Mahil S.; Peakman M.; Trembath R.; Barker J.; Capon F.; Wright J.
Interleukin (IL)-36a, -b and -c are innate IL-1 family cytokines, which are increasingly recognized as important mediators of mucosal and epidermal immune homeostasis. Indeed, mutations in genes that regulate IL-36 signalling (IL36RN and AP1S3) have been associated with inflammatory phenotypes, including generalized pustular psoriasis. IL-36 overexpression has also been detected in common plaque psoriasis, in which increased cytokine production amplifies IL-17-driven inflammatory responses. As IL-36 emerges as a promising therapeutic target, specific antagonists directed against its receptor (IL-36R) are being developed. However, the role of IL-36 in broader immune function remains partially undetermined, such that pharmacological blockade may have unexpected adverse effects. Here, we investigated the long-term consequences of IL-36 signalling inhibition, through the deep phenotyping of ‘human knockouts’ who lack a functional IL- 36 receptor. To identify such individuals, we queried the genotype data generated by ‘Born in Bradford’, a communitybased initiative to exome sequence 2162 British Pakistani individuals. In keeping with the increased parental relatedness reported for this cohort, we identified several participants (n = 28) with low-frequency homozygous changes in IL1RL2 (the gene encoding IL-36R). Among these, we recalled six individuals with biallelic missense changes predicted by multiple algorithms to be deleterious. IL-36 stimulation of peripheral blood mononuclear cells (PBMCs) from these individuals did not elicit an inflammatory response. However, clinical interview, examination and analyses of medical records did not indicate any anomalies in immune function. Full blood counts and antibody responses to past immunizations were also normal. PBMC stimulation with varied inflammatory agents (phorbol-12-myristate-13-acetate, Candida albicans extracts and Infanrix 5-in-1 vaccine) induced upregulation of inflammatory markers comparable with that observed in ethnically matched controls. These data suggest that IL-36 blockade is compatible with normal immune function and pave the way for preclinical safety studies of IL-36 inhibitors. More broadly, our study highlights the exciting utility of phenotyping individuals with null mutations in the preclinical assessment of novel drug targets.
