Self-Antigens Targeted by Regulatory T Cells in Type 1 Diabetes

Mitchell, Angela M.; Michels, Aaron

doi:10.3390/ijms23063155

Cited by 9 publications

(6 citation statements)

References 100 publications

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“…Specific deletion of Foxp3 + -induced Tregs completely abolished oral tolerance, and therefore, CD4 + CD25 + Foxp3 + Tregs contribute a lot to maintaining peripheral immune tolerance, and they are mandatory for induction of oral tolerance (Wing & Sakaguchi, 2010 ; Hadis et al., 2011 ). Therapeutic strategies which might expand Tregs in an antigen-dependent fashion may offer exciting avenues to induce tolerance in T1DM (Mitchell & Michels, 2022 ). Here, we observed that oral administration of the bivalent BLPs vaccines significantly increased the frequency of Tregs in PLNs compared to the monovalent BLPs vaccines treatment ( Figure 9 ).…”

Section: Discussionmentioning

confidence: 99%

Oral delivery of bi-autoantigens by bacterium-like particles (BLPs) against autoimmune diabetes in NOD mice

et al. 2023

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Induction of oral tolerance by vaccination with type 1 diabetes mellitus (T1DM)-associated autoantigens exhibits great potential in preventing and treating this autoimmune disease. However, antigen degradation in the gastrointestinal tract (GIT) limits the delivery efficiency of oral antigens. Previously, bacterium-like particles (BLPs) have been used to deliver a single-chain insulin (SCI-59) analog (BLPs-SCI-59) or the intracellular domain of insulinoma-associated protein 2 (IA-2ic) (BLPs-IA-2ic). Both monovalent BLPs vaccines can suppress T1DM in NOD mice by stimulating the corresponding antigen-specific oral tolerance, respectively. Here, we constructed two bivalent BLPs vaccines which simultaneously deliver SCI-59 and IA-2ic (Bivalent vaccine-mix or Bivalent vaccine-SA), and evaluated whether there is an additive beneficial effect on tolerance induction and suppression of T1DM by treatment with BLPs-delivered bi-autoantigens. Compared to the monovalent BLPs vaccines, oral administration of the Bivalent vaccine-mix could significantly reduce morbidity and mortality in T1DM. Treatment with the bivalent BLPs vaccines (especially Bivalent vaccine-mix) endowed the mice with a stronger ability to regulate blood glucose and protect the integrity and function of pancreatic islets than the monovalent BLPs vaccines treatment. This additive effect of BLPs-delivered bi-autoantigens on T1DM prevention may be related to that SCI-59- and IA-2-specific Th2-like immune responses could be induced, which was more beneficial for the correction of Th1/Th2 imbalance. In addition, more CD4 + CD25 + Foxp3 + regulatory T cells (Tregs) were induced by treatment with the bivalent BLPs vaccines than did the monovalent BLPs vaccines. Therefore, multiple autoantigens delivered by BLPs maybe a promising strategy to prevent T1DM by efficiently inducing antigen-specific immune tolerance.

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Section: Discussionmentioning

confidence: 99%

Oral delivery of bi-autoantigens by bacterium-like particles (BLPs) against autoimmune diabetes in NOD mice

et al. 2023

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“…Regulatory CD4+ T cells (Tregs) act as protectors against T1DM, recognizing antigens such as insulin or pancreatic islet peptides, presented in the context of HLA-DQ6 or DR15, which are protective haplotypes against diabetes ( 63 ). This interaction generates the production of anti-inflammatory cytokines, such as IL-10 and TGF-β and this activation of antigen-specific Tregs protects β-cells from destruction through four mechanisms: i) Damage to cells occurs when CD4+ T cell effectors recognize antigens of islet cells presented by APCs, in the HLA-DQ8 or DR4 context, which is a risk for T1DM, and are activated and migrate to the pancreas, where they induce β-cell destruction ( 64 ).…”

