Lymphocyte apoptosis in the pathogenesis of type 1 diabetes mellitus

Abstract

Background: Beta cell apoptosis has been associated with insulin dependent diabetes mellitus (IDDM) onset in newly diagnosed diabetic patients. There is an emerging evidence that T cell-induced apoptosis is a dominant effector mechanism in diabetes mellitus type 1 (DM1). Pancreatic β-cells derived from newly diagnosed type 1 diabetics were found to have increased cell surface expression of Fas (CD95) compared to β-cells from healthy subjects. Objective: The study investigates the spontaneous lymphocyte apoptosis via CD95 molecule expression to demonstrate activation induced cell death in children with high risk of DM1 and in type 1 diabetics under insulin therapy. Methods: This study comprised 90 children and adolescents, divided into 3 groups. G(1) comprised 40 type-1 diabetics, their ages ranging from 8.0 to 17.0 years and disease duration between 2.0 and 12.0 years. G(2) (prediabetics) included 30 euglycaemic subjects who were first degree relatives of type 1 diabetics, with normal fasting blood glucose and positive first phase insulin release (FPIR) and/or positive islet cell (ICA) or glutamic acid decarboxylase (GAD) antibodies. G(3) comprised 20 healthy, age and sex matched subjects with no clinical or laboratory signs or family history of type-1DM. Patients were subjected to clinical evaluation with special emphasis on signs suggestive of microvascular complications. The study measurements included random blood sugar (RBS), glycosylated hemoglobin (HbA_1c), urinary microalbumin assay and flow cytometric assessment of apoptosis by measuring CD95 percentage expression on CD3 lymphocytes. Results: The percentage of CD95 positive T-lymphocytes was significantly higher in prediabetics than in type-1 diabetics and controls (57.687±6.68, 45.01±6.648,16.75±4.98% respectively; p < 0.001). CD3 positive lymphocytes were significantly lower in prediabetics than type-1 diabetics and controls (52.93±11.64, 66.23±7.04, 63.910±3.4% respectively; p < 0.001). The percentage of CD95 on T-lymphocytes could not be correlated with age, insulin dose and RBS, but HbA1c was positively correlated with both CD3 lymphocytes and CD95% expression. Complicated type-1 diabetics showed higher CD95% expression compared to noncomplicated patients. Conclusion: Peripheral blood lymphocytes with CD95 antigen expression are increased in prediabetics. As CD95 is an important receptor for activation-induced cell death, CD95 mediated apoptosis could play a potential role in the pathogenesis of DM1.

Keywords: lymphocyte apoptosis; CD95 system; type 1 DM; prediabetes

Egypt J Pediatr Allergy Immunol 2008; 6(2): 57-67