Defective autologous mixed leukocyte reaction in newly diagnosed type 1 diabetes mellitus (original) (raw)
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The Journal of Clinical Endocrinology & Metabolism, 1999
Antigenic proliferative responses of peripheral blood mononuclear cells (PBMC) to insulin were studied in 44 type 1 new-onset diabetic subjects. Of them, 14 (32%) had a stimulation index (Ն3) above the mean ϩ 3 SD of 39 healthy controls and of 7 of 15 (47%) diabetic patients of long duration (P ϭ 0.001). Responses to insulin were not dictated by specific major histocompatibility complex class II association and were not observed in normal subjects with diabetes-associated human leukocyte antigen-DR/DQ alleles. Whereas no relation of PBMC reactivity with insulin autoantibodies was found, there was a positive correlation with the presence of at least one of the four autoantibodies tested and with IA-2 antibody. An interesting finding was that the proportion of patients with subsequent low insulin requirement, up to 24 months, was significantly higher in patients who showed PBMC reactivity to insulin (8 of 8) than in those who did not (10 of 24, 42%; P ϭ 0.004). The former had a higher mean stimulation index than the latter (3.3 Ϯ 2.6 vs. 1.5 Ϯ 0.6; P ϭ 0.006). Furthermore, interleukin-4 (IL-4) production was lower in type 1 diabetic patients who proliferated to insulin than in those who did not (23 Ϯ 15 vs. 64 Ϯ 47 pg/mL; P ϭ 0.04), but interferon-␥, IL-2, and IL-10 productions were similar. In conclusion, these results suggest that proliferation to insulin may reflect the presence of an higher residual -cell mass.
Preliminary analysis of immune activation in early onset type 2 diabetes
International Journal of Circumpolar Health, 2013
Introduction. First Nations and other Aboriginal children are disproportionately affected by cardiometabolic diseases, including type 2 diabetes (T2D). In T2D, the disruption of insulin signalling can be driven by proinflammatory immunity. Pro-inflammatory responses can be fueled by toll-like receptors (TLR) on immune cells such as peripheral blood mononuclear cells (PBMC, a white blood cell population). TLR4 can bind to lipids from bacteria and food sources activating PBMC to produce cytokines tumour necrosis factor (TNF)-a and interleukin (IL)-1b. These cytokines can interfere with insulin signalling. Here, we seek to understand how TLR4 activation may be involved in early onset T2D. We hypothesized that immune cells from youth with T2D (n 08) would be more reactive upon TLR4 stimulation relative to cells from age and body mass index (BMI)matched controls without T2D (n 08). Methods. Serum samples were assayed for adipokines (adiponectin and leptin), as well as cytokines. Freshly isolated PBMC were examined for immune reactivity upon culture with TLR4 ligands bacterial lipopolysaccharide (LPS, 2 and 0.2 ng/ml) and the fatty acid palmitate (200 mM). Culture supernatants were evaluated for the amount of TNF-a and IL-1b produced by PBMC. Results. Youth with T2D displayed lower median serum adiponectin levels compared to controls (395 vs. 904 ng/ml, pB0.05). PBMC isolated from youth with and without T2D produced similar levels of TNF-a and IL-1b after exposure to the higher LPS concentration. However, at the low LPS dose the T2D cohort exhibited enhanced IL-1b synthesis relative to the control cohort. Additionally, exposure to palmitate resulted in greater IL-1b synthesis in PBMCs isolated from youth with T2D versus controls (p B0.05). These differences in cytokine production corresponded to greater monocyte activation in the T2D cohort. Conclusion. These preliminary results suggest that cellular immune responses are exaggerated in T2D, particularly with respect to IL-1b activity. These studies aim to improve the understanding of the biology behind early onset T2D and its vascular complications that burden First Nations people.
