B Lymphocytes in Latent Autoimmune Diabetes in Adults: From Autoimmune Activation to Immunometabolic Heterogeneity and Precision Therapeutic Perspectives
ABSTRACT Latent autoimmune diabetes in adults (LADA) is a heterogeneous form of autoimmune diabetes characterised by adult onset, the presence of islet autoantibodies, and a slower progression to insulin dependence compared with classical type 1 diabetes. Positioned at the interface of type 1 and type 2 diabetes, LADA arises from complex interactions among genetic susceptibility, immune dysregulation, and metabolic stress. While autoreactive T cells are recognized as central mediators of β‐cell destruction, accumulating evidence indicates that B lymphocytes play a broader and dynamic role in disease pathogenesis than previously appreciated. Beyond autoantibody production, B cells contribute to LADA through antigen presentation, cytokine secretion, and regulation of T cell responses, thereby amplifying autoimmune circuits within pancreatic islets. Emerging studies further demonstrate perturbations in circulating B cell subsets, including expansion of memory B cells and plasmablasts and impairment of regulatory B cells. However, whether these alterations represent primary drivers of disease progression or secondary responses to ongoing β‐cell injury remains unresolved. In parallel, immunometabolic stress and β‐cell dysfunction promote neoantigen formation and may shape B cell activation and selection, linking metabolic perturbations to adaptive immune dysregulation. Together, these findings support a model in which B lymphocytes act as both effector and regulatory components within a dynamic immunometabolic network that determines disease heterogeneity and progression. Recent advances in molecular profiling have further revealed distinct LADA endotypes, particularly stratified by glutamic acid decarboxylase antibody levels, suggesting divergent autoimmune and metabolic contributions across patient subgroups. These insights provide a rationale for precision medicine approaches and highlight B lymphocyte‐targeted interventions as potential, although still investigational, therapeutic strategies aimed at preserving residual β‐cell function.