Potential Therapeutic Application of Regulatory T Cells in Diabetes Mellitus Type 1

Beń‐Skowronek, Iwona; Sieniawska, Joanna; Pach, E; Wrobel, Wiktoria; Skowronek, Anna; Tomczyk, Z; Rosolowska, Iga

doi:10.3390/ijms23010390

Cited by 12 publications

(8 citation statements)

References 91 publications

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“…identified that in A53 transgenic (A53T) PD mice, the expression levels of cytotoxic-T-lymphocyte-antigen-4 (CTLA-4) and inducible costimulator (ICOS) were markedly reduced in T regulatory lymphocytes (Tregs), a critical player in maintaining immune homeostasis ( 63 ). Similarly, Tregs were also found to exhibit functional defects in PD patients, implying an abolished suppressive effect on autoimmune response and a contributory factor for the emergence of T1D ( 64 ). Meanwhile, in the reverse direction MR analysis, we failed to observe a causal effect of T1D on the susceptibility to PD.…”

Section: Discussionmentioning

confidence: 99%

Investigation of the causal association between Parkinson’s disease and autoimmune disorders: a bidirectional Mendelian randomization study

Yang,

Lin,

et al. 2024

Front. Immunol.

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BackgroundTo date, an increasing number of epidemiological evidence has pointed to potential relationships between Parkinson’s disease (PD) and various autoimmune diseases (AIDs), however, no definitive conclusions has been drawn about whether PD is causally related to AIDs risk.MethodsBy employing summary statistics from the latest and most extensive genome-wide association studies (GWAS), we performed a bidirectional two-sample Mendelian randomization (MR) analysis to investigate the causal associations between PD and a variety of 17 AIDs, encompassing multiple sclerosis, neuromyelitis optica spectrum disorder, myasthenia gravis, asthma, inflammatory bowel disease, Crohn’s disease, ulcerative colitis, irritable bowel syndrome, celiac disease, primary biliary cirrhosis, primary sclerosing cholangitis, type 1 diabetes, ankylosing spondylitis, rheumatoid arthritis, systemic lupus erythematosus, psoriasis and vitiligo. Inverse-variance weighted (IVW) was adopted as the main statistical approach to obtain the causal estimates of PD on different AIDs, supplemented by a series of complementary analyses (weighted median, MR Egger regression, and MR-PRESSO) for further strengthening the robustness of results.ResultsOur MR findings suggested that genetically predicted higher liability to PD was causally associated with a decreased risk of irritable bowel syndrome (OR = 0.98; 95% CI: 0.96-0.99; P = 0.032). On the contrary, IVW analysis showed a potential positive correlation between genetically determined PD and the incidence of type 1 diabetes (OR = 1.10; 95%CI: 1.02-1.19; P = 0.010). Subsequent MR tests ended up in similar results, confirming our findings were reliable. Additionally, in the reverse MR analyses, we did not identify any evidence to support the causal relationship of genetic predisposition to AIDs with PD susceptibility.ConclusionIn general, a bifunctional role that PD exerted on the risk of developing AIDs was detected in our studies, both protecting against irritable bowel syndrome occurrence and raising the incidence of type 1 diabetes. Future studies, including population-based observational studies and molecular experiments in vitro and in vivo, are warranted to validate the results of our MR analyses and refine the underlying pathological mechanisms involved in PD-AIDs associations.

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Section: Discussionmentioning

confidence: 99%

Investigation of the causal association between Parkinson’s disease and autoimmune disorders: a bidirectional Mendelian randomization study

Yang,

Lin,

et al. 2024

Front. Immunol.

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“…While Tregs can have a suppressive effect on autoreactive T cells and prevent the development of autoimmune diseases, they may also exhibit functional defects in AD patients ( 53 ). These defects might limit their ability to effectively control immune responses, ultimately leading to the activation of autoreactive T cells that target pancreatic beta cells and contribute to the development of T1D ( 54 , 55 ). In addition, heightened production of pro-inflammatory cytokines generated by Th17 cells has demonstrated a positive correlation with the emergence of type 1 diabetes (T1D) ( 56 , 57 ).…”

Section: Discussionmentioning

confidence: 99%

Association of atopic dermatitis with autoimmune diseases: A bidirectional and multivariable two-sample mendelian randomization study

Zhou

Cai

et al. 2023

Front. Immunol.

