Abstract
Non-genetic factors are crucial in the pathogenesis of type 1 diabetes (T1D), a disease caused by autoimmunity against insulin-producing β-cells. Exposure to medications in the prenatal period may influence the immune system maturation, thus altering self-tolerance. Prenatal administration of betamethasone –a synthetic glucocorticoid given to women at risk of preterm delivery– may affect the development of T1D. It has been previously demonstrated that prenatal betamethasone administration protects offspring from T1D development in nonobese diabetic (NOD) mice. The direct effect of betamethasone on the immature and mature immune system of NOD mice and on target β-cells is analysed in this paper. In vitro, betamethasone decreased lymphocyte viability and induced maturation-resistant dendritic cells, which in turn impaired γδ T cell proliferation and decreased IL-17 production. Prenatal betamethasone exposure caused thymus hypotrophy in newborn mice as well as alterations in immune cells subsets. Furthermore, betamethasone decreased β-cell growth, reduced C-peptide secretion and altered the expression of genes related to autoimmunity, metabolism and islet mass in T1D target tissue. These results support the protection against T1D in the betamethasone-treated offspring and demonstrate that this drug alters the developing immune system and β-cells. Understanding how betamethasone generates self-tolerance could have potential clinical relevance in T1D.
Highlights
Type 1 diabetes mellitus (T1D) is a metabolic disease caused by the destruction of pancreatic β-cells by autoreactive T lymphocytes[1]
In a spontaneous type 1 diabetes (T1D) experimental model, the non-obese diabetic (NOD) mouse, we have recently shown that prenatal administration of betamethasone reduced T1D incidence in the offspring
The results provide an explanation for the reduced incidence of T1D in NOD offspring after prenatal betamethasone treatment, enlightening possible immunological mechanisms, and adding knowledge in the complex puzzle that shapes the development of the immune system
Summary
Type 1 diabetes mellitus (T1D) is a metabolic disease caused by the destruction of pancreatic β-cells by autoreactive T lymphocytes[1]. The challenge in finding a cure is based on the heterogeneity of mechanisms that lead to the development of autoimmune reactions For this reason, a better understanding of the influence of non-genetic factors in T1D susceptibility is needed. It has been previously demonstrated that prenatal betamethasone treatment results in a biased TCR repertoire, affecting the TCR (Vβ) relevant for T1D antigen recognition In this scenario, the lower frequency of pathogenic TCRs (Vβ12 in CD4+ T cells and Vβ6 in CD8+ T cells) was reflected in the reduced immune cell infiltration in the pancreas and contributed to protection from T1D in the NOD mice[11]. These results encouraged us to analyse in depth the effects of prenatal betamethasone
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