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

Abstract

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.

Keywords: Islet autoantibodies; Prediction of type 1 diabetes; Soluble PD-1; Soluble immune checkpoint molecules; Type 1 diabetes.