Revisiting the notion of type 1 diabetes being a T-cell-mediated autoimmune disease

Skog, Oskar; Korsgren, Stella; Melhus, Åsa; Korsgren, Olle

doi:10.1097/med.0b013e32835edb89

Cited by 60 publications

(50 citation statements)

References 37 publications

(20 reference statements)

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“…Although predicted, these CD4 + T cells have never been isolated from human islets, leaving a crucial piece missing from the chain of autoimmune causation in T1D. This gap in our knowledge has led some to question about the autoimmune basis of human T1D (18,19).…”

Section: Type 1 Diabetes (T1d) Is An Autoimmune Disease Caused By Thementioning

confidence: 99%

Proinsulin-Specific, HLA-DQ8, and HLA-DQ8-Transdimer–Restricted CD4+ T Cells Infiltrate Islets in Type 1 Diabetes

et al. 2014

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Type 1 diabetes (T1D) develops when insulin-secreting b-cells, found in the pancreatic islets of Langerhans, are destroyed by infiltrating T cells. How human T cells recognize b-cell-derived antigens remains unclear. Genetic studies have shown that HLA and insulin alleles are the most strongly associated with risk of T1D. These longstanding observations implicate CD4 + T-cell responses against (pro)insulin in the pathogenesis of T1D. To dissect the autoimmune T-cell response against human b-cells, we isolated and characterized 53 CD4 + T-cell clones from within the residual pancreatic islets of a deceased organ donor who had T1D. These 53 clones expressed 47 unique clonotypes, 8 of which encoded proinsulin-specific T-cell receptors. On an individual clone basis, 14 of 53 CD4 + T-cell clones (26%) recognized 6 distinct but overlapping epitopes in the C-peptide of proinsulin. These clones recognized C-peptide epitopes presented by HLA-DQ8 and, notably, HLA-DQ8 transdimers that form in HLA-DQ2/-DQ8 heterozygous individuals. Responses to these epitopes were detected in the peripheral blood mononuclear cells of some people with recent-onset T1D but not in HLAmatched control subjects. Hence, proinsulin-specific, HLA-DQ8, and HLA-DQ8-transdimer-restricted CD4 + T cells are strongly implicated in the autoimmune pathogenesis of human T1D.Type 1 diabetes (T1D) is an autoimmune disease caused by the CD4 + and CD8 + T-cell-mediated destruction of pancreatic insulin-producing b-cells (1). b-Cell destruction leads to primary insulin deficiency, which is treated by exogenous insulin therapy, and currently there is no cure. The pathogenesis of T1D has been well characterized using the NOD mouse model, but the immune basis of T1D in humans is less clear.Genetic association studies have provided powerful insights into the etiology of human T1D (2,3). The HLA class II region has the strongest impact on risk of T1D. Some HLA alleles-DQB1*06:02 for example-dominantly protect against T1D (4). In contrast, of all alleles, HLA-DQ2

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Section: Type 1 Diabetes (T1d) Is An Autoimmune Disease Caused By Thementioning

confidence: 99%

Proinsulin-Specific, HLA-DQ8, and HLA-DQ8-Transdimer–Restricted CD4+ T Cells Infiltrate Islets in Type 1 Diabetes

et al. 2014

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“…This picture is complicated by background infiltration in the exocrine pancreas, partly due to peri-mortem changes, with the highest levels of infiltration observed in young patients after prolonged life support [5]. Even independently of postmortem changes, type 1 diabetes affects the exocrine as well as the endocrine pancreas [6]; this raises the question whether the limited infiltration of leucocytes is specifically targeted to pancreatic beta cells. Moreover, this limited degree of cellular infiltration in human autopsy samples is in striking contrast to NOD mice, which display massive leucocyte infiltration, reflecting the well-documented immune-mediated destruction of the beta cells in this animal model.…”

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confidence: 99%

What is the role of autoimmunity in type 1 diabetes? A clinical perspective

2014

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Despite tremendous research efforts, type 1 diabetes is one of the few remaining autoimmune diseases without any approved immunological treatment. This observation compels us to reconsider the role of autoimmunity in the pathogenesis of this disease. In this commentary, we will review solely human data in an attempt to appreciate, in an unbiased manner, the importance and relevance of the immunological alterations in patients with type 1 diabetes. The aim of this paper is to generate reflection on this topic, rather than a controversy.

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“…Activation of the innate immune response in the islets of Langerhans has been suggested to be an important step in the development of type 1 diabetes (T1D) (1)(2)(3). In particular, viral infection of the b-cells leading to the production of type I interferon (IFN) and induction of several hundred IFN-stimulated genes (ISGs) has been suggested (4)(5)(6).…”

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confidence: 99%

Expression of Interferon-Stimulated Genes in Insulitic Pancreatic Islets of Patients Recently Diagnosed With Type 1 Diabetes

et al. 2016

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A primary insult to the pancreatic islets of Langerhans, leading to the activation of innate immunity, has been suggested as an important step in the inflammatory process in type 1 diabetes (T1D). The aim of this study was to examine whether interferon (IFN)-stimulated genes (ISGs) are overexpressed in human T1D islets affected with insulitis. By using laser capture microdissection and a quantitative PCR array, 23 of 84 examined ISGs were found to be overexpressed by at least fivefold in insulitic islets from living patients with recent-onset T1D, participating in the Diabetes Virus Detection (DiViD) study, compared with islets from organ donors without diabetes. Most of the overexpressed ISGs, including GBP1, TLR3, OAS1, EIF2AK2, HLA-E, IFI6, and STAT1, showed higher expression in the islet core compared with the peri-islet area containing the surrounding immune cells. In contrast, the T-cell attractant chemokine CXCL10 showed an almost 10-fold higher expression in the peri-islet area than in the islet, possibly partly explaining the localization of T cells mainly to this region. In conclusion, insulitic islets from recent-onset T1D subjects show overexpression of ISGs, with an expression pattern similar to that seen in islets infected with virus or exposed to IFN-γ/interleukin-1β or IFN-α.

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Revisiting the notion of type 1 diabetes being a T-cell-mediated autoimmune disease

Cited by 60 publications

References 37 publications

Proinsulin-Specific, HLA-DQ8, and HLA-DQ8-Transdimer–Restricted CD4+ T Cells Infiltrate Islets in Type 1 Diabetes

Proinsulin-Specific, HLA-DQ8, and HLA-DQ8-Transdimer–Restricted CD4+ T Cells Infiltrate Islets in Type 1 Diabetes

What is the role of autoimmunity in type 1 diabetes? A clinical perspective

Expression of Interferon-Stimulated Genes in Insulitic Pancreatic Islets of Patients Recently Diagnosed With Type 1 Diabetes

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