Immunopathology and immunotherapy of type 1 diabetes


Type 1 diabetes (T1D) is a complex autoimmune disease mediated by T cells, which leads to the production of insulin β Cell destruction and insufficient insulin secretion. Before insulin was discovered in 1921, T1D patients would die within one or two years after diagnosis; However, since the discovery and mass production of insulin, T1D is no longer an incurable disease. However, over time, many patients still have complications, including cardiovascular disease, retinopathy, neuropathy and kidney disease.

T1D is a genetic risk, environmental trigger, and B cell and T cell pair β The comprehensive results of the development of the autoreaction of cells and their products. The clinical stage of T1D can be divided into three stages: the first stage shows two or more islet autoantibodies with normal blood glucose, the second stage shows two or more islet autoantibodies with abnormal blood glucose, and the third stage is the clinical diagnosis of symptomatic T1D.

 

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Based on the successful experiment of T1D rat model, early attempts of immune regulation include the use of calcineurin inhibitor cyclosporin. Of the 30 patients who received treatment within 6 weeks after diagnosis, 16 returned to normal C-peptide level and became insulin-independent, which was an unprecedented result. The use of corticosteroids plus daily azathioprine also showed beneficial results in new T1D. Although these methods were not used due to side effects, these tests are still important in proving the potential of T1D immune regulation.

 

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Since then, there have been many immunotherapy studies aimed at reducing the number of key immune cells involved in the disease process and the cytokines they produce β Loss of cells. Some successful non-antigen-specific immunotherapy β The cell function even delays the development of T1D, showing promising prospects.

Immunopathology of T1D

Heredity, age and antigen-antibody specificity are all risk factors for T1D, among which susceptibility factors include higher T and B cell response to islet antigen, impaired immune regulation and abnormal congenital inflammation that impairs 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 disease, there is sufficient evidence that genetic factors contribute to T1D susceptibility. The evidence of genetics comes from family history research and genome-wide association research (GWAS). In families with T1D members, the average lifetime risk of siblings is 6-7%, while the risk of the general population is 0.4%. In addition, the risk of T1D in identical twins is greater than 70%.

The HLA region on the short arm of chromosome 6 accounts for 50% of the T1D gene association. The HLA region corresponds to the major histocompatibility complex (MHC) and encodes cell surface receptors that present antigens to T cells. For T1D, HLA-II alleles, HLA-DR and HLA-DQ have the strongest association with the highest risk genotype DR3-DQ2 and DR4-DQ8 and the protective genotype DQ * 0602. Specifically, T1D patients are carriers of HLA-DR3, DQB1 * 0201 (DR3-DQ2) or DR4, DQB1 * 0302 (DR4-DQ8). In addition, GWAS also found more than 60 single-nucleotide polymorphisms (SNPs) outside the HLA region associated with T1D susceptibility.

Aetiology

With the increase of T1D incidence rate, the contribution of high-risk HLA haplotypes decreases, which indicates that genetics alone is not enough to drive the development of T1D. Enterovirus infection and early rapid weight gain are both risk factors. Intestinal microbiota is also considered as a risk factor; Lack of microbial diversity and/or changes in microbiome seem to increase the risk of T1D.

Immunopathology

Studies have shown that some immune features related to T1D always exist in the course of disease development, while some other immune features only exist in specific stages of the disease. The reduced response of conventional CD4+T cells to IL-2, the expansion of transitional B cells and the increase of NK cell lysis function are examples of fixed immune characteristics observed when a single autoantibody first appeared, and appear in the whole disease progression process. On the contrary, the increased frequency of follicular T helper cells and peripheral T helper cells is acquired with the progression of disease after fixed immune interference, while the increased resistance of effector T cells to Treg mediated inhibition and more terminal NK differentiation are acquired immune characteristics, which occur in the transition phase to dominant clinical diabetes.

 

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Similarly, the enhanced response of T cells to IL-6 and the expansion of unresponsive B cells were also obtained, but only after the onset of clinical disease. Interestingly, the response of B cells to IL-21 or BCR signals is dynamic, and the response of high-risk subjects with positive autoantibodies is enhanced, but the response in patients with clinical diagnosis and confirmed T1D is weakened. The frequency of unresponsive B cells is also dynamic. The frequency before onset decreases and the frequency in T1D increases. Therefore, some immune changes may occur at or near the beginning of the disease and affect the overall disease risk.

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