Leukocytes in type 1 diabetes mellitus: the changes they undergo and induce
Studia Biologica
As leukocytes represent cellular and humoral immunity at the same time, they are a vital part of every immune process. This also stands for autoimmune processes and disorders, such as diabetes, specifically type 1 diabetes mellitus. Diabetes mellitus is one of the most widespread autoimmune diseases. Development of type 1 diabetes mellitus is mediated through complicated mechanisms of intercellular communication where leukocytes function as the key element, being both effectors and regulators. However, the immunocompetent cells are also affected by diabetic alterations, powered by chronic hyperglycemia. For example, the products of non-enzymatic interaction of glucose or other reducing sugars with either proteins or lipids, called advanced glycation end products, are associated with the development of long-term negative changes in diabetes. By binding to the receptors for advanced glycation end-products, they trigger the signaling pathways involved in expression of pro-inflammatory ...
Cellular Immunology, 2003
We have recently described an impaired proliferative response of CD4 þ T-cells to primary antigens in patients with insulindependent diabetes mellitus (IDDM) [Clin. Immunol. 103 (2002) 249]. In order to further investigate possible mechanisms underlying this impairment, several factors known to be involved in the down-regulation of the immune response both at the level of APCs and CD4 þ T-cells were investigated: Monocyte-derived dendritic cells (MDDC) from IDDM patients were shown to express elevated amounts of CD86 (B7.2) (p ¼ 0:003) and reduced amounts of the adhesion molecule CD54 (ICAM-1) (p ¼ 0:03) on their cell surface compared to age-matched healthy controls and patients with non-insulin-dependent diabetes mellitus (NIDDM) as well as decreased SDS-PAGE stability of HLA-DQ and-DR peptide complexes directly isolated from the IDDM patientsÕ peripheral blood mononuclear cells (PBMCs). Expression of CTLA-4 (CD152), known to be involved in the down-regulation of the immune response, was shown to be increased on CD4 þ T-cells from IDDM patients after exposure to the primary antigen KLH (keyhole limpet hemocyanin) presented by MDDC (p ¼ 0:0047). Likewise, purified CD4 þ T-cells from IDDM patients produced elevated levels of the cytokine TGF-b1 after stimulation with immobilized monoclonal antibodies directed against CD3 and CD28 (p ¼ 0:014). When monocytes from IDDM patients were stimulated with lipopolysaccharide (LPS), an increased tendency to produce the inhibitory cytokine interleukin (IL)-10 (p ¼ 0:007) and the acute phase cytokine IL-6 (p ¼ 0:044) was observed, whereas the concentrations of tumor necrosis factor (TNF)-a, IL-1b, and IL-12 were comparable to controls. Taken together, our data suggest that a deviation in the expression of certain molecules known to be involved in the peripheral control of the immune response is present in IDDM patients and is underlying the observed impairment of the primary immune response.
Long-term study on T lymphocyte subsets in newly diagnosed type 1 diabetes mellitus
Journal of Paediatrics and Child Health, 1988
T lymphocyte subsets in peripheral blood from 16 newly diagnosed type 1 diabetic children were studied prospectively at four time intervals: as soon as possible after diagnosis and 1, 4 and 12 months later. T lymphocyte subsets were analysed using monoclonal antibodies and counted by cytofluorimetry. The percentage of T lymphocytes (OKT3+ cells) did not change at the four study times. The percentage of helperlinducer T cells (OKT4+ cells) was high at the diagnosis (43.1 2 2.1%), but decreased after 1 and 4 months with no difference in the control values. The percentage of suppressorlcytotoxic T lymphocytes (OKT8+ cells) was low at the diagnosis, but increased after 1 and 4 months. The OKT,/OKT6 ratio was 2.31 ~t 0.22 at the diagnosis study, decreasing to 1.83 after 1 month, compared with 16 sex-and age-matched control children. The high percentage of helperlinducer T lymphocytes and low number of suppressorlcytotoxic T cells at onset of diabetes favour immune reactions that lead to @-cell damage.
