Autoimmunity directed against pancreatic β cells in type 1 diabetes

Abstract

Type 1 diabetes (T1D) is a chronic inflammatory autoimmune disease characterized by the selective destruction of pancreatic β cells. It has traditionally been regarded as an exclusively immune-mediated disease in which T cells recognize β-cell autoantigens -including insulin/proinsulin, GAD65, IA-2, and ZnT8- and trigger a progressive inflammatory process that ultimately leads to insulin deficiency.

More recently, a model has gained acceptance in which the β cell is not merely a passive victim of autoimmunity but actively participates in bidirectional crosstalk with the immune system, thereby contributing to the initiation, amplification, and progression of cellular damage¹.

Genetic susceptibility is associated with HLA class II haplotypes, particularly HLA-DR3-DQ2 and HLA-DR4-DQ8, although numerous non-HLA genes also contribute to disease risk. Environmental factors, including viral infections, diet, gut microbiota, and metabolic stress, may act as triggers in genetically predisposed individuals. Before the clinical onset of the disease, there is a preclinical phase of variable duration characterized by the presence of islet autoantibodies and functional alterations in β cells.

It is now recognized that β cells exposed to inflammatory, metabolic, or endoplasmic reticulum (ER) stress can become markedly more immunogenic. Exposure to proinflammatory cytokines activates intracellular stress pathways, increases the expression of HLA class I molecules, promotes chemokine production, and favors the generation of neoantigens capable of amplifying the autoimmune response. In addition, processes such as alternative splicing, hybrid peptide formation, and various post-translational modifications can generate novel epitopes recognized by autoreactive T cells. One example is the citrullination of the chaperone protein BiP/GRP78 (binding immunoglobulin protein), which generates immunogenic neoepitopes detected in patients with T1D². These findings position the β cell as a dynamic participant in immune crosstalk.

Understanding the bidirectional interaction between the immune system and β cells has important therapeutic implications. Although immunomodulatory treatments, such as anti-CD3 antibodies, can delay disease progression, their efficacy remains limited³. Therefore, novel and more comprehensive therapeutic strategies should combine immunotherapy with approaches aimed at preserving or enhancing β-cell resilience. These may include agents that reduce ER stress, inhibitors of intracellular inflammatory pathways, metabolic modulators, and strategies capable of inducing protective adaptive responses through hormesis⁴.

Taken together, this perspective proposes that T1D arises from a complex interplay among genetic predisposition, the immune system, and the intrinsic vulnerability of β cells, thereby opening new opportunities for combination therapies designed both to suppress cell-mediated autoimmunity and to preserve β-cell function.