Natural killer cell and islet killer cell activities in Type 1 (insulin-dependent) diabetes

Negishi, Kiyohiko; Waldeck, N; Chandy, George; Buckingham, Bruce A.; Kershnar, Ann K.; Fisher, Lynda K.; Gupta, Sudhir; Charles, M. Arthur

doi:10.1007/bf00903343

Cited by 52 publications

(43 citation statements)

References 22 publications

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“…Type 1 and type 2 diabetics have an in creased susceptibility to infection [2,3] and an increased risk of certain malignancies [4], NK cells appear to have a central role in our immune defense against both viral infection and tumor formation [1,6,7], and their func tion appears to be reduced in tvpe 1 diabetics [5]. Hyperglycemia is one of the consequences of diabetes mellitus; thus, the effects of ele vated glucose levels on NK cytolytic function may have a role in the depression of NK func tion seen in diabetics.…”

Section: Discussionmentioning

confidence: 99%

“…NK cells are able to lyse the above-mentioned target cells without prior sensitization, putting them at the forefront of the lymphocyte defense against tumor cells and virally infected cells HiType 1 and type 2 diabetes mellitus are associated with an increased susceptibility to viral infection [2,3], as well as an increased incidence of certain malignancies [4]. The NK function of lymphocytes from type 1 diabetics is reduced [5]. This decrease in NK cell func tion may be one aspect of the diabetic im mune dysfunction that results in increased viral infection and malignancy.…”

Section: Introductionmentioning

confidence: 99%

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Inhibition of Human Natural Killer Cell Function in vitro by Glucose Concentrations Seen in Poorly Controlled Diabetes

Whalen¹

1997

Cell Physiol Biochem

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Type 1 and type 2 diabetes mellitus are associated with an increased risk of viral infections and certain tumors. Natural killer (NK) cells appear to have a central role in the immune defense against viral infection as well as tumor cells, and impairment of NK function could result in an increased incidence of infection or tumors. We show that exposure of NK cells to elevated glucose concentrations (in the range seen in poorly controlled diabetes) results in a significant inhibition of their cytolytic function. When glucose is elevated to 44 mM (800 mg/dl), there is a 59% decrease in NK cytolytic function compared to that seen when glucose is in the normal range (4.4-5.5 mM). Specific lysis is inhibited by 42% by 33 mM glucose, and 22 mM glucose produce a 31 % inhibition of specific lysis. This inhibition is not due to a disruption of NK cell binding to target cells. The effect is reversible under the in vitro conditions used, indicating that it is not due to the glycation of proteins that can occur with elevated glucose levels. Exposure of NK cells to 44 mM glucose results in a significant elevation of cAMP, indicating that elevation of this potent inhibitor of NK cytolysis may be in part responsible for the glucose-induced inhibition of NK function.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Inhibition of Human Natural Killer Cell Function in vitro by Glucose Concentrations Seen in Poorly Controlled Diabetes

Whalen¹

1997

Cell Physiol Biochem

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“…Increased NK cell activity has been reported in the periphery of individuals with type 1 diabetes [1][2][3][4][5][6], but a role for these innate immune cells in the pathogenesis of type 1 diabetes has not, however, been elucidated. NK cells act by either activating or inhibiting cytolysis [7] and their activity is controlled by the balance of inhibitory and activating receptors on the cell surface [8].…”

Section: Introductionmentioning

confidence: 99%

An increased frequency of NK cell receptor and HLA-C group 1 combinations in early-onset type 1 diabetes

Mehers

Long

Slik³

et al. 2011

Diabetologia

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Aims/hypothesis Natural killer (NK) cells serve as primary immune surveillance and are partially regulated by combinations of killer immunoglobulin-like receptor (KIR) genes and their HLA class I ligands. Alterations in NK cell activity have been associated with type 1 diabetes. The aim of this study was to determine whether KIR-HLA class I gene frequency: (1) is altered in a current population with type 1 diabetes compared with healthy controls; and (2) has changed over the half century in which the incidence of type 1 diabetes has increased rapidly.Methods KIR-HLA class I gene frequencies were compared in 551 individuals diagnosed with type 1 diabetes ≤15 years of age (394 in a current cohort and 157 from the historical 'Golden Years' cohort) and 168 healthy controls. The overall balance of activation and inhibition was analysed using KIR-HLA genotype models. Results Children with type 1 diabetes who were positive for KIR2DS2/KIR2DL2 and KIR2DL3 were more often homozygous for HLA-C group 1 and this effect was strongest in children diagnosed with diabetes before the age of 5 years (p=0.003, corrected p [p corr ]=0.012) and (p=0.001, p corr = 0.004), respectively. Children with type 1 diabetes have fewer inhibitory KIRs with their corresponding ligands compared with healthy controls (p=1.9×10 −4 ). This pattern of NK activation has not changed significantly in individuals with type 1 diabetes over the last half century. Conclusions/interpretation Activating combinations of KIR-HLA genes are more frequent in young children with type 1 diabetes diagnosed in the first 5 years of life, suggesting that NK cell responses may be altered in this group.

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“…However, small study groups were often involved, the antibodies used to identify NK cells were limited and lacked specificity, and NK cell function was assessed by cytotoxicity on tumor targets, an incomplete reflection of the entire NK pool. Some studies suggested a numeric deficiency of NK cells in the peripheral blood of patients with type 1 diabetes (18,21) or a functional abnormality (18,24). In some of these cases, there were permanent numeric and/or functional deficits (20,23), whereas in others, transitory abnormalities were associated with the stage of disease (18,24).…”

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confidence: 99%

Altered Natural Killer Cells in Type 1 Diabetic Patients

et al. 2007

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Evidence from animal models suggests that natural killer (NK) cells can be important players in the development of type 1 diabetes, although data in humans are still sparse. We studied the frequency and activation state of blood NK cells at different stages of human type 1 diabetes, and whether genetic or phenotypic NK cell peculiarities could be associated with an early onset of diabetes. The onset period is marked by a slight reduction in blood NK cells, but these are unusually activated in some patients (␥-interferon expression). This activation status does not correlate, however, with a particularly young age at onset. In contrast, NK cells in patients with long-standing type 1 diabetes had a markedly lower expression of p30/p46 NKactivating receptor molecules compared with those of control subjects. A slightly decreased expression of NKG2D in all type 1 diabetic patients relative to control subjects was observed, independent of the duration of disease, parallel to prior observations in the NOD mouse. Finally, type 1 diabetic patients had an increased frequency of KIR gene haplotypes that include the activating KIR2DS3 gene, with a genetic interaction between the KIR and HLA complexes. The reduced activation of NK cells in individuals with long-standing type 1 diabetes would seem to be a consequence rather than a cause, but other peculiarities may relate to type 1 diabetes pathogenesis. Diabetes 56: 177-185, 2007

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Natural killer cell and islet killer cell activities in Type 1 (insulin-dependent) diabetes

Cited by 52 publications

References 22 publications

Inhibition of Human Natural Killer Cell Function in vitro by Glucose Concentrations Seen in Poorly Controlled Diabetes

Inhibition of Human Natural Killer Cell Function in vitro by Glucose Concentrations Seen in Poorly Controlled Diabetes

An increased frequency of NK cell receptor and HLA-C group 1 combinations in early-onset type 1 diabetes

Altered Natural Killer Cells in Type 1 Diabetic Patients

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