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Summary: Background: Alopecia areata (AA) is a common autoimmune disease, causing patchy hair loss that can progress to involve the entire scalp (totalis) or body (universalis). CD8+NKG2D+ T cells dominate hair follicle pathogenesis, but the specific mechanisms driving hair loss are not fully understood. Objectives: To provide a detailed insight into the systemic cytokine signature associated with AA, and to assess the association between cytokines and depression. Methods: We conducted multiplex analysis of plasma cytokines from patients with AA, patients with psoriatic arthritis (PsA) and healthy controls. We used the Hospital Anxiety and Depression Scale (HADS) to assess the occurrence of depression and anxiety in our cohort. Results: Our analysis identified a systemic inflammatory signature associated with AA, characterized by elevated levels of interleukin (IL)‐17A, IL‐17F, IL‐21 and IL‐23 indicative of a type 17 immune response. Circulating levels of the type 2 cytokines IL‐33, IL‐31 and IL‐17E (IL‐25) were also significantly increased in AA. In comparison with PsA, AA was associated with higher levels of IL‐17F, IL‐17E and IL‐23. We hypothesized that circulating inflammatory cytokines may contribute to wider comorbidities associated with AA. Our assessment of psychiatric comorbidity in AA using HADS scores showed that 18% and 51% of people with AA experienced symptoms of depression and anxiety, respectively. Using linear regression modelling, we identified that levels of IL‐22 and IL‐17E are positively and significantly associated with depression. Conclusions: Our data highlight changes in both type 17 and type 2 cytokines among people with AA, suggesting that complex systemic cytokine profiles may contribute both to the pathogenesis of AA and to the associated depression. What's already known about this topic? NKG2D+CD8+ T cells cause hair loss in alopecia areata (AA) but the immunological mechanisms underlying the disease are not fully understood.AA is associated with changes in levels of interleukin (IL)‐6, tumour necrosis factor‐α, IL‐1β and type 17 cytokines.Psychiatric comorbidity is common among people with AA. What does this study add? People with AA have increased plasma levels of the type 2 cytokines IL‐33, IL‐31 and IL‐17E (IL‐25), in addition to the type 17 cytokines IL‐17A, IL‐21, IL‐23 and IL‐17F.Levels of IL‐17E and IL‐22 positively predict depression score. What is the translational message? AA is associated with increased levels of multiple inflammatory cytokines, implicating both type 17‐ and type 2 immune pathways.Our data indicate that therapeutic strategies for treating AA may need to address the underlying type 17‐ and type 2 immune dysregulation, rather than focusing narrowly on the CD8+ T‐cell response.An immunological mechanism might contribute directly to the depression observed in people with AA. Plain language summary available online Linked Comment: Ohyama. Br J Dermatol 2020; 182:15–16. [ABSTRACT FROM AUTHOR]