Prevention of type I diabetes transfer by glutamic acid decarboxylase 65 peptide 206-220-specific T cells

Glutamic acid decarboxylase (GAD) 65 is one of the major pancreatic antigens targeted by self-reactive T cells in type I diabetes mellitus. T cells specific for GAD65 are among the first to enter inflamed islets and may be important for the initiation of autoimmune diabetes. However, we previously reported that nonobese diabetic (NOD) mice transgenic for a T cell antigen receptor (TCR) specific for one of the immunodominant epitopes of GAD65, peptide 286-300 (G286), are protected from insulitis and diabetes. To examine whether other GAD65-reactive T cells share this phenotype, we have generated TCR transgenic NOD mice for a second immunodominant epitope of GAD65, peptide 206-220 (G206). As in G286 mice, G206 mice do not develop islet inflammation or diabetes. When adoptively transferred along with diabetogenic T cells, activated G206 T cells significantly delayed the onset of diabetes in NOD.scid recipients. Both G206 and G286 T cells produce immunoregulatory cytokines IFN-gamma and IL-10 at low levels when activated by cognate antigens. These data suggest that GAD65-specific T cells may play a protective role in diabetes pathogenesis by regulating pathogenic T cell responses. A better understanding of the functions of autoreactive T cells in type I diabetes will be necessary for choosing desirable targets for immunotherapy.     

Chronic liver disease in transfusion-dependent thalassaemia: hepatitis B virus marker studies.

The systematic screening of 253 children with transfusion-dependent homozygous beta-thalassaemia revealed a high incidence of hepatitis B virus markers. The highest frequencies of hepatitis B surface antigen (HBsAg) and antibody to hepatitis B core antigen (anti-HBc) were found in the group of patients with the smallest number of transfusions, while the highest frequency of antibody to hepatitis B surface antigen (anti-HBs) was detected in the patients who had had the largest number of transfusions. Follow-up of these patients showed (a) a high incidence of acute hepatitis B, which was mainly subclinical; (b) normal hepatitis B surface antigen clearance and normal antibody to hepatitis B surface development; and (c) a high frequency of increased transaminase values for over six months. In all the subjects with persistently high transaminase, histological examination revealed chronic persistent hepatitis or chronic active hepatitis. Apart from two cases of chronic active hepatitis with no B virus markers, and two cases of chronic persistent hepatitis with HBsAg and anti-HBc in the serum, all these subjects were anti-HBs positive but HGsAg and anti-HBc negative.     

Cardiac features of Emery-Dreifuss muscular dystrophy caused by lamin A/C gene mutations.

AIMS: Retrospective studies have identified a mutation in the lamin A/C (LMNA) gene in patients selected on the basis of a phenotype characterized by dilated cardiomyopathy, atrioventricular conduction disturbances and sudden death. However, the features of cardiac abnormalities in patients with an initial diagnosis of Emery-Dreifuss muscular dystrophy (EDMD) are poorly known. Aim of the present study was to investigate the spectrum of cardiac disease in patients with an initial diagnosis of EDMD caused by a mutation in the LMNA gene. METHODS AND RESULTS: Ten consecutive patients with EDMD and a LMNA gene mutation were evaluated with structured medical interview, physical examination, ECG, echocardiogram and 24-h Holter monitoring. Electrophysiological testing and cardiac catheterization were performed if a class 1 or 2 American Heart Association guidelines indication was present. Cardiac disease was found in eight of 10 patients and consisted in the variable combination of supraventricular arrhythmias, disorders of atrioventricular conduction, ventricular arrhythmias, dilated cardiomyopathy, non-dilated cardiomyopathy, restrictive cardiomyopathy and sudden death despite pacemaker implant. CONCLUSIONS: Cardiac disease is common in patients with an initial diagnosis of EDMD caused by a mutation in the LMNA gene and consists of arrhythmias, disorders of atrioventricular conduction, cardiomyopathies and sudden death despite pacemaker implant.     

