Progression of type 1 diabetes is associated with high levels of soluble PD-1 in islet autoantibody-positive children

Aims/hypothesis Type 1 diabetes is an autoimmune disorder that is characterised by destruction of pancreatic beta cells by autoreactive T lymphocytes. Although islet autoantibodies (AAb) are an indicator of disease progression, specific immune biomarkers that can be used as target molecules to halt development of type 1 diabetes have not been discovered. Soluble immune checkpoint molecules (sICM) play a pivotal role in counteracting excessive lymphocyte responses, but their role in type 1 diabetes is unexplored. In this longitudinal study, we measured sICM levels in AAb-positive (AAb + ) children to identify molecules related to type 1 diabetes progression. Methods We measured the levels of 14 sICM in the sera of AAb + children ( n =57) compared to those with recent-onset type 1 diabetes ( n =79) and healthy children ( n =44), obtained from two cohorts. AAb + children were followed up and divided based on their progression to type 1 diabetes (AAb P ) or not (AAb NP ) (if they lost islet autoimmunity and did not develop disease in subsequent years). sICM were also measured in the sample taken at the visit closest to disease onset in AAb P children. Results We found that AAb + children had a distinct sICM profile compared with healthy children and those with recent-onset type 1 diabetes. In addition, AAb + children who progressed to type 1 diabetes (AAb P ) had higher sICM concentrations than non-progressors (AAb NP ). Further, sICM levels decreased in AAb P children close to disease onset. Application of Cox regression models highlighted that high concentrations of soluble programmed cell death protein 1 (sPD-1) are associated with type 1 diabetes progression (HR 1.71; 95% CI 1.16, 2.51; p =0.007). Conclusions/interpretation This study reveals an sICM profile that is dysregulated during the preclinical stage of type 1 diabetes, and identifies sPD-1 as a pathophysiologically-relevant molecule that is associated with disease progression, offering a potential target for early interventions in autoimmune diabetes. Graphical Abstract