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　　Type 1 diabetes (T1D) is a complex autoimmune disease mediated by T cells, leading to the destruction of pancreatic beta cells and insufficient insulin secretion. Before the discovery of insulin in 1921, patients with T1D would typically die within one to two years after diagnosis; however, since the discovery and large-scale production of insulin, T1D has ceased to be an incurable condition. Nevertheless, over time, many patients still develop complications, including cardiovascular disease, retinopathy, neuropathy, and kidney disease.

　　T1D is a condition resulting from a combination of genetic risk factors and environmental triggers, as well as the immune response of B cells and T cells against the β cells themselves and their byproducts. The clinical staging of T1D can be divided into three phases: The first phase is characterized by the presence of two or more islet autoantibodies with normal blood glucose levels; the second phase is marked by the presence of two or more islet autoimmunity indicators accompanied by abnormal blood glucose levels; and the third phase corresponds to a clinical diagnosis of symptomatic T1D.

　　Building on successful experiments using a T1D rat model, early attempts at immune modulation included the use of the calcineurin inhibitor cyclosporine. Among 30 patients who received treatment within 6 weeks of diagnosis, 16 patients regained normal C-peptide levels and became insulin-independent— an unprecedented outcome. Combination therapy with corticosteroids and daily azathioprine for newly diagnosed T1D also showed promising results. Although these approaches have not been widely adopted due to side effects, such trials remain crucial in demonstrating the potential of immune modulation in T1D.

　　Since then, numerous immunotherapy studies have aimed to reduce the number of key immune cells involved in the disease process and to mitigate the loss of β cells, which produce cytokines. Some successful, non-antigen-specific immunotherapies have even delayed the onset of T1D by preserving β-cell function, demonstrating promising potential.

　　Immunopathology of T1D

　　Genetics, age, and antigen-antibody specificity are all risk factors for T1D. Among these, susceptibility factors include a heightened immune response of T and B cells to islet antigens, impaired immune regulation, and abnormal innate inflammation that disrupts immune regulation and homeostasis.

　　Genetics is a key factor in the pathogenesis and progression of T1D.

　　Although 85% of T1D patients have no family history of the disease, there is substantial evidence indicating that genetic factors contribute to susceptibility to T1D. The genetic evidence comes from family history studies and genome-wide association studies (GWAS). In families with a member affected by T1D, the average lifetime risk for siblings is 6–7%, whereas the risk in the general population is only 0.4%. Moreover, identical twins have a risk of developing T1D exceeding 70%.

　　The HLA region on the short arm of chromosome 6 accounts for 50% of the genetic associations with T1D. The HLA region corresponds to the major histocompatibility complex (MHC) and encodes cell-surface receptors that present antigens to T cells. In the case of T1D, HLA class II alleles—specifically HLA-DR and HLA-DQ—are most strongly associated with the highest-risk genotypes DR3-DQ2 and DR4-DQ8, as well as with the protective genotype DQ*0602. Specifically, T1D patients are carriers of either HLA-DR3 and DQB1*0201 (DR3-DQ2) or DR4 and DQB1*0302 (DR4-DQ8). In addition, genome-wide association studies (GWAS) have identified more than 60 single-nucleotide polymorphisms (SNPs) outside the HLA region that are associated with susceptibility to T1D.

　　Pathogenetics

　　As the incidence of T1D increases, the contribution of high-risk HLA haplotypes diminishes, suggesting that genetics alone are insufficient to drive the development of T1D. Enterovirus infections and rapid weight gain in early life are both risk factors. The gut microbiota is also considered a risk factor; a lack of microbial diversity and/or alterations in the microbiome appear to increase the risk of T1D.

　　Immunopathology

　　Studies have shown that some immune features associated with T1D persist throughout the disease progression, while others are present only at specific stages of the disease. Reduced responsiveness of conventional CD4+ T cells to IL-2, expansion of transitional B cells, and increased NK cell cytotoxicity are examples of stable immune features observed when a single autoantibody first appears, and these features persist throughout the entire course of disease progression. In contrast, the increased frequency of follicular helper T cells and peripheral helper T cells is acquired as the disease progresses following initial immune perturbation. Meanwhile, enhanced resistance of effector T cells to Treg-mediated suppression and further differentiation of NK cells into more advanced subsets represent acquired immune features that emerge during the transition toward overt clinical diabetes.

　　Similarly, an enhanced T-cell response to IL-6 and expansion of B cells that do not respond were also observed—but only after the onset of clinical disease. Interestingly, the B-cell response to IL-21 or BCR signaling is dynamic: in high-risk subjects who are already positive for autoantibodies, the response is enhanced; however, in patients with clinically diagnosed and confirmed type 1 diabetes, the response is diminished. The frequency of B cells that fail to respond is also dynamic—its pre-onset frequency is reduced, while its frequency increases once type 1 diabetes has developed. Thus, certain immune changes may occur at or near the onset of the disease and could influence overall disease risk.