Leptin increase in multiple sclerosis associates with reduced number of CD4(+)CD25+ regulatory T cells

We analyzed the serum and cerebrospinal fluid (CSF) leptin secretion and the interaction between serum leptin and CD4(+)CD25+ regulatory T cells (T(Regs)) in naive-to-therapy relapsing-remitting multiple sclerosis (RRMS) patients. Leptin production was significantly increased in both serum and CSF of RRMS patients and correlated with IFN-gamma secretion in the CSF. T cell lines against human myelin basic protein (hMBP) produced immunoreactive leptin and up-regulated the expression of the leptin receptor (ObR) after activation with hMBP. Treatment with either anti-leptin or anti-leptin-receptor neutralizing antibodies inhibited in vitro proliferation in response to hMBP. Interestingly, in the RRMS patients, an inverse correlation between serum leptin and percentage of circulating T(Regs) was also observed. To better analyze the finding, we enumerated T(Regs) in leptin-deficient (ob/ob) and leptin-receptor-deficient (db/db) mice and observed the significant increase in T(Regs). Moreover, treatment of WT mice with soluble ObR fusion protein (ObR:Fc) increased the percentage of T(Regs) and ameliorated the clinical course and progression of disease in proteolipid protein peptide (PLP(139-151))-induced relapsing-experimental autoimmune encephalomyelitis (R-EAE), an animal model of RRMS. These findings show an inverse relationship between leptin secretion and the frequency of T(Regs) in RRMS and may have implications for the pathogenesis of and therapy for multiple sclerosis.     

Selenium and immune functions in humans

Earlier animal experiments have shown that selenium depletion may decrease immune functions. In this human study, 40 volunteers from a population with low serum selenium concentrations were supplemented with selenium or placebo for 11 weeks. Blood samples were drawn at intervals for analysis of selenium status and immune function. At the end of the supplementation period, plasma selenium levels were 74 ng/ml in the placebo group and 169 ng/ml in the supplemented group. The improvement in selenium status was associated with a 57% increase in the activity of platelet glutathione peroxidase in the group supplemented with selenium, but there was no increase in the activity of this enzyme in the placebo-treated subjects. Immune function was measured in vitro by tests of lymphocyte and granulocyte activity. Intracellular killing of Staphylococcus aureus by granulocytes was slightly lower in the placebo group than in the selenium group at the end of the supplementation period (77.2 compared to 85.2%; P less than 0.05). No significant changes were observed in phagocytosis, chemotactic factor generation, antibody or leukocyte migration inhibitory factor production by lymphocytes, or proliferative responses to phytohemagglutinin or concanavalin A. These results suggest that the selenium deficiency of the order found in Finland and some other areas of the world has little, if any, influence on the immune functions measured in this study.     

Alcohol consumption and the risk of stroke among hypertensive and overweight men

High blood pressure and overweight are risk factors for stroke. The aim of the present study was to examine the association between alcohol consumption and the risk of stroke according to the level of blood pressure and body weight. This study is a population-based sample of men with an average follow-up of 14.9 years from eastern Finland. A total of 2,599 men with no history of stroke at baseline participated. During the follow-up period, 224 strokes occurred, of which 181 were ischemic strokes. After adjustment for age, year of examination, socioeconomic status, serum LDL cholesterol, body mass index, smoking and energy expenditure of physical activity (kcal/day), there was a significant trend of an increased risk for any and ischemic stroke among hypertensive men. Hypertensive (blood pressure of over 140/90 mm Hg) men, who did not consume alcohol had a 1.72-fold (95 % CI 1.12–2.66; p = 0.014) relative risk (RR) for any stroke and a 1.90-fold (95 % CI 1.15–3.13; p = 0.012) RR for ischemic stroke. Among hypertensive men who consumed alcohol RR was 1.86-fold (95 % CI 1.20–2.89; p = 0.005) for any stroke and 2.02-fold (95 % CI 1.21–3.35; p = 0.007) for ischemic stroke. Men who did not consume alcohol with elevated BMI (≥26.4 kg/m²) had a 1.63-fold RR (95 % CI 1.11–2.40; p = 0.013) for any stroke and a 1.33-fold RR (95 % CI 0.87–2.04; p = 0.199) for ischemic stroke after adjusting for risk factors. Overweight men (≥26.4 kg/m²) who consumed alcohol had a 1.73-fold RR (95 % CI 1.18–2.54; p = 0.005) for any stroke and a 1.71-fold RR (95 % CI 1.14–2.57; p = 0.010) for ischemic stroke after being adjusted for risk factors. In conclusion, this population-based prospective study shows that hypertensive and overweight men who consumed alcohol had an increased risk for stroke.