Deciphering heterogeneity: immune and epigenetic biomarkers and modulators of partial remission in type 1 diabetes

Abstract

Type 1 diabetes (T1D1) is an autoimmune disease that destroys the β-cells of the pancreas, which are responsible for insulin production. After initiation of insulin therapy, many pediatric patients go through a phase called partial remission (PR) or “honeymoon”. During this phase, the β-cells partially recover, which reduces the need for exogenous insulin and improves control of blood glucose levels. The mechanisms of this phase are not yet clear, but may involve reduced pressure on β-cells due to correction of hyperglycemia, as well as improvements in cell viability, insulin sensitivity, and immune regulation. The aim of the research is to identify immunological and epigenetic biomarkers related to RP in pediatric patients with DT1. This may provide insights into the processes that protect β-cells and regulate the immune system, which is crucial for developing more personalized and effective treatments. The study began by analyzing up to 55 immune cell subpopulations in peripheral blood at the time of DT1 diagnosis, in order to predict which patients would have a remission phase. A predictive model, based on immunological variables and age, was able to identify patients with 81% accuracy, which could be used to monitor disease progression and personalize treatment. In a longitudinal analysis, changes in immune cell subpopulations and in cytokine and microRNA (miRNA) levels were observed in patients' plasma during the RP phase. Alterations were found in regulatory T and B lymphocytes, NK cells, monocytes and in the concentration of the cytokine IL-17A. In addition, a distinctive miRNA profile was identified in patients in remission, with miR-30d-5p being the most relevant, being involved in processes related to stress response, insulin signaling, apoptosis and regulation of the immune system. The study suggests that miR-30d-5p plays a key role in the regulation of biological pathways that could influence β-cell protection, promoting both immunoregulation and cell regeneration. Inhibition of this miRNA in T lymphocytes showed that it is required for the expression of immunosuppressive molecules such as PD-1, suggesting that it could help to curb autoimmune responses that attack β-cells. In addition, miR-30d-5p was shown to stimulate the formation of new insulin-producing β-cells in the pancreas and activate insulin synthesis and secretion. In mouse models of type 1 diabetes, inhibition of miR-30d-5p aggravated autoimmunity, with increased leukocyte infiltrate in pancreatic islets and decreased immune regulation (less PD-1 expression in lymphocytes). However, its regulation seems to be linked to the expression of genes such as CD200, involved in immune modulation. In conclusion, this study identified new immune and epigenetic biomarkers related to the RP phase in DT1, especially the key role of miR-30d-5p. These findings provide a basis for new therapeutic strategies focused on preserving and regenerating β-cells, which could transform the treatment of pediatric diabetes. Although further research is needed, this work offers a significant advance in understanding the immunological and epigenetic processes that occur during PR, paving the way toward more precise and personalized interventions.

Date of Award	20 Nov 2024
Original language	English
Supervisor	Marta Vives Pi (Director)