Defective Suppressor Function in CD4+CD25+ T-Cells From Patients With Type 1 Diabetes (original) (raw)
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Annals of the New York Academy of Sciences, 2006
Type 1 diabetes mellitus (T1DM) is characterized by a loss of self-tolerance to islet antigens. In health, immunological tolerance is maintained by multiple central and peripheral mechanisms including the action of a specialized set of regulatory T cells characterized by expression of CD4 and CD25 (CD4 + CD25 + Treg). It has been suggested that a defect in this cell population, either numerically or functionally, could contribute to the development of autoimmune diseases, such as T1DM. To investigate this possibility, several research groups have studied the frequency and suppressive capacity of this cell population in individuals with T1DM and, to date, there are four such studies published. We therefore performed a mini meta-analysis to compare the results in the four published studies, account for differences in their findings, and draw a consensus view on the role of this important cell subset in human T1DM.
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.
Study of Regulatory T-cells in Type 1 Diabetes
Al-Azhar International Medical Journal, 2021
Background: T1D is a common autoimmune disease, globally, diabetes affects over four hundred million individuals, with Type 1 (insulindependent) diabetes (T1D) accounting for up to 10 percent of cases. Aim of the work: to shed light on and evaluate the frequency of Treg cells in patients with type 1 diabetes. Patients and methods: This study is a cross-sectional study that was conducted in the period 9/2019 to 3/2020 at diabetes and Internal medicine clinics of Al-Azhar and Ain Shams University Hospitals. 60 adult males and females aged between 19-40 years old who were diagnosed with type 1 DM (Group I) were offered participation in the study, later we subdivided them regarding the percentage of HBA1C to two groups:-(Ia) controlled DM, (Ib) uncontrolled DM. Results: There is a considerable decrease of Tregs in patients with T1D in comparison with those in healthy subjects. There was a highly significant difference between patients with type 1 DM and healthy subjects regarding Tregs percentage, being higher in healthy subjects. There was a highly significant difference between patients with T1D and healthy subjects regarding FOXP3 percentage, being higher in healthy subjects while its level in diabetic subjects. Conclusion: There is a considerable decrease of Tregs in patients with T1D in comparison with those in healthy subjects, there is no correlation between Treg percentage and the patients' age, there is no relation between the frequency of Tregs and the control of blood sugar in type 1 diabetic patients.
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.
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.
Type 1 Diabetes: Etiology, Immunology, and Therapeutic Strategies
Physiological Reviews, 2011
Type 1 diabetes (T1D) is a chronic autoimmune disease in which destruction or damaging of the beta-cells in the islets of Langerhans results in insulin deficiency and hyperglycemia. We only know for sure that autoimmunity is the predominant effector mechanism of T1D, but may not be its primary cause. T1D precipitates in genetically susceptible individuals, very likely as a result of an environmental trigger. Current genetic data point towards the following genes as susceptibility genes: HLA, insulin, PTPN22, IL2Ra, and CTLA4. Epidemiological and other studies suggest a triggering role for enteroviruses, while other microorganisms might provide protection. Efficacious prevention of T1D will require detection of the earliest events in the process. So far, autoantibodies are most widely used as serum biomarker, but T-cell readouts and metabolome studies might strengthen and bring forward diagnosis. Current preventive clinical trials mostly focus on environmental triggers. Therapeutic t...
Functional Defects and the Influence of Age on the Frequency of CD4+CD25+ T-Cells in Type 1 Diabetes
Diabetes, 2005
CD4 ؉ CD25 ؉ T-cells appear to play a crucial role in regulating the immune response. Therefore, we evaluated the peripheral blood frequency and function of CD4 ؉ CD25 ؉ T-cells in 70 type 1 diabetic patients and 37 healthy individuals. Interestingly, a positive correlation was observed between increasing age and CD4 ؉ CD25 ؉ T-cell frequency in both subject groups. In contrast to previous studies of nonobese diabetic mice and type 1 diabetic patients, similar frequencies of CD4 ؉ CD25 ؉ and CD4 ؉ CD25 ؉Bright T-cells were observed in healthy control subjects and type 1 diabetic patients of similar age. There was no difference between type 1 diabetic subjects of recent-onset versus those with established disease in terms of their CD4 ؉ CD25 ؉ or CD4 ؉ CD25 ؉Bright T-cell frequency. However, type 1 diabetic patients were markedly defective in their ability to suppress the proliferation of autologous effector T-cells in vitro. This type 1 diabetes-associated defect in suppression was associated with reduced production of interleukin (IL)-2, ␥-interferon, and transforming growth factor-, whereas other cytokines including those of adaptive and innate immunity (IL-10, IL-1, IL-6, IL-8, IL-12p70, and tumor necrosis factor-␣) were similar in control subjects and type 1 diabetic patients. These data suggest that age strongly influences the frequency of CD4 ؉ CD25 ؉ T-cells and that function, rather than frequency, may represent the means by which these cells associate with type 1 diabetes in humans. Diabetes 54:1407-1414, 2005
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.
Diabetologia, 1983
T lymphocyte subsets in peripheral blood from 11 newly diagnosed Type 1 (insulin-dependent) diabetic patients were studied prospectively at three time intervals: as soon as possible after diagnosis, 3 weeks and 5 months later. Lymphocytes were marked with monoclonal OKT antibodies and examined in a fluorescence-activated cell sorter. The percentage of T lymphocytes (OKT 3) did not change significantly at the three study times. The percentage of helper/inducer T cells (OKT 4) was high the first week after diagnosis, but decreased at the 5-month examination (p< 0.05). The percentage of suppressor/cytotoxic T cells (OKT 8) was low at diagnosis but increased at 3 weeks (p< 0.02) and 5 months (p< 0.01). The ratio OKT 4/OKT 8 lymphocytes was 2.28 at diagnosis, decreasing to 1.77 at 3 weeks and 1.87 at 5 months, compared with 1.46 for 16 age-matched control subjects. There was no significant change in the absolute number of lymphocytes. It is concluded that the distribution of T cell subsets was abnormal at the time of diagnosis, but changed towards normal within a few weeks, after which there was no significant change at 5 months. It is as yet unknown whether the high proportion of helper/inducer T cells and/or the low percentage of suppressor/cytotoxic T cells at diagnosis favour immune reactions involved in the pathogenesis of Type 1 diabetes.