High levels of blood circulating immune checkpoint molecules in children with new-onset type 1 diabetes are associated with the risk of developing an additional autoimmune disease

Bruzzaniti, Sara; Piemonte, Erica; Mozzillo, Enza; Bruzzese, Dario; Lepore, Maria Teresa; Carbone, Fortunata; Candia, Paola de; Strollo, Rocky; Porcellini, Antonio; Marigliano, Marco; Maffeis, Claudio; Bifulco, Maurizio; Ludvigsson, Johnny; Franzese, Adriana; Matarese, Giuseppe; Galgani, Mario

doi:10.1007/s00125-022-05724-3

Cited by 3 publications

(1 citation statement)

References 17 publications

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“…Immune checkpoint molecules perform as a strong immune regulator of self-tolerance and autoimmunity and regulate the response of various immune cells, including T cells, natural killer cells, dendritic cells, innate lymphoid cells, macrophages, and myeloid cells, and specific immune checkpoint mechanisms also participate in pathological processes of T1D ( 99 – 101 ). A recent cohort study also showed that higher levels of circulating immune checkpoint molecules, especially CD137/4-1BB and PD-1, may serve as prognostic biomarkers for new-onsets T1D and risk factors for the growth of an additional autoimmune disease ( 102 ). Considering the above characteristics, what follows in the passage reviews the possible therapeutic implications in T1D via regulating immune checkpoint molecules ( Figure 3 ), including co-inhibitory molecules ( Table 1 ) and co-stimulatory molecules ( Table 2 ), especially CTLA-4, PD-1, LAG3, and TIGIT, which seems to be considered as pivotal regulatory molecules with excellent clinical application value.…”

Section: Potential Clinical Application Of Immune Checkpoint Molecule...mentioning

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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Section: Potential Clinical Application Of Immune Checkpoint Molecule...mentioning

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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Progression of type 1 diabetes is associated with high levels of soluble PD-1 in islet autoantibody-positive children

Bruzzaniti,

Piemonte,

Bruzzese

et al. 2024

Diabetologia

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Aims/hypothesis Type 1 diabetes is an autoimmune disorder that is characterised by destruction of pancreatic beta cells by autoreactive T lymphocytes. Although islet autoantibodies (AAb) are an indicator of disease progression, specific immune biomarkers that can be used as target molecules to halt development of type 1 diabetes have not been discovered. Soluble immune checkpoint molecules (sICM) play a pivotal role in counteracting excessive lymphocyte responses, but their role in type 1 diabetes is unexplored. In this longitudinal study, we measured sICM levels in AAb-positive (AAb+) children to identify molecules related to type 1 diabetes progression. Methods We measured the levels of 14 sICM in the sera of AAb+ children (n=57) compared to those with recent-onset type 1 diabetes (n=79) and healthy children (n=44), obtained from two cohorts. AAb+ children were followed up and divided based on their progression to type 1 diabetes (AAbP) or not (AAbNP) (if they lost islet autoimmunity and did not develop disease in subsequent years). sICM were also measured in the sample taken at the visit closest to disease onset in AAbP children. Results We found that AAb+ children had a distinct sICM profile compared with healthy children and those with recent-onset type 1 diabetes. In addition, AAb+ children who progressed to type 1 diabetes (AAbP) had higher sICM concentrations than non-progressors (AAbNP). Further, sICM levels decreased in AAbP children close to disease onset. Application of Cox regression models highlighted that high concentrations of soluble programmed cell death protein 1 (sPD-1) are associated with type 1 diabetes progression (HR 1.71; 95% CI 1.16, 2.51; p=0.007). Conclusions/interpretation This study reveals an sICM profile that is dysregulated during the preclinical stage of type 1 diabetes, and identifies sPD-1 as a pathophysiologically-relevant molecule that is associated with disease progression, offering a potential target for early interventions in autoimmune diabetes. Graphical Abstract

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Soluble Immune Checkpoints Associated With Disease Activity and Treatment Response in GD and TED

Yin,

Zhu,

Song

et al. 2024

The Journal of Clinical Endocrinology &Amp; Metabolism

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Context Soluble immune checkpoints play an important role in peripheral tolerance that has seldom been investigated in Graves’ disease (GD) and thyroid eye disease (TED). Objective The objective of this work is to examine the alteration of soluble immune checkpoints in GD and TED. Methods We performed a quantitative multiplex analysis of 17 immune checkpoint proteins in serum from 50 GD patients without TED, 28 GD patients with TED and 40 healthy controls. The association with demographical, serological, clinical features and 27 cytokines was analyzed. A follow-up was conducted in GD patients without TED. Functional outcomes of sLAG-3 and sGITR were assessed in cell cultures using rh-LAG3, rh-GITR, an antagonistic LAG-3 antibody and an antagonistic GITR antibody. Results GD patients with TED had distinct sICP and cytokine profiles compared with GD patients without TED. Active TED patients exhibited elevation in the levels of sBTLA, sLAG-3, sGITR, sCD80, sCD86 and sPD-L1. Further, GD patients without TED with high sBTLA, sCD27 and sCD40 levels at baseline showed a better improvement in thyrotropin receptor antibody (TRAb) titers after antithyroid drug (ATD) treatment. Adding recombinant human GITR and LAG-3 to PBMC cultures resulted in increased inflammatory cytokine secretion and decreased anti-inflammatory cytokine secretion. Conclusions The present study uncovers disturbed soluble immune checkpoints and cytokines in GD patients with and without TED, and may pave the way for novel immunological screening, allowing for identification of TED patients at higher risk of developing active disease and GD patients with better treatment response after ATD treatment.

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High levels of blood circulating immune checkpoint molecules in children with new-onset type 1 diabetes are associated with the risk of developing an additional autoimmune disease

Cited by 3 publications

References 17 publications

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

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

Progression of type 1 diabetes is associated with high levels of soluble PD-1 in islet autoantibody-positive children

Soluble Immune Checkpoints Associated With Disease Activity and Treatment Response in GD and TED

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