Distinct enterovirus antigen landscape in children with islet autoimmunity

Enteroviruses (EVs) have long been implicated in the development of islet autoimmunity (IA) and type 1 diabetes (T1D). However, given the ubiquity of EV infections in children, disease susceptibility is likely driven by host-specific immune responses rather than viral exposure alone. To investigate the host antibody response to EVs, we employed virome-wide serological profiling (VirScan), to compare the EV antigen landscapes in children with IA-positive cases versus IA-negative controls across two independent paediatric cohorts separated by 12 years, using samples collected at the singular timepoint of seroconversion. For the first time, we identified a reproducible and distinct EV-specific antibody signature in IA-positive cases, with a borderline significant enriched immunogenic hotspot localised within a highly conserved region in the 3D RNA-dependent RNA polymerase. Additionally, IA-positive males exhibited heightened antibody responses against the VP1 capsid protein. Our findings provide paradigm-shifting evidence that differential antiviral humoral responses, rather than the specific type of EV infections, play a central role in IA development, highlighting the need for an updated framework to study host-virus interactions in autoimmune pathogenesis.