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Innate lymphoid cells (ILCs) are increasingly appreciated as key regulators of tissue immunity. However, their role in human tissue homeostasis and disease remains to be fully elucidated. Here we characterize the ILCs in human skin from healthy individuals and from the inflammatory skin disease psoriasis. We show that a substantial proportion of IL-17A and IL-22 producing cells in the skin and blood of normal individuals and psoriasis patients are CD3-negative innate lymphocytes. Deep immunophenotyping of human ILC subsets showed a statistically significant increase in the frequency of circulating NKp44+ ILC3 in the blood of psoriasis patients compared with healthy individuals or atopic dermatitis patients. More than 50% of circulating NKp44+ ILC3 expressed cutaneous lymphocyte–associated antigen, indicating their potential for skin homing. Analysis of skin tissue revealed a significantly increased frequency of total ILCs in the skin compared with blood. Moreover, the frequency of NKp44+ ILC3 was significantly increased in non-lesional psoriatic skin compared with normal skin. A detailed time course of a psoriasis patient treated with anti–tumor necrosis factor showed a close association between therapeutic response, decrease in inflammatory skin lesions, and decrease of circulating NKp44+ ILC3. Overall, data from this initial observational study suggest a potential role for NKp44+ ILC3 in psoriasis pathogenesis.

In this issue, Dowlatshahi et al. publish results from their population-based study in Rotterdam showing that, despite an increase in body mass index and smoking, individuals with psoriasis have no increased risk of incident cardiovascular disease. These results should be interpreted with caution: the study included relatively small numbers of patients with psoriasis, most of whom had mild disease.

Methotrexate is the gold standard therapy for moderate to severe psoriasis, but there is marked interpersonal variation in its efficacy and toxicity. We hypothesized that in psoriasis patients, specific common polymorphisms in folate, pyrimidine, and purine metabolic enzymes are associated with methotrexate efficacy and/or toxicity. DNA from 203 retrospectively recruited psoriasis patients treated with methotrexate was collected and genotyped by restriction endonuclease digestion or length polymorphism assays. The reduced folate carrier (RFC) 80A allele and the thymidylate synthase (TS) 3’-untranslated region (3′-UTR) 6 bp deletion were associated with methotrexate-induced toxicity (P=0.025 and P=0.025, respectively). RFC 80A and 5-aminoimidazole-4-carboxamide ribonucleotide transformylase (ATIC) 347G were associated with methotrexate discontinuation (P=0.048 and P=0.038). The TS 5′-UTR 28 bp 3R polymorphism correlated with poor clinical outcome (P=0.029), however, this was not the case when patients with palmoplantar pustular psoriasis were not included in the analysis. Stronger associations between specific polymorphisms and methotrexate-induced toxicity and discontinuation were found in a subanalysis of patients on methotrexate not receiving folic acid supplementation. We have demonstrated preliminary evidence that specific polymorphisms of enzymes involved in folate, pyrimidine, and purine metabolism could be useful in predicting clinical response to methotrexate in patients with psoriasis.