Decreased dendritic cell numbers but increased TLR9-mediated interferon-alpha production in first degree relatives of type 1 diabetes patients

Kayserová, Jana; Včeláková, Jana; Stechova, Katerina; Dudkova, Eva; Hromadkova, Hana; Šumnı́k, Zdenĕk; Koloušková, Stanislava; Špíšek, Radek; Šedivá, Anna

doi:10.1016/j.clim.2014.03.018

Cited by 18 publications

(15 citation statements)

References 35 publications

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“…Both T1D subjects and their family members have quantitatively fewer peripheral dendritic cells than healthy controls; however, the peripheral dendritic cells of high-risk T1D relatives produce more IFNα in response to TLR9 stimulation than controls (98). Further, the PBMCs of children with T1D and their first degree relatives express higher spontaneous and mitogen-stimulated levels of TNF-α and IFN-γ, both β-cell toxic cytokines (93).…”

Section: Evidence Of An Underlying Innate Inflammatory State Associatmentioning

confidence: 99%

Innate inflammation in type 1 diabetes

Cabrera

Henschel

Hessner

2016

Translational Research

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Type 1 diabetes mellitus (T1D) is an autoimmune disease often diagnosed in childhood that results in pancreatic β-cell destruction and life-long insulin dependence. T1D susceptibility involves a complex interplay of genetic and environmental factors and has historically been attributed to adaptive immunity, though there is now increasing evidence for a role of innate inflammation. Here, we review studies that define a heightened age-dependent innate inflammatory state in T1D families that is paralleled with high fidelity by the T1D-susceptible BioBreeding rat. Innate inflammation may be driven by changes in interactions between the host and environment, such as through an altered microbiome, intestinal hyper-permeability, or viral exposures. Special focus is placed on the temporal measurement of plasma induced transcriptional signatures of recent onset T1D patients and their siblings as well as in the Biobreeding rat as it defines the natural history of innate inflammation. These sensitive and comprehensive analyses have also revealed that those who successfully managed T1D risk develop an age-dependent immunoregulatory state, providing a possible mechanism for the juvenile nature of T1D. Therapeutic targeting of innate inflammation has been proven effective in preventing and delaying T1D in rat models. Clinical trials of agents that suppress innate inflammation have had more modest success, but efficacy is improved by the addition of combinatorial approaches that target other aspects of T1D pathogenesis. An understanding of innate inflammation and mechanisms by which this susceptibility is both potentiated and mitigated offers important insight into T1D progression and avenues for therapeutic intervention.

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Section: Evidence Of An Underlying Innate Inflammatory State Associatmentioning

confidence: 99%

Innate inflammation in type 1 diabetes

Cabrera

Henschel

Hessner

2016

Translational Research

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“…Zhang et al (2010) found that TLR9 −/− NOD mice expressed lower levels of IFN-α in PLNs and reduced frequencies of diabetogenic CD8 + T cells, both of which may contribute to diabetes protection seen in TLR9 −/− NOD mice [88]. A recent human study by Kayserova et al (2014) analyzed the frequency of myeloid (mDCs) and pDCs in 97 T1D patients (69 new onset, 28 long-term diabetic patients), 67 first-degree relatives, and 64 controls in the Czech Republic [89]. The authors observed a lower number of mDCs and pDCs in patients with T1D and their first-degree relatives.…”

Section: Tlrs and T1dmentioning

confidence: 99%

“…The authors observed a lower number of mDCs and pDCs in patients with T1D and their first-degree relatives. Of all the tested TLR ligands, only stimulation with CpG 2216 induced IFN-α production and the highest level was found in the first-degree relatives of patients with T1D who were positive for islet autoantibodies [89]. However, it is likely that other mechanisms are also involved in diabetes protection in addition to reduction in IFN-α in TLR9 −/− NOD mice.…”

