Altered natural killer (NK) cell frequency and phenotype in latent autoimmune diabetes in adults (LADA) prior to insulin deficiency

Åkesson, Caroline Piercey; Uvebrant, Kristina; Oderup, Cecilia; Lynch, Kristian; Harris, Robert A.; Lernmark, Åke; Agardh, Carl‐David; Cilio, Corrado

doi:10.1111/j.1365-2249.2010.04114.x

Cited by 48 publications

(51 citation statements)

References 52 publications

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“…Although studies have reported no significant change in total B cells in peripheral blood of patients with T1D (21,24), little is known about B-cell subpopulations with distinct immune functions that may play a role in the diabetes spectrum of T1D, LADA, and T2D. We hypothesized that an altered phenotype of B-cell subsets is associated with autoimmune diabetes.…”

Section: Introductionmentioning

confidence: 93%

“…Considerable evidence shows that patients with autoimmune diabetes have altered frequencies of circulating immune cells, including T cells (19), dendritic cells (20), natural killer cells (21,22), and neutrophils (23). Although studies have reported no significant change in total B cells in peripheral blood of patients with T1D (21,24), little is known about B-cell subpopulations with distinct immune functions that may play a role in the diabetes spectrum of T1D, LADA, and T2D.…”

Section: Introductionmentioning

confidence: 99%

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Altered Peripheral B-Lymphocyte Subsets in Type 1 Diabetes and Latent Autoimmune Diabetes in Adults

et al. 2015

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OBJECTIVEB lymphocytes play an important role in the immunopathogenesis of autoimmune diabetes. We hypothesized that the altered B-cell subset phenotype is associated with autoimmune diabetes.RESEARCH DESIGN AND METHODSPatients with type 1 diabetes (T1D) (n = 81), latent autoimmune diabetes in adults (LADA) (n = 82), or type 2 diabetes (T2D) (n = 95) and healthy control subjects (n = 218) with normal glucose tolerance (NGT) were recruited. We determined the percentage of circulating B-lymphocyte subsets, including CD19+CD23−CD21+ (marginal zone B [MZB]), CD19+CD23+CD21− (follicular B [FoB]), and CD19+CD5+CD1dhi (interleukin-10–producing regulatory B [B10]) cells by flow cytometry.RESULTSPatients with T1D or LADA had increased percentages of MZB cells and decreased percentages of FoB cells compared with healthy control subjects with NGT and patients with T2D. Moreover, patients with T1D showed the lowest frequency of B10 cells compared with patients with LADA or T2D, whereas healthy control subjects expressed the highest frequency of B10 cells. Of note, the frequency of MZB cells was negatively associated and the frequency of FoB cells was positively associated with fasting C-peptide (FCP). The frequency of B10 cells was positively correlated with FCP and negatively correlated with hemoglobin A1c.CONCLUSIONSThe data show that patients with T1D or LADA express an altered frequency of B-cell subsets, which is associated with islet function and glycemia. These findings suggest that B lymphocytes may be involved in loss of self-tolerance and β-cell destruction and could be used as a biomarker and potential target for immunological intervention.

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Section: Introductionmentioning

confidence: 93%

Section: Introductionmentioning

confidence: 99%

Altered Peripheral B-Lymphocyte Subsets in Type 1 Diabetes and Latent Autoimmune Diabetes in Adults

et al. 2015

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“…During the early phase of disease, individuals with LADA can retain good metabolic control through diet alone or by taking oral hypoglycemic drugs, and this state can last from months to years. However, a percentage of LADA patients progress toward insulin requirement, indicating that LADA involves a slow and progressive loss of b-cells (5), although the factors influencing this progression are not completely known (6). The first evidence, demonstrating that a high GADA titer is a stronger predictor of insulin requirement than a general GADA positivity, was obtained from two studies with a limited number of LADA patients (7,8).…”

Section: Introductionmentioning

confidence: 99%

High GADA titer increases the risk of insulin requirement in LADA patients: a 7-year follow-up (NIRAD study 7)

