Circulating β cell-specific CD8+ T cells restricted by high-risk HLA class I molecules show antigen experience in children with and at risk of type 1 diabetes

Yeo, Lorraine; Pujol‐Autonell, Irma; Baptista, Roman; Eichmann, Martin; Kronenberg‐Versteeg, Deborah; Heck, Susanne; Dolton, Garry; Sewell, Andrew K.; Härkönen, Taina; Mikk, Mari‐Liis; Toppari, Jorma; Veijola, Riitta; Knip, Mikael; Ilonen, Jorma; Peakman, Mark

doi:10.1111/cei.13391

Cited by 28 publications

(19 citation statements)

References 98 publications

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“…This finding is consistent with previous studies stipulating that the HLA locus is the strongest risk allele in the development of IBM 10 . HLA alleles are known to be associated with a variety of autoimmune diseases, such as systemic lupus erythematosus (SLE), 11 type 1 diabetes mellitus 12 and rheumatoid arthritis(RA) 13 . The genes products in this region play a fundamental role in the immune response.…”

Section: Discussionsupporting

confidence: 92%

Bioinformatics analysis of gene expression profiles of Inclusion body myositis

2020

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Inclusion body myositis (IBM) is a disease with a poor prognosis and limited treatment options. This study aimed at exploring gene expression profile alterations, investigating the underlying mechanisms and identifying novel targets for IBM. We analysed two microarray datasets (GSE39454 and GSE128470) derived from the Gene Expression Omnibus (GEO) database. The GEO2R tool was used to screen out differentially expressed genes (DEGs) between IBM and normal samples. Gene Ontology(GO)function and Kyoto Encyclopedia of Genes and Genomes(KEGG)pathway enrichment analysis were performed using the Database for Annotation, Visualization and Integrated Discovery to identify the pathways and functional annotation of DEGs. Finally, protein-protein interaction (PPI) networks were constructed using STRING and Cytoscape, in order to identify hub genes. A total of 144 upregulated DEGs and one downregulated DEG were iden-

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Section: Discussionsupporting

confidence: 92%

Bioinformatics analysis of gene expression profiles of Inclusion body myositis

2020

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“…Interestingly, in recent onset cases, different islets harbored different reactivities, which could reflect different stages of the autoimmune process. More recently, a high proportion of preproinsulin (PPI) specific cells have been detected in the islets of donors with T1D (17,18), confirming previous data obtained from blood samples and highlighting the role of PPI as one of the most prominent antigens in disease pathogenesis (15,(19)(20)(21)(22). Attempts to detect neoantigens in situ have not been reported so far but are on the horizon.…”

Section: The Evolving Understanding Of the Pathogenesis Of Human T1dsupporting

confidence: 77%

“…In addition, their potential role in sustaining the effector functions of CD8+ T-cells should not be neglected (14). Both CD4+ and CD8+ Tcell populations decline with beta-cell loss, suggesting that their presence is driven by a beta-cell antigen (11,12,15). However, the exact role infiltrating T-cells play in the pathogenesis of the disease remains to be determined both in terms of specificity and function.…”

Section: The Evolving Understanding Of the Pathogenesis Of Human T1dmentioning

confidence: 99%

Neoepitopes in Type 1 Diabetes: Etiological Insights, Biomarkers and Therapeutic Targets

et al. 2021

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The mechanisms underlying type 1 diabetes (T1D) pathogenesis remain largely unknown. While autoantibodies to pancreatic beta-cell antigens are often the first biological response and thereby a useful biomarker for identifying individuals in early stages of T1D, their role in T1D pathogenesis is not well understood. Recognition of these antigenic targets by autoreactive T-cells plays a pathological role in T1D development. Recently, several beta-cell neoantigens have been described, indicating that both neoantigens and known T1D antigens escape central or peripheral tolerance. Several questions regarding the mechanisms by which tolerance is broken in T1D remain unanswered. Further delineating the timing and nature of antigenic responses could allow their use as biomarkers to improve staging, as targets for therapeutic intervention, and lead to a better understanding of the mechanisms leading to loss of tolerance. Multiple factors that contribute to cellular stress may result in the generation of beta-cell derived neoepitopes and contribute to autoimmunity. Understanding the cellular mechanisms that induce beta-cells to produce neoantigens has direct implications on development of therapies to intercept T1D disease progression. In this perspective, we will discuss evidence for the role of neoantigens in the pathogenesis of T1D, including antigenic responses and cellular mechanisms. We will additionally discuss the pathways leading to neoepitope formation and the cross talk between the immune system and the beta-cells in this regard. Ultimately, delineating the timing of neoepitope generation in T1D pathogenesis will determine their role as biomarkers as well as therapeutic targets.

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“…On the other hand, other studies demonstrated no significant differences between T1D and control individuals in the frequencies of circulating CD8 T cells reactive to multiple A*02:01-restricted beta-cell epitopes (PPI 14 (3,4,6,10). However, beta cell-specific CD8 T cells are more differentiated in patients with newly diagnosed T1D compared to healthy controls (6), and memory T cell subsets were enriched within PPI 5-12 -specific CD8 T cell populations in HLA-B*39:06 + children with newly diagnosed T1D, but not in healthy control subjects (10). Overall, these studies suggest that phenotypic subset analysis of such circulating autoreactive T cells could help to identify patients with T1D.…”

Section: Mini-review What Distinguishes T1d Patients From Healthy Indmentioning

confidence: 95%

New Insights Into the Role of Autoreactive CD8 T Cells and Cytokines in Human Type 1 Diabetes

2021

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Since the establishment of the network for pancreatic organ donors with diabetes (nPOD), we have gained unprecedented insight into the pathology of human type 1 diabetes. Many of the pre-existing “dogmas”, mostly derived from studies of animal models and sometimes limited human samples, have to be revised now. For example, we have learned that autoreactive CD8 T cells are present even in healthy individuals within the exocrine pancreas. Furthermore, their “attraction” to islets probably relies on beta-cell intrinsic events, such as the over-expression of MHC class I and resulting presentation of autoantigens such as (prepro)insulin. In addition, we are discovering other signs of beta-cell dysfunction, possibly at least in part due to stress, such as the over-expression of certain cytokines. This review summarizes the latest developments focusing on cytokines and autoreactive CD8 T cells in human type 1 diabetes pathogenesis.

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Circulating β cell-specific CD8+ T cells restricted by high-risk HLA class I molecules show antigen experience in children with and at risk of type 1 diabetes

Cited by 28 publications

References 98 publications

Bioinformatics analysis of gene expression profiles of Inclusion body myositis

Bioinformatics analysis of gene expression profiles of Inclusion body myositis

Neoepitopes in Type 1 Diabetes: Etiological Insights, Biomarkers and Therapeutic Targets

New Insights Into the Role of Autoreactive CD8 T Cells and Cytokines in Human Type 1 Diabetes

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