Abstract
Birth by Cesarean section increases the risk of developing type 1 diabetes later in life. We aimed to elucidate common regulatory processes observed after Cesarean section and the development of islet autoimmunity, which precedes type 1 diabetes, by investigating the transcriptome of blood cells in the developing immune system. To investigate Cesarean section effects, we analyzed longitudinal gene expression profiles from peripheral blood mononuclear cells taken at several time points from children with increased familial and genetic risk for type 1 diabetes. For islet autoimmunity, we compared gene expression differences between children after initiation of islet autoimmunity and age-matched children who did not develop islet autoantibodies. Finally, we compared both results to identify common regulatory patterns. We identified the pentose phosphate pathway and pyrimidine metabolism - both involved in nucleotide synthesis and cell proliferation - to be differentially expressed in children born by Cesarean section and after islet autoimmunity. Comparison of global gene expression signatures showed that transcriptomic changes were systematically and significantly correlated between Cesarean section and islet autoimmunity. Moreover, signatures of both Cesarean section and islet autoimmunity correlated with transcriptional changes observed during activation of isolated CD4+ T lymphocytes. In conclusion, we identified shared molecular changes relating to immune cell activation in children born by Cesarean section and children who developed autoimmunity. Our results serve as a starting point for further investigations on how a type 1 diabetes risk factor impacts the young immune system at a molecular level.
Highlights
Type 1 diabetes is an autoimmune disease in which immune cells destroy insulin-producing beta cells in the pancreas
We identified coherent gene expression signatures for Cesarean section, an early risk factor for type 1 diabetes, and islet autoantibody positivity, an obligatory stage of autoimmune response prior to the development of autoimmune type 1 diabetes
At the transcriptome level, we identified two pathways involved in nucleotide synthesis and cell proliferation that were regulated in peripheral blood mononuclear cells (PBMCs) of children born by Cesarean section
Summary
Type 1 diabetes is an autoimmune disease in which immune cells destroy insulin-producing beta cells in the pancreas. Some reports indicate that the mode of delivery affects colonization of microbiota in the intestinal tract[9], which in turn affects the developing immune system of infants[10]. Such differences in the gut microbiome and its interaction with the immune system may lead to increased risk of asthma, childhood allergies[11], and autoimmune diseases, such as type 1 diabetes. We first investigated the effects of Cesarean section on gene expression profiles of children in the first year of life (Fig. 1b) To this end, we analyzed data from several time points in this early period in children with an increased familial risk for type 1 diabetes.
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