and IL-9/T(H)9 cytokine activation, suggesting consideration of anti-T(H)2, anti-T(H)1, and anti-IL-23 targeting strategies. Similar to psoriasis and AD, clinical trials with selective antagonists are required to dissect key pathogenic pathways.