Redox status and immune function in type I diabetes families

Abstract

SUMMARYBecause abnormalities in redox balance cluster in type I diabetes families and the intracellular thiol redox status seems to modulate immune function, we aimed to investigate the relationship between oxidative stress and immunological features. We measured oxidative markers, serum proinflammatory cytokines, soluble cytokine receptors and subsets of peripheral blood lymphocytes (by varying combinations of CD4, CD8, CD23 or low-affinity IgE receptor, and CD25 or IL-2 receptor) from 38 type I patients, 76 low-risk (i.e. without underlying islet autoimmunity) non-diabetic first-degree relatives of diabetic patients, and 95 healthy subjects. In type I diabetes families, protein and lipid oxidation was confirmed by the presence of reduced sulphhydryl groups, increased advanced oxidation protein products, and increased plasma and erythrocyte malondialdehyde. Relatives had decreased counts of monocytes, of cells co-expressing CD23 and CD25 and of CD25 + cells in peripheral blood. Patients with TIDM had similar defects and, in addition, showed decreased counts of peripheral CD4 + CD8+ lymphocytes and increased serum levels of soluble receptors for interleukin (IL)-6 and IL-2. Abnormal indicators of oxidative stress were related in part to immune abnormalities. In the whole study group, we found a correlation (multiple R 0·5, P < 0·001) of CD23 + CD25+ cells with blood counts of monocytes, CD4 + CD8 + cells, CD25 + cells, basal haemolysis and plasma levels of thiols. In type I diabetics, anti-GAD65 antibody levels were associated (multiple R 0·6, P = 0·01) positively with sIL-6R, negatively with duration of diabetes and CD23 + CD25 + counts; plasma creatinine correlated positively (multiple R 0·6, P < 0·001) with both sIL-2R and tumour necrosis factor (TNF)-a concentration. Our study reports the first evidence that the oxidative stress observed in type I families is related to immunological hallmarks (decreased peripheral numbers of monocytes as well as cells bearing a CD4 + CD8 + , CD23 + CD25 + and CD25 + phenotype) from which the involvement of some immunoregulatory mechanisms could be suspected. It remains to be elucidated the course of events culminating in the loss of physiological immune homeostasis and disease pathology.

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“…Work in clinical diabetes supports this concept. Measures of oxidative stress including TRAP (Total Radical Antioxidant Potential), thiobarbituric acid reactive substances (TBARS, a measure of oxidized lipids), and advanced glycation end products (AGEs) are all elevated in diabetic patients (Rosenson, 2004;Matteucci et al, 2004;Siemionow and Demir, 2004) and in experimental models of diabetes (Toth et al, 2004;Hounsom et al, 2001). …”

The Enlarging List of Phenotypic Characteristics That Might Allow the Clinical Identification of Families at Risk for Type 1 Diabetes

“…We concluded that anthropometric and anamnestic data on child and family yield more accurate estimates of risk profile: fat distribution seems relevant for metabolic and cardiovascular disorders. Since our initial investigations on type 1 diabetes families, we found that first degree relatives' BMI tended to be higher when compared with healthy control subjects who had no first-degree relative with type 1 diabetes, although the difference did not always reach statistical significance (Matteucci & Giampietro, 2000a;Matteucci et al 2004aMatteucci et al , 2004bMatteucci et al 2006). In recent years, on the contrary, the difference in BMI between unaffected siblings of type 1 diabetic probands and healthy control subjects has reached the statistical significance ( Figure 1, .…”

“…We measured oxidative markers, serum pro-inflammatory cytokines, soluble cytokine receptors, and subsets of peripheral blood lymphocytes (by varying combinations of CD4, CD8, CD23, and CD25) from type 1 patients, low-risk (i.e. without underlying islet autoimmunity) non-diabetic first-degree relatives of diabetic patients, and healthy subjects (Matteucci et al, 2004a). In these families, protein and lipid oxidation was confirmed from reduced sulfhydryl groups, increased advanced oxidation protein products, increased plasma and erythrocyte malondialdehyde.…”

Cardiovascular Risk by Gender in an Italian Pilot Study

“…Plasma thiols (P SH), erythrocyte glutathione (RBC GSH), plasma and erythrocyte membrane malondialdehyde (P and RBC MDA), RBC NHE activity, and RBC vfcy were measured as previously reported [3][4][5][6][7]11].…”