Mattia Locatelli

Genetic prediction of type 1 diabetes in a population with low frequency of HLA risk genotypes and low incidence of the disease (the DIABFIN study)

To develop a sensitive, specific screening strategy for predicting genetic risk for type 1 diabetes mellitus (T1DM) in the low‐incidence continental Italian population, and to define with this tool, a cohort of high‐to‐moderate risk infants for an immunological follow‐up study aimed at identifying environmental risk factors for T1DM.

Identification of Tyrosine Phosphatase 2(256–760) Construct as a New, Sensitive Marker for the Detection of Islet Autoimmunity in Type 2 Diabetic Patients: The Non–Insulin Requiring Autoimmune Diabetes (NIRAD) Study 2

OBJECTIVE—The presence of autoantibodies to islet antigens GAD and/or tyrosine phosphatase 2 (IA-2) in type 2 diabetic patients (latent autoimmune diabetes in adults [LADA]) identifies subjects at high risk to develop insulin dependency. The aim of this study was to dissect humoral anti–IA-2 immune response in Caucasian LADA patients, identifying the most sensitive construct to evaluate IA-2 immunoreactivity and comparing LADA IA-2 epitope specificities to those found in type 1 diabetes. RESEARCH DESIGN AND METHODS—We analyzed 177 LADA and 978 type 2 diabetic patients with different disease duration, collected in a nationwide Italian survey, the Non–Insulin Requiring Autoimmune Diabetes (NIRAD) study aimed at assessing prevalence and characteristics of autoimmune diabetes in type 2 diabetic patients and 106 newly diagnosed type 1 diabetic patients (53 children, 53 adults). By radioimmunoassay, we analyzed humoral immunoreactivity to seven IA-2 constructs: IA-2PTP (687–979), IA-2(761–964), IA-2(256–760), IA-2JM (601–630), IA-2IC (605–979), IA-2BDC (256–556:630–979), and IA-2FL (1–979). RESULTS—IA-2(256–760) fragment was identified as the marker with the highest sensitivity for detection of humoral IA-2 immunoreactivity in LADA patients, identifying IA-2 autoantibodies in ∼30% of GAD antibody (GADA)-positive LADA patients and in 3.4% of GADA-negative type 2 diabetic patients. LADA IA-2(256–760)A positivity was associated with an increased frequency of autoimmune diabetes HLA-susceptible genotypes and with a higher risk for developing thyroid autoimmunity compared with autoantibody-negative type 2 diabetic patients. At disease diagnosis, adult-onset type 1 diabetic and LADA patients showed a lower IA-2 COOH-terminal immunoreactivity compared with childhood-onset type 1 diabetic patients. CONCLUSIONS—IA-2 immunoreactivity in LADA patients has thus far been underestimated, and IA-2(256–760) autoantibody detection may represent a novel diagnostic tool for the identification of islet autoimmunity in these patients.

Human herpes virus-8 infection among pregnant women and their children: Results from the sardinia-IDDM study 2

Marked variations exist in the distribution of human herpesvirus 8 (HHV-8) infection in different geographical and socioeconomic settings, mirroring variations in incidence rates of classic Kaposi’s sarcoma (KS). Thus, HHV-8 infection is more frequent in Italy than in the United States 1–3 and, within Italy, in Sardinia and Sicily, 2 regions with high incidence rates of classic KS, than in the northern part of the country, where classic KS is less frequent. 3–6 In Western countries, HHV-8 infection is usually acquired after adolescence ( i.e., at the beginning of sexual activity), whereas in Africa it occurs commonly in childhood, with prevalence reaching relatively high levels before the age of sexual activity.7 This finding indicates that transmission modes other than sexual intercourse may be important for HHV-8 acquisition also in Western countries, possibly through vertical and/or horizontal transmission. 8,9

Serum transforming growth factor β1 during diabetes development in non-obese diabetic mice and humans

Recent data show that regulatory cells with transforming growth factor (TGF)‐β1‐dependent activity are able to restore self‐tolerance in overtly diabetic non‐obese diabetic (NOD) mice. Thus, TGF‐β1 seems to have a relevant role in protection from autoimmune diabetes. Our aim was to investigate the possible significance of serum TGF‐β1 measurement in the natural history of diabetes in NOD mice, as well as in children positive for at least one islet‐related antibody. Serum TGF‐β1 (both total and active) was measured by enzyme‐linked immunosorbent assay at monthly intervals in 26 NOD mice during the spontaneous development of diabetes and, on a yearly basis, in nine siblings of patients with type 1 diabetes (T1D) with a follow‐up of 4 years. Diabetes appeared between the 12th week of age and the end of the study period (36 weeks) in 17 mice. TGF‐β1 serum level variations occurred in the prediabetic period in both NOD mice and humans and diabetes diagnosis followed a continuing reduction of active TGF‐β1 (aTGF‐β1) serum levels. In mice, aTGF‐β1 serum levels measured at 4 weeks of age correlated positively with severity of insulitis, and negatively with percentage of insulin‐positive cells. Our findings suggest that in NOD mice serum TGF‐β1 levels during the natural history of the diabetes reflect the course of islet inflammation. The measurement of aTGF‐β1 in islet‐related antibody‐positive subjects may provide insights into the natural history of prediabetic phase of T1D.