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BackgroundObservational studies have suggested the association between atopic dermatitis (AD) and the risks of autoimmune diseases. It is still unclear, however, whether or in which direction causal relationships exist, because these associations could be confounded.ObjectivesOur study seeks to assess the possibility of AD as a cause of autoimmune diseases, and to estimate the magnitude of the causal effect.MethodsTwo-sample mendelian randomization (MR) analyses were performed using genome-wide association study (GWAS) summary-level statistics. Specifically, bidirectional MR analyses were conducted to examine the direction of association of AD with autoimmune diseases; multivariable MR analyses (MVMR1) were used to test the independence of causal association of AD with autoimmune diseases after controlling other atopic disorders (asthma and allergic rhinitis), while MVMR2 analyses were conducted to account for potential confounding factors such as smoking, drinking, and obesity. Genetic instruments for AD (Ncases=22 474) were from the latest GWAS meta-analysis. The GWAS summary data for asthma and allergic rhinitis were obtained from UK Biobank. The GWAS summary data for smoking, alcohol consumption, obesity and autoimmune diseases (alopecia areata, vitiligo, systemic lupus erythematosus, ankylosing spondylitis, rheumatoid arthritis, and type 1 diabetes) were selected from the largest GWASs available. Causal estimates were derived by the inverse-variance weighted method and verified through a series of sensitivity analyses.ResultsGenetically predicted AD linked to higher risks of rheumatoid arthritis (OR, 1.28; P=0.0068) (ORMVMR1, 1.65; P=0.0020) (ORMVMR2, 1.36; P<0.001), type 1 diabetes (OR, 1.37; P=0.0084) (ORMVMR1, 1.42; P=0.0155) (ORMVMR2, 1.45; P=0.002), and alopecia areata (OR, 1.98; P=0.0059) (ORMVMR1, 2.55; P<0.001) (ORMVMR2, 1.99; P=0.003) in both univariable and multivariable MR. These causal relationships were supported by sensitivity analyses. No causal effect of AD was identified in relation to systemic lupus erythematosus, vitiligo, and ankylosing spondylitis. Concerning the reverse directions, no significant association was noted.ConclusionThe results of this MR study provide evidence to support the idea that AD causes a greater risk of rheumatoid arthritis, type 1 diabetes and alopecia areata. Further replication in larger samples is needed to validate our findings, and experimental studies are needed to explore the underlying mechanisms of these causal effects.

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“…Clinical trials using Treg have shown improved but not as promising results as expected, with only a few clinical studies showing that higher levels of Tregs and IL2 appear to improve endogenous insulin secretion in T1D, and the exploration of insulinogenic-specific Tregs in the immune response of patients with T1DM needs to continue in-depth ( 34 – 37 ). Therefore, how to use Tregs to target the autoimmunity against islet β cells that occurs in T1D has become a hot topic in scientific research ( 38 , 39 ). In many studies using a mouse model of autoimmune diabetes, the use of IL-2 to modulate Treg was found to reduce interferon production by pancreatic infiltrating T cells, increase beta-cell numbers, and mitigate other immune therapies that interfere with Treg homeostasis and prevent disease ( 40 – 42 ).…”

Section: Tregs Cells In T1dmentioning

confidence: 99%

Mechanisms and therapeutic strategies of immune checkpoint molecules and regulators in type 1 diabetes

Ding

Yang²,

Lin³

et al. 2023

Front. Endocrinol.

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BackgroundConsidered a significant risk to health and survival, type 1 diabetes (T1D) is a heterogeneous autoimmune disease characterized by hyperglycemia caused by an absolute deficiency of insulin, which is mainly due to the immune-mediated destruction of pancreatic beta cells.Scope of reviewIn recent years, the role of immune checkpoints in the treatment of cancer has been increasingly recognized, but unfortunately, little attention has been paid to the significant role they play both in the development of secondary diabetes with immune checkpoint inhibitors and the treatment of T1D, such as cytotoxic T-lymphocyte antigen 4(CTLA-4), programmed cell death protein-1(PD-1), lymphocyte activation gene-3(LAG-3), programmed death ligand-1(PD-L1), and T-cell immunoglobulin mucin protein-3(TIM-3). Here, this review summarizes recent research on the role and mechanisms of diverse immune checkpoint molecules in mediating the development of T1D and their potential and theoretical basis for the prevention and treatment of diabetes.Major conclusionsImmune checkpoint inhibitors related diabetes, similar to T1D, are severe endocrine toxicity induced with immune checkpoint inhibitors. Interestingly, numerous treatment measures show excellent efficacy for T1D via regulating diverse immune checkpoint molecules, including co-inhibitory and co-stimulatory molecules. Thus, targeting immune checkpoint molecules may exhibit potential for T1D treatment and improve clinical outcomes.

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Potential Therapeutic Application of Regulatory T Cells in Diabetes Mellitus Type 1

Cited by 12 publications

References 91 publications

Investigation of the causal association between Parkinson’s disease and autoimmune disorders: a bidirectional Mendelian randomization study

Investigation of the causal association between Parkinson’s disease and autoimmune disorders: a bidirectional Mendelian randomization study

Association of atopic dermatitis with autoimmune diseases: A bidirectional and multivariable two-sample mendelian randomization study

Mechanisms and therapeutic strategies of immune checkpoint molecules and regulators in type 1 diabetes

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