Increased IFN-α–Producing Plasmacytoid Dendritic Cells (pDCs) in Human Th1-Mediated Type 1 Diabetes: pDCs Augment Th1 Responses through IFN-α Production

Xia, Chang; Peng, Ruihua; Chernatynskaya, Anna; Yuan, Ling; Carter, Carolyn; Valentine, John F.; Sobel, Eric S.; Atkinson, Mark A.; Clare‐Salzler, Michael

doi:10.4049/jimmunol.1303230

Cited by 56 publications

(52 citation statements)

References 70 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We also observed increased proportion of CD11b + CD11c + DCs on day 10 in spleens of MLDSTZ mice (Figure C). Next, we examined the proportion of pDCs (CD11b − CD11c + B220 + PDCA‐1 + cells) as it has been reported that these cells are up‐regulated in the early development of T1D in both NOD mice and T1D patients . Indeed, we found that the proportions of pDCs were increased on day 3 in PDLNs of MLDSTZ, (Figure D).…”

Section: Resultsmentioning

confidence: 77%

Kinetics of immune cell responses in the multiple low‐dose streptozotocin mouse model of type 1 diabetes

et al. 2019

View full text Add to dashboard Cite

In type 1 diabetes (T1D), the insulin‐producing β cells are destructed by immune mechanisms. It has been hypothesized that the very first immune response in T1D onset comes from innate immune cells, which further activates the adaptive immune cells to attack the islets. Despite intensive research on characterization of islet‐infiltrating immune cells, the kinetics of different immune cells in multiple low‐dose streptozotocin (MLDSTZ)‐induced T1D mouse model is still much unclear. Therefore, we investigated the proportions of innate immune cells such as neutrophils, dendritic cells (DCs), plasmacytoid dendritic cells (pDCs), macrophages, natural killer (NK) cells, and adaptive immune cells (T and B lymphocytes) in thymi, pancreatic‐draining lymph nodes, and spleens of MLDSTZ mice on days 3, 7, 10, and 21 after the first injection of STZ by flow cytometry. The proportions of DCs and B cells were increased from day 3, while the proportions of B‐1a lymphocytes and interferon‐γ+ cells among NK cells were increased, but NK cells were decreased on day 10 in MLDSTZ‐treated mice, illustrating that the initial immune response is induced by DCs and B cells. Later, the proportions of T helper 1 and cytotoxic T cells were increased from day 7, suggesting that the innate immune cells precede adaptive immune cell response in MLDSTZ mice. Altogether, our data demonstrate a possible sequence of events regarding the involvement of DCs, pDCs, NK cells, B‐1a lymphocytes, B, and T cells at the early stage of T1D development.

show abstract

Section: Resultsmentioning

confidence: 77%

Kinetics of immune cell responses in the multiple low‐dose streptozotocin mouse model of type 1 diabetes

et al. 2019

View full text Add to dashboard Cite

show abstract

“…Furthermore, B cell exhaustion in the NOD was recently correlated with a chronic IFN-I response [67]. Our group has also revealed a higher number of plasmacytoid dendritic cells (pDC) in the periphery of patients at risk for and with T1D which responded to viral infection with increased expression of IFNα [68]. Previous research has shown that IFNβ priming of pDCs leads to an enhanced activation response [69].…”

Section: Resultsmentioning

confidence: 93%

Effects of Type 1 Diabetes-Associated IFIH1 Polymorphisms on MDA5 Function and Expression

et al. 2015

Self Cite

View full text Add to dashboard Cite

Recent evidence has highlighted the role of the innate immune system in type 1 diabetes (T1D) pathogenesis. Specifically, aberrant activation of the interferon response prior to seroconversion of T1D-associated autoantibodies supports a role for the interferon response as a precipitating event toward activation of autoimmunity. Melanoma differentiation-associated protein 5 (MDA5), encoded by IFIH1, mediates the innate immune system's interferon response to certain viral species that form double-stranded RNA (dsRNA), the MDA5 ligand, during their life cycle. Extensive research has associated single nucleotide polymorphisms (SNPs) within the coding region of IFIH1 with T1D. This review discusses the different risk and protective IFIH1 alleles in the context of recent structural and functional analysis that relate to MDA5 regulation of interferon responses. These studies have provided a functional hypothesis for IFIH1 T1D-associated SNPs' effects on MDA5-mediated interferon responses as well as supporting the genome-wide association (GWA) studies that first associated IFIH1 with T1D.

show abstract

“…For this study, CpG was chosen to study the TLR9-mediated activation of DCs because this type 1 IFN-inducing signal mimics innate signals that contribute to diabetes pathogenesis (7, 35, 36). First, we measured serum levels of IFN-α and IFN-β from NOD and B6 mice 6 h post-CpG i.v.…”

Section: Resultsmentioning

confidence: 99%

Despite Increased Type 1 IFN, Autoimmune Nonobese Diabetic Mice Display Impaired Dendritic Cell Response to CpG and Decreased Nuclear Localization of IFN-Activated STAT1

Rahman

Rahir

Dong

et al. 2016

The Journal of Immunology

View full text Add to dashboard Cite

Innate immune signals help break self-tolerance to initiate autoimmune diseases such as type 1 diabetes, but innate contributions to subsequent regulation of disease progression are less clear. Most studies have measured in vitro innate responses of GM-CSF dendritic cells (DCs) that are functionally distinct from conventional DCs (cDCs) and do not reflect in vivo DC subsets. To determine whether autoimmune NOD mice have alterations in type 1 IFN innate responsiveness, we compared cDCs from prediabetic NOD and control C57BL/6 (B6) mice stimulated in vivo with the TLR9 ligand CpG, a strong type 1 IFN inducer. In response to CpG, NOD mice produce more type 1 IFN and express higher levels of CD40, and NOD monocyte DCs make more TNF. However, the overall CpG-induced transcriptional response is muted in NOD cDCs. Of relevance the costimulatory proteins CD80/CD86, signals needed for regulatory T cell homeostasis, are upregulated less on NOD cDCs. Interestingly, NOD Rag1−/− mice also display a defect in CpG-induced CD86 upregulation compared with B6 Rag1−/−, indicating this particular innate alteration precedes adaptive autoimmunity. The impaired response in NOD DCs is likely downstream of the IFN-α/β receptor because DCs from NOD and B6 mice show similar CpG-induced CD86 levels when anti–IFN-α/β receptor Ab is added. IFN-α–induced nuclear localization of activated STAT1 is markedly reduced in NOD CD11c+ cells, consistent with lower type 1 IFN responsiveness. In conclusion, NOD DCs display altered innate responses characterized by enhanced type 1 IFN and activation of monocyte-derived DCs but diminished cDC type 1 IFN response.

show abstract

Increased IFN-α–Producing Plasmacytoid Dendritic Cells (pDCs) in Human Th1-Mediated Type 1 Diabetes: pDCs Augment Th1 Responses through IFN-α Production

Cited by 56 publications

References 70 publications

Kinetics of immune cell responses in the multiple low‐dose streptozotocin mouse model of type 1 diabetes

Kinetics of immune cell responses in the multiple low‐dose streptozotocin mouse model of type 1 diabetes

Effects of Type 1 Diabetes-Associated IFIH1 Polymorphisms on MDA5 Function and Expression

Despite Increased Type 1 IFN, Autoimmune Nonobese Diabetic Mice Display Impaired Dendritic Cell Response to CpG and Decreased Nuclear Localization of IFN-Activated STAT1

Contact Info

Product

Resources

About