Immunological pathways to β‐cell damage in Type 1 diabetes

Peakman, Mark

doi:10.1111/dme.12085

Cited by 30 publications

(37 citation statements)

References 62 publications

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“…All immune cell types of the innate and adaptive immune system might be involved in the pathogenesis of autoimmune diabetes [36][37][38]. This has been proposed for monocytes/macrophages, T cells and B cells [39][40][41][42].…”

Section: Discussionmentioning

confidence: 99%

Variable immune cell frequencies in peripheral blood of LEW.1AR1-iddmrats over time compared to other congenic LEW strains

Arndt

Jörns

Hedrich

et al. 2014

Clinical and Experimental Immunology

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SummaryThe LEW.1AR1-iddm rat is an animal model of human type 1 diabetes (T1D), which arose through a spontaneous mutation within the major histocompatibility complex (MHC)-congenic background strain LEW.1AR1. The LEW.1AR1-iddm rat is characterized by two phenotypes: diabetes development with a diabetes incidence of 60% and a variable T cell frequency in peripheral blood. In this study the immune cell repertoire of LEW.1AR1-iddm rats was analysed over time from days 30 to 90 of life and compared to the background strain LEW.1AR1 and the LEW rat strain as well as the LEW.1WR1 rat strain. The LEW.1AR1-iddm rats are characterized by a high variability of CD3 + , CD4 + and CD8 + T cell frequencies in peripheral blood over time, and the frequency is unique for each animal. The variability within the frequencies resulted in changes of the CD4 + : CD8 + T cell ratio. The other three rat strains studied were characterized by a stable but nevertheless strain-specific T cell frequency resulting in a specific CD4 + : CD8 + T cell ratio. The frequency of natural killer (NK) cells and B cells in LEW.1AR1-iddm rats was increased, with a higher variability compared to the other strains. Only monocytes showed no differences in frequency and variability between all strains studied. These variabilities of immune cell frequencies in the LEW.1AR1-iddm rats might lead to imbalances between autoreactive and regulatory T cells in peripheral blood as a prerequisite for diabetes development.

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Section: Discussionmentioning

confidence: 99%

Variable immune cell frequencies in peripheral blood of LEW.1AR1-iddmrats over time compared to other congenic LEW strains

Arndt

Jörns

Hedrich

et al. 2014

Clinical and Experimental Immunology

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“…This exposes the β cells to attack by the autoreactive CD8 + T cells with specificity for antigens in the pancreas [44]. Type 1 interferons also activate the dendritic cells (DCs) and promote the presentation of β cell antigens to T cells.…”

Section: Pathophysiologymentioning

confidence: 99%

Interplay between Type 1 Diabetes Mellitus and Celiac Disease: Implications in Treatment

Kaur

Bhadada

Minz

et al. 2018

Dig Dis

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Background: A complex interplay between genetic and environmental factors contributes to disease etiology of most of the autoimmune disorders. Type 1 diabetes mellitus (T1DM) and celiac disease (CD) are polygenic autoimmune diseases that have high propensity to coexist due to shared etiological factors like genetics and clinico-pathological overlaps. Summary: The mean prevalence rate for coexistence of these diseases is 8%, and this value is a gross underestimation as reported from biopsy-proven symptomatic cases. The prevalence rate will rise when studies will excavate bottom layers of the “celiac iceberg” to detect potential and silent celiac cases. The concomitant presence of both these disorders is a complex situation immunologically as well as clinically. There is an accentuated breakdown of tolerance and proinflammatory cytokine storm that leads to the progression of organ-specific autoimmunity to systemic. No immunomodulating drugs are advocated as exogenous insulin supplementation and gluten exclusion are recommended for T1DM and CD respectively. Nevertheless, these pose certain challenges to both the clinicians and the patients, as gluten free diet (GFD) has been described to have an impact on glycemic control, bone health, and vascular complications. Also intermittent gluten intake by these patients due to non-compliance with GFD also stimulates the autoreactive immune cells that result in an augmented immune response. Key Messages: Large public health studies are needed to estimate the prevalence of all forms of CD in T1DM patients. Strict global guidelines need to be formulated for the disease management and prognosis, and there is also a need for an extensive research on each front to thoroughly understand the co-occurrence of these diseases.

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“…T ype 1 diabetes (T1D) is an autoimmune disease characterized by autoreactive T cell-mediated destruction of the insulin-producing pancreatic b cells (1)(2)(3)(4). There is great interest in defining islet autoantigen-derived immunogenic epitopes that are recognized by CD4 T cells involved in autoimmune responses in T1D.…”

mentioning

confidence: 99%

Dendritic Cells Guide Islet Autoimmunity through a Restricted and Uniquely Processed Peptidome Presented by High-Risk HLA-DR

Lummel

Veelen

et al. 2016

The Journal of Immunology

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Identifying T cell epitopes of islet autoantigens is important for understanding type 1 diabetes (T1D) immunopathogenesis and to design immune monitoring and intervention strategies in relationship to disease progression. Naturally processed T cell epitopes have been discovered by elution from HLA-DR4 of pulsed B lymphocytes. The designated professional APC directing immune responses is the dendritic cell (DC). To identify naturally processed epitopes, monocyte-derived DC were pulsed with preproinsulin (PPI), glutamic acid decarboxylase (65-kDa isoform; GAD65), and insulinoma-associated Ag-2 (IA-2), and peptides were eluted of HLA-DR3 and -DR4, which are associated with highest risk for T1D development. Proteome analysis confirmed uptake and processing of islet Ags by DC. PPI peptides generated by DC differed from those processed by B lymphocytes; PPI signal-sequence peptides were eluted from HLA-DR4 and -DR3/4 that proved completely identical to a primary target epitope of diabetogenic HLA-A2–restricted CD8 T cells. HLA-DR4 binding was confirmed. GAD65 peptides, eluted from HLA-DR3 and -DR4, encompassed two core regions overlapping the two most immunodominant and frequently studied CD4 T cell targets. GAD65 peptides bound to HLA-DR3. Strikingly, the IA-2 ligandome of HLA-DR was exclusively generated from the extracellular part of IA-2, whereas most previous immune studies have focused on intracellular IA-2 epitopes. The newly identified IA-2 peptides bound to HLA-DR3 and -DR4. Differential T cell responses were detected against the newly identified IA-2 epitopes in blood from T1D patients. The core regions to which DC may draw attention from autoreactive T cells are largely distinct and more restricted than are those of B cells. GAD65 peptides presented by DC focus on highly immunogenic T cell targets, whereas HLA-DR–binding peptides derived from IA-2 are distinct from the target regions of IA-2 autoantibodies.

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Immunological pathways to β‐cell damage in Type 1 diabetes

Cited by 30 publications

References 62 publications

Variable immune cell frequencies in peripheral blood of LEW.1AR1-iddmrats over time compared to other congenic LEW strains

Variable immune cell frequencies in peripheral blood of LEW.1AR1-iddmrats over time compared to other congenic LEW strains

Interplay between Type 1 Diabetes Mellitus and Celiac Disease: Implications in Treatment

Dendritic Cells Guide Islet Autoimmunity through a Restricted and Uniquely Processed Peptidome Presented by High-Risk HLA-DR

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