Section: Pathogenesis Of T1dmmentioning

confidence: 99%

“…iii) Tregs can reduce antigen-independent granzyme-mediated APC death. iv) Alternatively, Tregs can induce antigen-dependent APC death when the antigen is presented to the T cell receptor (TCR) of Tregs ( 63 ).…”

Section: Pathogenesis Of T1dmmentioning

confidence: 99%

Viruses as a potential environmental trigger of type 1 diabetes mellitus (Review)

Alves Abrantes,

Veríssimo de Azevedo,

Fernandes

et al. 2024

Biomed Rep

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The etiopathogenesis of type 1 diabetes mellitus (T1DM) is a complex multifactorial process that involves an intricate network of genetic, epigenetic, immunological, and environmental factors. Despite the advances in recent years, some aspects of the mechanisms involved in triggering the disease are still unclear. Infections with certain viruses have been suggested as possible environmental triggers for the autoimmune process that leads to selective and progressive destruction of pancreatic β-cells and insufficiency of insulin production, which is its hallmark. In this review, advances in knowledge and evidence that suggest the participation of certain viruses in the mechanisms of disease initiation and progression are described. It has been accepted that environmental factors, including viruses, can initiate and possibly sustain, accelerate, or slow down the autoimmune process and consequently damage insulin-producing pancreatic β-cells. Although the role of these agents, especially human enteroviruses, has been exhaustively studied as the most likely triggers of the activation of autoimmunity that destroys pancreatic islets and leads to T1DM, certain doubts remain. Clinical epidemiological and experimental studies in humans and animals provide consistent and increasing evidence that persistent viral infections, especially with human enteroviruses and rotavirus infections, are associated with an increased risk of the disease in individuals genetically predisposed to autoimmunity.

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“…Tregs may also play a role in the protection toward T1D development [157]. The protective (DQ6) T1D MHC-II molecules prevent the binding of islet-specific antigens to predisposing (DQ8) MHC-II molecules by engaging epitopes in different binding registers [158].…”

Section: The Role Of Protective Mhc-ii Alleles In the Development Of ...mentioning

confidence: 99%

MHC Class II Presentation in Autoimmunity

Ishina

Захарова

Kurbatskaia

et al. 2023

Cells

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Antigen presentation by major histocompatibility complex class II (MHC-II) molecules is crucial for eliciting an efficient immune response by CD4+ T cells and maintaining self-antigen tolerance. Some MHC-II alleles are known to be positively or negatively associated with the risk of the development of different autoimmune diseases (ADs), including those characterized by the emergence of autoreactive T cells. Apparently, the MHC-II presentation of self-antigens contributes to the autoimmune T cell response, initiated through a breakdown of central tolerance to self-antigens in the thymus. The appearance of autoreactive T cell might be the result of (i) the unusual interaction between T cell receptors (TCRs) and self-antigens presented on MHC-II; (ii) the posttranslational modifications (PTMs) of self-antigens; (iii) direct loading of the self-antigen to classical MHC-II without additional nonclassical MHC assistance; (iv) the proinflammatory environment effect on MHC-II expression and antigen presentation; and (v) molecular mimicry between foreign and self-antigens. The peculiarities of the processes involved in the MHC-II-mediated presentation may have crucial importance in the elucidation of the mechanisms of triggering and developing ADs as well as for clarification on the protective effect of MHC-II alleles that are negatively associated with ADs.

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Self-Antigens Targeted by Regulatory T Cells in Type 1 Diabetes

Cited by 9 publications

References 100 publications

Oral delivery of bi-autoantigens by bacterium-like particles (BLPs) against autoimmune diabetes in NOD mice

Oral delivery of bi-autoantigens by bacterium-like particles (BLPs) against autoimmune diabetes in NOD mice

Viruses as a potential environmental trigger of type 1 diabetes mellitus (Review)

MHC Class II Presentation in Autoimmunity

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