Recent advances in the characterization of type 1 diabetes and LADA: towards a better understanding of the autoimmune spectrum

Abstract

Autoimmune diabetes is a disease characterized by progressive destruction of pancreatic β-cells, leading to a relative or absolute deficiency of insulin. This response is promoted by autoreactive T lymphocytes, whose activation and expansion are influenced by genetic, immunological and environmental factors.

Within the spectrum of autoimmune diabetes, two main clinical forms are recognized: Type 1 diabetes (DBT-1) has predominantly childhood onset and rapid progression, while latent autoimmune diabetes in adults (LADA) manifests in later stages of life and progresses slowly. Both entities share common pathogenic mechanisms but differ in clinical and immunogenetic aspects and the kinetics of β-cell destruction.

Early activation of the innate immune system results in a proinflammatory environment that promotes the breakdown of immunological tolerance and the activation of autoreactive CD4+ and CD8+ T lymphocytes. Distinct subsets of CD4+ T lymphocytes differentially participate in the immunopathogenesis of these entities, modulating both cellular and humoral immune responses. However, the specific role of these populations in LADA remains unexplored, representing a significant knowledge gap.

From a genetic perspective, major histocompatibility complex alleles (MHC) constitute the main component of the hereditary risk, while non-MHC variants have also been associated with susceptibility and disease progression. However, environmental factors can act as triggers in genetically predisposed individuals.

Despite advances in exogenous insulin therapy and glycemic monitoring, most patients do not reach optimal treatment goals, increasing the risk of chronic complications. In this scenario, specific immunotherapies aimed at preserving functional β-cell mass and modulating the immune response represent promising strategies.

The objective of this review is to provide a comprehensive update on the immunological, genetic and environmental mechanisms involved in the pathogenesis of DBT-1 and LADA. It also highlights similarities and differences between these two clinical forms, emphasizing existing knowledge gaps and emerging therapeutic approaches.