Diabetologia, 1984
Humoral and cell-mediated disorders in Type 1 (insulin-dependent) diabetes suggest that an imbalance of immunoregulatory T-cell subsets exists. In 23 newly diagnosed (onset T lymphocyte subsets were analyzed using monoclonal antibodies (OKT3, OKT4, OKT8, OKM1). The newly diagnosed patients showed a reduction with a significant difference from healthy controls in total T cells (OKT3+: 58.1 ±8.5% versus 70.7±8.0%), helper/inducer cells (OKT4+: 33.8 ±7.0% versus 47.1 ±8.3%), suppressor/cytotoxic cells (OKT8+: 18.5±7.3% versus 32 ± 6.8%) and monocytes (OKM1+: 11.5±3.8% versus 19.9±5.2%) (pp+/OKT8+) was higher in newly diagnosed patients than in control subjects (2.2±1.3 versus 1.5±0.3; p+ cells in the newly diagnosed diabetic patients appeared more marked: the mean (18.5%) coincided with the lower limit of normal subjects (18.3%). Ten of the newly diagnosed Type 1 diabetic patients had a value below the normal lower limit. Our data point to the occurrence of different immunoregulatory abnormalities in newly diagnosed Type 1 diabetic patients, especially in OKT8+ and OKT4+ cells. The imbalance in T lymphocyte subsets is further proof of the role of cellular autoimmunity in the pathogenesis of the early phases of Type 1 diabetes.
Immune Dysfunction in Diabetes Mellitus (DM)
https://www.ijhsr.org/IJHSR\_Vol.7\_Issue.12\_Dec2017/IJHSR\_Abstract.039.html, 2017
Diabetes mellitus patients are more prone to infection and also the wound healing capacity is very less. As the immune cells are well established mechanisms to protect us from pathogens. So, this article tried to combine all the recent updates of the relevant scientific data that have been done till now on-The effect of diabetes mellitus on the immune cells‖. It has been well described that there is no or less effect of diabetes mellitus on the adaptive immune system. But if it comes to innate immune system diabetic mellitus affects the cellular functions like chemotaxis, phagocytosis, and killing of pathogens by monocytes, macrophages, and neutrophils. Most studies showed that decrease in normal cellular function, and alteration in enzyme activity and cytokine secretion in diabetic monocytes, macrophages, and neutrophils when compared to control cells. Improvement in cellular functions can be achieved by controlling diabetes mellitus. By understanding how the immune cells were altered in diabetes mellitus further we can proceed by targeting therapeutically to achieve better results in regulation of diabetic complication and improve the lifespan of diabetic patients.
Lymphocyte subpopulations at the onset of type 1 (insulin-dependent) diabetes
Diabetologia, 1984
Percentages of various T-lymphocyte subpopulations in the blood were studied at the onset of Type I (insulindependent) diabetes. The number of lymphocytes with OKT8 markers was higher in the diabetic patients than in control subjects (p < 0.005) and the ratio between helper and suppressor/cytotoxic T-cells (OKT4/OKT8 ratio) was lower in the diabetic patients than in the control group (p < 0.005). The values in the diabetic patients were, however, essentially within the normal range. When Ia-antigen-positive cells were analysed in T-cell-enriched cell populations, Type 1 diabetic patients had higher percentages of these cells (p< 0.01), suggesting T-cell activation. When patients with either of the two major HLA risk antigens (Dw3 or Dw4) were compared, there was a significant difference in the OKT4/OKT8 ratio (p< 0.005), as Dw3-positive patients had higher and Dw4-positive patients lower ratios. This finding supports the concept of heterogeneity of the disease and can also explain the discrepant findings of earlier studies. When patients with complementfixing islet cell antibodies were compared with patients without islet cell antibodies, there was no significant difference, although the OKT4/OKT8 ratio was slightly lower in the complement-fixing islet cell antibody-positive patients.