Severe cardiac inflammation during febrile illness, in patients with HIKESHI mutation is mediated by immune recognition of HSP70

HIKESHI is a small adaptor protein involved in the localization of Heat-Shock protein 70 (HSP70) into the nucleus during cellular stress. Rare recessive mutations in HIKESHI result in severe neuro-developmental disabilities. Dysfunctional HIKESHI leads to impaired cellular heat-shock response and prolonged recovery.

We propose that patients homozygous to the HIKESHI mutations are more susceptible to cardiac inflammation post febrile illness, due to poor recovery from the induced stress, as a result of the impaired HIKESHI-HSP70 protein interaction.

We established an ex vivo model based on IPSCs-derived cardiomyocytes to examine our hypothesis. We managed to reprogram fibroblasts into stable IPSCs lines and differentiate those cells into cells exhibiting all the properties of cardiomyocytes, including expression of cardiotropinin, and spontaneous pulsing.

Our preliminary data on IPSCs support previous research regarding impaired localization of HSP70 into the nucleus after heat shock. In addition, we show that patient baseline expression of HSP70 in IPSCs lines is higher than in control and rises even higher after heat shock. Moreover, cells derived from homozygous patients elicit a more robust killing response from NK92 cells, supporting an immune reaction mediated by membranal interaction.

All in all, our research demonstrates that IPSCs can serve as a basic model for immune response in syndromes associated with rare mutations and may offer some clues regarding the effective treatment of these complicated neuro-developmental disabilities.