Zampetti

Campagna

Tiberti

et al. 2014

European Journal of Endocrinology

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Objective: The aim of this study was to determine whether glutamic acid decarboxylase antibody (GADA) titer and other clinical parameters could define the risk of progression to insulin therapy in latent autoimmune diabetes in adults (LADA) patients during a 7-year follow-up. Methods: This study involved 220 LADA and 430 type 2 diabetes subjects followed up for 7 years from the time of GADA screening to evaluate their progression toward insulin therapy. Kaplan-Meier curves and multivariate logistic regression analysis were performed to identify the markers capable of influencing this progression. Results: During the follow-up, the drop out was 4% in both groups. A total of 119 (56.1%) out of 212 LADA patients required insulin during the 7 years of follow-up. The Kaplan-Meier plots showed that 74/104 (71.1%) of high GADA titer required insulin compared with 45/108 (41.6%) of low GADA titer and with 86/412 (20.9%) of type 2 diabetes (P!0.0001 for both). A BMI of %25 kg/m 2 and IA-2 IC and zinc transporter 8 (ZnT8) positivity were also shown as the markers of faster progression (P!0.0001 for both). The proportion of LADA patients requiring insulin was significantly higher in the group of subjects treated also with sulfonylurea in the first year from diagnosis compared with those treated with diet and/or insulin sensitizers (P!0.001). The multivariate analysis confirmed that the presence of high GADA titer was a significant predictor of insulin requirement (P!0.0001, ORZ6.95). Conclusions: High GADA titer, BMI % 25, ZnT8 and IA-2 IC positivity and sulfonylurea treatment, in the first year from diagnosis, significantly increase the progression toward insulin requirement in LADA patients.

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“…A study in humans showed that they are more frequent in the visceral adipose tissue and express higher levels of proinflammatory IFN␥ compared with the subcutaneous adipose tissue (13,42). NK cells are also involved in the development of latent autoimmune diabetes in adults and diabetes in nonobese diabetic mice (2,8) but have been suggested to be protective against the development of metabolic syndrome in obese humans (34). Studies using leptin receptor-deficient mice (db/db) have indicated that leptin is necessary for normal NK cell development (52).…”

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confidence: 97%

Short-term and long-term leptin exposure differentially affect human natural killer cell immune functions

Wrann

Laue²,

Hübner³

et al. 2012

American Journal of Physiology-Endocrinology and Metabolism

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Epidemiological studies have indicated that obesity is associated with a higher risk for certain cancers caused by elevated levels of adipocyte-derived hormones. Leptin, one such hormone produced by adipocytes, is a major regulator of metabolism and has also been shown to modulate immunity. However, its role in regulating human natural killer (NK) cell functions is largely unknown. Here, we show that the leptin receptor (Ob-R) is expressed on 5% of NK cells isolated from blood donors, as measured with flow cytometry, and expression of the signal-transducing long form of the leptin receptor Ob-Rb was confirmed with quantitative PCR. The Ob-R+ subpopulation displayed a lower expression of CD16, a cell surface receptor mediating antibody-dependent activation. Short-term stimulation with leptin increased IFNγ secretion, CD69 activation marker expression, and cytotoxic lysis of tumor cells; this was mediated by an improved conjugate forming between NK cells and tumor cells as well as higher expression of tumor necrosis factor-related apoptosis-inducing ligand. On the contrary, long-term incubation with leptin significantly impaired these NK cell immune functions and decreased cell proliferation. In addition, phosphorylation of Jak-2 after leptin stimulation was reduced in peripheral mononuclear blood cells from obese humans compared with normal-weight controls. NK cells represent an immune cell population that is crucial for an effective antitumor response. Here, we show that long-term exposure to leptin, similarly to the situation in obese individuals with elevated serum leptin levels, significantly impairs integral parts of NK cell immune functions, possibly linking leptin to increased cancer susceptibility in obesity.

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Altered natural killer (NK) cell frequency and phenotype in latent autoimmune diabetes in adults (LADA) prior to insulin deficiency

Cited by 48 publications

References 52 publications

Altered Peripheral B-Lymphocyte Subsets in Type 1 Diabetes and Latent Autoimmune Diabetes in Adults

Altered Peripheral B-Lymphocyte Subsets in Type 1 Diabetes and Latent Autoimmune Diabetes in Adults

High GADA titer increases the risk of insulin requirement in LADA patients: a 7-year follow-up (NIRAD study 7)

Short-term and long-term leptin exposure differentially affect human natural killer cell immune functions

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