Section: Tlrs and T1dmentioning

confidence: 99%

The role of the innate immune system in destruction of pancreatic beta cells in NOD mice and humans with type I diabetes

Tai

Wong

2016

Journal of Autoimmunity

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Type 1 diabetes (T1D) is an organ-specific autoimmune disease characterized by T cell-mediated destruction of the insulin-producing pancreatic β cells. A combination of genetic and environmental factors eventually leads to the loss of functional β cells mass and hyperglycemia. Both innate and adaptive immunity are involved in the development of T1D. In this review, we have highlighted the most recent findings on the role of innate immunity, especially the pattern recognition receptors (PRRs), in disease development. In murine models and human studies, different PRRs, such as toll-like receptors (TLRs) and nucleotide-binding domain, leucine-rich repeat-containing (or NOD-like) receptors (NLRs), have different roles in the pathogenesis of T1D. These PRRs play a critical role in defending against infection by sensing specific ligands derived from exogenous microorganisms to induce innate immune responses and shape adaptive immunity. Animal studies have shown that TLR7, TLR9, MyD88 and NLPR3 play a disease-predisposing role in T1D, while controversial results have been found with other PRRs, such as TLR2, TLR3, TLR4, TLR5 and others. Human studies also shown that TLR2, TLR3 and TLR4 are expressed in either islet β cells or infiltrated immune cells, indicating the innate immunity plays a role in β cell autoimmunity. Furthermore, some human genetic studies showed a possible association of TLR3, TLR7, TLR8 or NLRP3 genes, at single nucleotide polymorphism (SNP) level, with human T1D. Increasing evidence suggest that the innate immunity modulates β cell autoimmunity. Thus, targeting pathways of innate immunity may provide novel therapeutic strategies to fight this disease.

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“…Furthermore, compared with controls, leucocytes from diabetic patients and their family members exhibit elevated responsiveness, as evidenced by the liberation of higher levels of IL-1 upon mitogen stimulation in vitro [84–87]. Both type 1 diabetic patients and their family members have quantitatively fewer peripheral dendritic cells than healthy controls, but produce more IFNα in response to Toll-like receptor-9 stimulation than controls [88]. Furthermore, global serum-based proteomic analysis of type 1 diabetic patients and unrelated healthy controls has provided corroborating evidence of an innate inflammatory state associated with autoimmune diabetes [89].…”

Section: Blood-based Signaturesmentioning

confidence: 99%

Blood-based signatures in type 1 diabetes

et al. 2015

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Type 1 diabetes mellitus is one of the most common chronic diseases in childhood. It develops through autoimmune destruction of the pancreatic beta cells and results in lifelong dependence on exogenous insulin. The pathogenesis of type 1 diabetes involves a complex interplay of genetic and environmental factors and has historically been attributed to aberrant adaptive immunity; however, there is increasing evidence for a role of innate inflammation. Over the past decade new methodologies for the analysis of nucleic acid and protein signals have been applied to type 1 diabetes. These studies are providing a new understanding of type 1 diabetes pathogenesis and have the potential to inform the development of new biomarkers for predicting diabetes onset and monitoring therapeutic interventions. In this review we will focus on blood-based signatures in type 1 diabetes, with special attention to both direct transcriptomic analyses of whole blood and immunocyte subsets, as well as plasma/serum-induced transcriptional signatures. Attention will also be given to proteomics, microRNA assays and markers of beta cell death. We will also discuss the results of blood-based profiling in type 1 diabetes within the context of the genetic and environmental factors implicated in the natural history of autoimmune diabetes.

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Decreased dendritic cell numbers but increased TLR9-mediated interferon-alpha production in first degree relatives of type 1 diabetes patients

Cited by 18 publications

References 35 publications

Innate inflammation in type 1 diabetes

Innate inflammation in type 1 diabetes

The role of the innate immune system in destruction of pancreatic beta cells in NOD mice and humans with type I diabetes

Blood-based signatures in type 1 diabetes

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