Increased serum type I interferon activity in organ-specific autoimmune disorders: clinical, imaging, and serological associations.

BACKGROUND: Activation of the type I interferon (IFN) pathway has been implicated in the pathogenesis of systemic autoimmune disorders but its role in the pathogenesis of organ-specific autoimmunity is limited. We tested the hypothesis that endogenous expression of type I IFN functional activity contributes to the pathogenesis of autoimmune thyroid disease (ATD) and type I diabetes (T1DM). METHODS: We studied 39 patients with ATD and 39 age and sex matched controls along with 88 T1DM patients and 46 healthy matched controls respectively. Available clinical and serological parameters were recorded by chart review, and thyroid ultrasound was performed in 17 ATD patients. Type I IFN serum activity was determined in all subjects using a reporter cell assay. The rs1990760 SNP of the interferon-induced helicase 1 gene was genotyped in ATD patients. RESULTS: Serum type I IFN activity was increased in patients with ATD and T1DM compared to controls (p-values: 0.002 and 0.04, respectively). ATD patients with high type I IFN serum activity had increased prevalence of antibodies against thyroglobulin (anti-Tg) and cardiopulmonary manifestations compared to those with low IFN activity. Additionally, the presence of micronodules on thyroid ultrasound was associated with higher type I IFN levels. In patients with T1DM, high IFN levels were associated with increased apolipoprotein-B levels. CONCLUSION: Serum type I IFN activity is increased in ATD and T1DM and is associated with specific clinical, serological, and imaging features. These findings may implicate type I IFN pathway in the pathogenesis of specific features of organ-specific autoimmunity.

Extracellular matrix-associated (GAGs, CTGF), angiogenic (VEGF) and inflammatory factors (MCP-1, CD40, IFN-γ) in type 1 diabetes mellitus nephropathy.

BACKGROUND: The aim of the present study was to evaluate the role of extracellular matrix-associated glycosaminoglycans (GAGs), connective tissue growth factor (CTGF), angiogenic vascular endothelial growth factor (VEGF) and inflammatory factors (MCP-1, CD40, IFN-γ) in the development of diabetic nephropathy in type 1 diabetes (T1DM). METHODS: Plasma and urine samples from 30 T1DM patients and 20 healthy controls were used to measure the levels of CTGF, VEGF, MCP-1, CD40 and IFN-γ by ELISA. Plasma and urine GAGs were measured using a spectrophotometric method. RESULTS: Plasma levels of GAGs, CD40 and MCP-1 and urine levels of GAGs and CTGF were significantly elevated in normoalbuminuric T1DM patients. A tendency to higher plasma VEGF levels was found in patients compared to controls. The urine/plasma GAGs ratio of T1DM patients was almost similar to that of healthy subjects (HS), whereas the urine/plasma CTGF ratio was about three times greater in diabetic patients compared to HS. CONCLUSIONS: Conclusively, increased GAGs and CTGF excretion are evident in T1DM normoalbuminuric juveniles, possibly reflecting early renal injury signs, before the initiation of albuminuria.

Alterations in biomarkers of endothelial function following on-pump coronary artery revascularization.

BACKGROUND: Cardiopulmonary bypass (CPB) has been associated with activation and injury of endothelial cells, probably responsible for the systemic inflammatory response syndrome (SIRS) taking place in these patients. METHODS: We measured plasma concentrations of soluble P-selectin (sP-s), E-selectin (sE-s), tetranectin (TN), vonWillebrand factor (vWF) levels, and angiotensin-converting enzyme (ACE) activity in 31 adult patients undergoing elective coronary artery bypass grafting, just before and up to three days after surgery, and in 25 healthy volunteers. RESULTS: Patients showed higher plasma sP-s and sE-s and ACE concentrations, just before surgery, but significantly lower TN levels, compared with controls. During the first three postoperative days (PD), the concentration of each of the molecules followed a different and independent pattern, although in the third PD, the levels of sP-s, sE-s and ACE were higher and those of vWF and TN lower, compared with the preoperative ones. However, patients had higher sP-s (P=0.06), sE-s (P=0.07), and vWF (P=0.005), but lower TN concentrations (P=0.02) on the third PD compared with controls. CONCLUSIONS: CPB is characterised by pronounced changes in plasma sP-s, sE-s, TN, vWF levels, and ACE activity, which are associated with significant alteration in the intra- and early postoperative endothelial function observed in open heart surgery.

The antioxidant effect of angiotensin II receptor blocker, losartan, in streptozotocin-induced diabetic rats.

