Type 1 diabetes and inborn errors of immunity: complete strangers or sides of the same coin?

Recent advances in the immunological, molecular, and genetic technologies such as next-generation sequencing have increased the number of inborn errors of immunity (IEI) diagnosed. Some IEI, caused by mutations in genes that regulate Treg development and function, are associated with elevated incidence of type 1 diabetes (T1D). As the genetic spectrum of IEIs becomes unraveled, molecular pathways underlying human monogenic auto-immune/inflammatory syndromes become identified including their association with T1D pathogenesis. There is significant overlap between some of these molecular pathways and single nucleotide polymorphisms identified in T1D genome-wide association studies. The study of monogenic IEIs with a variable incidence of T1D has the potential to give important insights into the mechanisms leading to T1D, thus contributing to the definition of T1D endotypes and explaining disease heterogeneity. In this review, we aimed to comprehensively summarize and discuss the mechanisms underlying the interconnected pathogenic pathways of autoimmunity, beta cell function, and primary immunodeficiency. We also discuss the role of environmental factors in determining disease penetrance and the circumstantial evidence of therapies developed for IEI in preventing and curing T1D, thus suggesting the repositioning of these drugs.