Latent autoimmune diabetes in adults or type 1.5 diabetes is considered to be a T-cell-mediated autoimmune disease. However, identification of patients is based commonly on autoantibody (Ab) detection. To determine whether measuring T-cell reactivity to islet proteins compared with measuring Abs improves detection of autoimmune diabetes and how beta-cell function correlates with T-cell reactivity compared with Ab positivity, we assessed the T-cell proliferative responses and Ab responses (islet cell autoantibodies, insulin autoantibodies, insulinoma-associated protein-2 autoantibodies, and GAD Abs) to islet proteins of 36 phenotypic type 2 diabetic patients. To be considered Ab(+) or T-cell(+), patients were required to be positive for a minimum of two consecutive time points. beta-Cell function was measured with fasting and glucagon-stimulated C-peptide. Independent of T-cell reactivity, Ab(+) and Ab(-) patients had comparable fasting and glucagon-stimulated C-peptide. Independent of Ab status, T-cell(+) patients demonstrated significantly lower glucagon-stimulated (P < 0.003) C-peptide compared with T-cell(-) patients. These data suggest that measuring T-cell responses to multiple islet proteins in phenotypic type 2 diabetic patients improves identification of patients with autoimmune diabetes and delineates those who have a more severe beta-cell lesion compared with Ab assessment alone.
"We have been investigating T cell responses in classic T1D and in adult phenotypic T2D patients and have identified T cell responses to islet proteins (Brooks-Worrell et al., 1996, 1999, 2001, 2004). Moreover, we (Goel et al., 2007) have also demonstrated a correlation between T cell positivity and diminished beta cell function. Our data demonstrate that identifying patients with diabetes who have T cell responses to islet proteins identifies the patients with a more severe beta cell lesion compared with autoantibody assessment alone. "
[Show abstract][Hide abstract] ABSTRACT: Diabetes mellitus is comprised primarily of two clinically separate diseases: type 1 (T1D) and type 2 diabetes (T2D). T1D is a cell-mediated autoimmune disease directed against the beta cells and characterized by autoantibody (Ab) and T cell reactivity to islet proteins whereas, T2D is non-autoimmune. Despite the fact that the pathological process in autoimmune diabetes involves T cells, immune markers of diabetes have primarily centered on the presence of circulating serum islet autoantibodies. In two masked NIH sponsored workshops, our cellular immunoblotting T cell assay, which uses isolated human islets separated into 18 molecular weight fractions, has been validated to be able to distinguish T1D patients from controls with excellent specificity and sensitivity. In this study, we utilized the first workshop to select eight molecular weight fractions of human islets that were the most discriminatory between T1D patients and controls. Using these eight molecular weight fractions identified in the first workshop, we validated the preferential recognition of these 8 blot sections in a second workshop. We then re-calculated the sensitivity and specificity of the cellular immunoblotting assay for both workshops using only the data from these 8 blot sections.We observed increases in both sensitivity and specificity compared to the original workshop data for both workshops. The use of 8 instead of 18 molecular weight regions allows for a significant reduction in the amount of blood needed from patients, thus allowing cellular immunoblotting to be performed on pediatric patients participating in immunomodulatory studies. This improved T cell assay, which directly measures islet reactive T cell responses in autoimmune diabetes patients with excellent sensitivity and specificity, will likely improve patient follow-up during intervention studies.
[Show abstract][Hide abstract] ABSTRACT: Interleukin (IL) 22 is a recently identified T-cell-derived cytokine. IL-22 binds at the cell surface to a heterodimer receptor complex composed of IL-22 receptor (R) 1 and IL-10R2. In this study, we performed immunohistochemical analyses for IL-22R1 expression in human pancreatic tissue.
Normal human pancreatic tissue (n = 8) was immunostained with antihuman IL-22R1 antibodies following standard immunohistochemical procedures.
In the normal human pancreas, IL-22R1 was expressed in the islets of Langerhans. IL-22R1 was not expressed by the acinar cells and ductal epithelium. Double-immunostaining experiments showed that the majority of insulin-expressing beta cells and glucagon-expressing alpha cells were immunopositive for IL-22R1.
The islets of Langerhans are the local site for IL-22R1 expression in the human pancreas. It may be that the T-cell-mediated immune response modulates cell islet function through IL-22 signaling.
[Show abstract][Hide abstract] ABSTRACT: About 10% of patients with the clinical presentation of type 2 diabetes suffer from an autoimmune form of diabetes associated with a rapid decline of residual beta-cell mass and subsequent development of insulin dependency. In this condition, called latent autoimmune diabetes in adults (LADA), there are clinical and metabolic features intermediate between type 1 and type 2 diabetes. Recent studies provide novel information on the immune markers associated with progressive beta-cell loss in LADA patients. However, LADA pathogenesis is still poorly understood; further studies are needed to establish general recommendation for preventing and treating this subtype of autoimmune diabetes.
Current Diabetes Reports 05/2008; 8(2):94-100. DOI:10.1007/s11892-008-0018-x · 3.08 Impact Factor
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