We determined the effect of a short-term angiotensin II signaling blockade on vascular endothelial growth factor (VEGF), soluble intercellular adhesion molecule-1 (sICAM-1), nitric oxide (NO), and malondialdehyde (MDA) (index of lipid peroxidation) levels in the systemic circulation and on peroxynitrite generation and insulitis development in the streptozotocin (STZ) diabetic rats' pancreas. Diabetes was induced in Wistar rats by intraperitoneal STZ injection. Diabetic rats were treated for 1 week with losartan (20 mg/kg/body weight/day in the drinking water), and pancreas and blood were collected for histochemical, immunohistochemical, and biochemical studies. Diabetic rats showed greater VEGF, sICAM-1, NO, and MDA levels, a high score of insulitis, increased nitrotyrosine staining, and markedly reduced pancreatic insulin content when compared with controls. Losartan treatment suppressed the excessive NO and lipid peroxidation production systemically without restoring them to that of healthy subjects and reduced VEGF levels while leaving sICAM-1 levels unchanged. The insulitis score and nitrotyrosine staining were reduced, whereas the pancreatic islets and the beta-cell area were increased significantly in the treated group, indicating the reduction of inflammation and nitrosative stress and an early regeneration of beta-cell mass in the pancreas. Conclusively, in the STZ diabetic rat model, even a short-term losartan treatment improves oxidative and nitrosative stress systemically and locally, improving the islets' environment and accelerating beta-cell regeneration.

The pattern of inflammatory/anti-inflammatory cytokines and chemokines in type 1 diabetic patients over time.

AIMS: To evaluate the profile of pro- and anti-inflammatory cytokines in type 1 diabetes mellitus (T1DM) and the way they are connected in co-regulated networks and determine whether disease duration influences their pattern. METHODS: Plasma levels of 20 cytokines and soluble CD40 (sCD40) from 44 uncomplicated patients and 22 healthy controls (HCs) were measured using enzyme-linked immunosorbent assay (ELISA) and protein array technology. RESULTS: Patients showed significantly higher levels of sCD40, IL-1a, IL-2, IL-4, IL-5, IL-10, granulocyte-macrophage colony-stimulating factor (GM-CSF), macrophage inflammatory protein (MIP)-1a, MIP-1b, regulated on activation normal T cell expressed and secreted (RANTES), matrix metalloproteinase (MMP)-9, and a trend to higher IL-6 than did HCs. RANTES and sCD40 discriminated significantly between diabetics and HCs. In patients with disease duration >6 months, cytokines were organized in two clusters mainly regulated by Th17 and Th1/Th2 cells respectively, while in those with disease duration

CD40/CD40L signaling and its implication in health and disease.

CD40, a transmembrane receptor of the tumor necrosis factor gene superfamily is expressed on a variety of cells, such as monocytes, B-cells, antigen presenting cells, endothelial, smooth muscle cells, and fibroblasts. The interaction between CD40 and CD40 ligand (CD40L) enhances the expression of cytokines, chemokines, matrix metalloproteinases, growth factors, and adhesion molecules, mainly through the stimulation of nuclear factor kappa B. The aim of this review is to summarize the molecular and cellular characteristics of CD40 and CD40L, the mechanisms that regulate their expression, the cellular responses they stimulate and finally their implication in the pathophysiology of inflammatory and autoimmune diseases.

The use of animal models in the study of diabetes mellitus.

Animal models have enormously contributed to the study of diabetes mellitus, a metabolic disease with abnormal glucose homeostasis, due to some defect in the secretion or the action of insulin. They give researchers the opportunity to control in vivo the genetic and environmental factors that may influence the development of the disease and establishment of its complications, and thus gain new information about its handling and treatment in humans. Most experiments are carried out on rodents, even though other species with human-like biological characteristics are also used. Animal models develop diabetes either spontaneously or by using chemical, surgical, genetic or other techniques, and depict many clinical features or related phenotypes of the disease. In this review, an overview of the most commonly used animal models of diabetes are provided, highlighting the advantages and limitations of each model, and discussing their usefulness and contribution in the field of diabetes research.

Oxidative stress and adhesion molecules in children with type 1 diabetes mellitus: a possible link.

OBJECTIVE: To examine whether oxidative stress parameters were correlated with adhesion molecules derived from endothelial/platelet activation in a group of juveniles with type 1 diabetes mellitus (T1DM). SUBJECTS AND METHODS: Indicative parameters of patient oxidant/antioxidant capacity were measured and associated with P-selectin and tetranectin (TN), markers of endothelial/platelet activation, in the plasma of 45 diabetic children and adolescents and 20 healthy age-matched subjects (HS). RESULTS: Significantly, higher nitrate/nitrite (NOx) and lipid hydroperoxide (LPO) levels (p=0.049 and p=0.0011, respectively), lower glutathione peroxidase activity (GPx; p=0.038), and elevated TN and P-selectin plasma levels (p=0.0046 and p=0.042, respectively) were found in T1DM children compared with HS. Well-controlled T1DM children (HbA1c 7%) showed significantly higher TN, sP-selectin and LPO (p=0.0064, p=0.0234 and p=0.0121, respectively), a tendency to higher NOx (p=0.063) compared with HS and only TN higher (p=0.0123) compared with well-controlled patients. Patients with shorter diabetes duration (3 yr) differed significantly in all the examined parameters (TN, p=0.0015; GPx, p=0.0420; NOx, p=0.0196; LPO, p=0.0054; sP-selectin, p=0.0187) compared with HS. CONCLUSIONS: Decreased antioxidative protection from simultaneous LPO and NOx overproduction is evident in T1DM juveniles with a parallel endothelial/platelet activation even in the first years of the disease, being more pronounced later in diabetes progression, contributing to the vascular complications of the disease.