Innate inflammation drives NK cell activation to impair Treg activity

Dean, Joseph; Peters, Leeana D.; Fuhrman, Christopher A.; Seay, Howard R.; Posgai, Amanda L.; Stimpson, Scott E.; Brusko, Todd M.; Perry, Daniel J.; Yeh, Wen-I; Newby, Brittney N.; Haller, Michael J.; Muir, Andrew; Atkinson, Mark A.; Mathews, Clayton E.

doi:10.1016/j.jaut.2020.102417

Cited by 36 publications

(33 citation statements)

References 76 publications

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“…Interestingly, pathogenetic studies of T1D—a disease in which persistent enteroviral infections are suspected—have provided results compatible with those observed for slow infection due to diabetes-related EV strains. Diabetes studies have indicated that: (a) IL6 is normally expressed in islet beta and alpha cells, but its production is reduced in the pancreas of diabetics [ 37 ]; (b) elevated levels of IL-18 are found in the blood cells of T1D patients and may promote NK cell activation and abrogation of the suppressive capacity of T regulatory cells [ 38 ]; and (c) peripheral blood mononuclear cells of children who developed beta-cell autoimmunity have upregulated IL32 transcripts before the appearance of T1D-associated autoantibodies [ 39 ]. Finally, increased expression of MCP1 has been reported in newly diagnosed T1D children [ 40 ].…”

Section: Discussionmentioning

confidence: 99%

Immune Transcriptome of Cells Infected with Enterovirus Strains Obtained from Cases of Type 1 Diabetes

et al. 2020

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Enterovirus (EV) infection of insulin-producing pancreatic beta cells is associated with type 1 diabetes (T1D), but little is known about the mechanisms that lead the virus to cause a persistent infection and, possibly, to induce beta cell autoimmunity. A cell line susceptible to most enterovirus types was infected with EV isolates from cases of T1D and, for comparison, with a replication-competent strain of coxsackievirus B3. The transcription of immune-related genes and secretion of cytokines was evaluated in infected vs. uninfected cells. Acutely infected cells showed the preserved transcription of type I interferon (IFN) pathways and the enhanced transcription/secretion of IL6, IL8, LIF, MCP1, and TGFB1. On the other hand, infection by defective EV strains obtained from diabetic subjects suppressed IFN pathways and the transcription of most cytokines, while enhancing the expression of IL8, IL18, IL32, and MCP1. IL18 and IL32 are known for their pathogenic role in autoimmune diabetes. Thus, the cytokine profile of AV3 cells infected by diabetes-derived EV strains closely matches that observed in patients at the early stages of T1D. The concordance of our results with clinically verified information reinforces the hypothesis that the immune changes observed in type 1 diabetic patients are due to a hardly noticeable virus infection.

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Section: Discussionmentioning

confidence: 99%

Immune Transcriptome of Cells Infected with Enterovirus Strains Obtained from Cases of Type 1 Diabetes

et al. 2020

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“…A decrease in cytolytic activity of NK cells toward group B coxsackievirus (CV-B)-infected pancreatic β cells contributed to the persistence of CV-B and triggered autoimmunity in T1DM patients (197,202). However, other studies found no correlation between T1DM clinical status and abnormalities in the number or function of NK cells (203,204). One report showed that NK cells were rarely detected even in heavily inflamed pancreatic islets of T1DM patients, suggesting that they are not required for the death of pancreatic β cells (205).…”

Section: Nk Cells and T1dmmentioning

confidence: 99%

NK Cells in Autoimmune Diseases: Protective or Pathogenic?

2021

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Autoimmune diseases generally result from the loss of self-tolerance (i.e., failure of the immune system to distinguish self from non-self), and are characterized by autoantibody production and hyperactivation of T cells, which leads to damage of specific or multiple organs. Thus, autoimmune diseases can be classified as organ-specific or systemic. Genetic and environmental factors contribute to the development of autoimmunity. Recent studies have demonstrated the contribution of innate immunity to the onset of autoimmune diseases. Natural killer (NK) cells, which are key components of the innate immune system, have been implicated in the development of multiple autoimmune diseases such as systemic lupus erythematosus, type I diabetes mellitus, and autoimmune liver disease. However, NK cells have both protective and pathogenic roles in autoimmunity depending on the NK cell subset, microenvironment, and disease type or stage. In this work, we review the current knowledge of the varied roles of NK cell subsets in systemic and organic-specific autoimmune diseases and their clinical potential as therapeutic targets.

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“…Consistently, IFN-γ as well as IL-12 were found to be elevated in T1D patients without microvascular complications (MVC), the latter significantly (Shruthi et al, 2016[ 170 ]). Furthermore, a model of T1D pathogenesis has been proposed, wherein IL-12 and IL-18 synergistically enhance cytotoxic T lymphocyte and NK cell cytotoxic activity and disrupt immune regulation by T regs (Dean et al, 2020[ 44 ]).…”

Section: Relevance Of Il-12 In Different Diseases and Disease Modelsmentioning

confidence: 99%

Immunology of IL-12: An update on functional activities and implications for disease

Ullrich

Schulze

Paap

et al. 2020

EXCLI Journal; 19:Doc1563; ISSN 1611-2156

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Innate inflammation drives NK cell activation to impair Treg activity

Cited by 36 publications

References 76 publications

Immune Transcriptome of Cells Infected with Enterovirus Strains Obtained from Cases of Type 1 Diabetes

Immune Transcriptome of Cells Infected with Enterovirus Strains Obtained from Cases of Type 1 Diabetes

NK Cells in Autoimmune Diseases: Protective or Pathogenic?

Immunology of IL-12: An update on functional activities and implications for disease

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