Mahil S.; Peakman M.; Trembath R.; Wright J.; Barker J.; Capon F.
IL-36a, -b and -g are increasingly recognised as important mediators of mucosal/epidermal immune homeostasis. Indeed, mutations in genes that regulate IL-36 signaling (IL36RN and AP1S3) are associated with inflammatory phenotypes, including generalised pustular psoriasis. IL-36 over-expression has been detected in plaque psoriasis, where it amplifies IL-17 responses. As IL-36 emerges as a promising therapeutic target, antagonists against its receptor (IL-36R) are being developed. However, the role of IL-36 in broader immune function remains undetermined, such that pharmacological blockade may have unexpected effects. We investigated the consequences of IL-36 signalling inhibition through the deep phenotyping of human knockouts who lack a functional IL-36 receptor. We queried the genotype data generated by Born in Bradford, an initiative to exome sequence 2,162 British-Pakistani individuals. In keeping with the parental relatedness reported for this cohort, we identified several participants (n=28) with low-frequency homozygous changes in IL1RL2 (encoding IL-36R). We recalled 6 subjects with bi-allelic missense changes predicted to be deleterious. IL-36 stimulation of PBMCs did not elicit an inflammatory response. However, clinical interview/examination did not indicate anomalies in immune function. Antibody responses to past immunizations were normal. PBMC stimulation with PMA, C. albicans and Infanrix 5-in-1 vaccine induced up-regulation of inflammatory markers comparable to controls. These data suggest that IL-36 blockade is compatible with normal immune function and pave the way for pre-clinical safety studies of IL-36 inhibitors. Our study highlights the exciting utility of phenotyping human subjects with null mutations in the pre-clinical assessment of novel drug targets.
Open Access
