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Mahil S.K.; Peakman M.; Trembath R.; Barker J.; Capon F.; Wright J.
The IL-1 family cytokines IL-36 a, -b and eg are important in maintaining mucosal and epidermal immune homeostasis. As such, mutations in genes regulating IL-36 signalling (IL36RN and AP1S3) have been associated with inflammatory phenotypes e.g. pustular psoriasis. IL-36 may amplify IL-17 driven inflammatory responses and over-expression has been detected in common plaque psoriasis. IL-36 may thus be a promising therapeutic target, and antagonists directed against its receptor (IL-36R) are being developed. However, since the function of IL-36 in broader immune responses remains undetermined, pharmacological blockade may have unexpected adverse effects. We investigated the consequences of IL-36 signalling inhibition through the deep phenotyping of human knockouts who lack a functional IL-36R. These individuals were identified by querying the genotype data generated by “Born in Bradford”, a community-based initiative to exome sequence 2,162 British- Pakistanis. In keeping with the increased parental relatedness in this cohort, we identified numerous participants (n=28) with low-frequency homozygous changes in IL1RL2 (encoding IL-36R). We recalled 6 subjects harbouring bi-allelic missense changes predicted to be deleterious. IL- 36 stimulation of PBMCs from these individuals did not elicit an inflammatory response. However, clinical examinations and medical records did not indicate anomalies in immune function. Full blood counts and antibody responses to past immunizations were normal. PBMC treatment with varied inflammatory stimuli (PMA, poly(I: C), C. albicans and Infanrix vaccine) induced up-regulation of inflammatory markers comparable to that observed in ethnically matched
controls. Thus, these data suggest that IL-36 blockade may be compatible with normal immune function and pave the way for pre-clinical safety studies of IL-36 inhibitors. Our study also highlights the utility of phenotyping human knockouts in the preclinical assessment of novel drug targets.