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E Bosi

Publications and source records attributed to E Bosi.

At least 19 recordsLinked to original sources
PubMed2006

Increased intestinal permeability precedes clinical onset of type 1 diabetes.

AIMS/HYPOTHESIS: Recent observations have shown subclinical intestinal abnormalities in human type 1 diabetes. Whether these are related to the pathogenetic process or secondary to the diabetes remains to be clarified. The aim of this study was to investigate this issue by examining intestinal permeability to sugars in subjects at different stages of type 1 diabetes: preclinical, new-onset and long-term established disease. METHODS: Eighty-one subjects with islet autoimmunity (18 preclinical, 28 new-onset and 35 long-term type 1 diabetes) and 40 healthy control subjects were investigated by a lactulose-mannitol test, consisting of oral administration of the two sugars and measurement of their urinary excretion. RESULTS: All groups of subjects with islet autoimmunity showed an increase in intestinal permeability (p < or = 0.009 vs controls) to the disaccharide lactulose, indicative of a damaged barrier, but a similar permeability to the monosaccharide mannitol (NS vs controls), indicative of an integral surface mucosa; consequently there was an increase in the lactulose:mannitol excretion ratio (p < or = 0.025 vs controls). CONCLUSIONS/INTERPRETATION: These findings indicate the presence of a subclinical enteropathy associated with type 1 diabetes that is already detectable before clinical onset of the disease, and suggest that the small intestine is an organ participating in the pathogenetic process of type 1 diabetes.

Adolescent↗
PubMed2006

Clinical phenotype and beta-cell autoimmunity in Italian patients with adult-onset diabetes.

OBJECTIVE: To characterize the phenotype of a large population of Italian patients with adult onset (> or =40 years) diabetes who were attending outpatient clinics and who were screened for glutamic acid decarboxylase 65 autoantibodies (GADA), protein tyrosine phosphatase IA-2 (IA-2A) and IA-2beta/phogrin (IA-2betaA). DESIGN AND METHODS: This was a cross-sectional study comprising a total of 881 patients, aged < or = 70 years, diagnosed with type 2 diabetes after the age of 40 years, and consecutively recruited in five clinics located in different geographic areas of Italy (Milan, Florence, Rome, Naples and Catania). Their mean disease duration was 8.1 (6.9; s.d.) years. GADA, IA-2A and IA-2betaA were measured with radiobinding assays with in vitro translated S-methionine-labelled glutamic acid decarboxylase 65 (GAD65) or IA-2 or IA-2beta. Anthropometric and clinical data were collected and compared amongst patients with or without autoantibodies. RESULTS: Sixty-three (7.1%) patients had one or more autoantibodies, 58 (6.6%) had GADA, 22 (2.5%) had IA-2A, six (0.7%) had IA-2betaA and 19 (2.15%) had two or more autoantibodies. IA-2A or IA-2betaA, in the absence of GADA, were found in only five patients. Autoantibody-positive patients were more often female (63.5 vs 36.5%; P < 0.009), had higher glycated haemoglobin (Hb A1c) (P < 0.001), lower body mass index (BMI; P < 0.0005) and waist/hip ratio (WHR; P < 0.01); female gender being the main contributor to BMI and WHR. We did not observe any differences in age at diagnosis or duration of disease with respect to the presence or absence of islet autoantibodies. The proportion of patients on insulin therapy was higher in patients with two or more antibodies, compared with those with one antibody only, and no antibodies (P for trend < 0.001), and among patients with GADA, in those with higher antibody titre (73.9% in those with > 10 units vs 42.0% in those with < or = 10 units; P < 0.007). CONCLUSIONS: Patients with adult onset diabetes characterized by autoimmunity to beta-cells showed a clinical phenotype with anthropometric features that differed from those classically observed in patients with type 2 diabetes. The number and titre of autoantibodies, which reflect the severity of autoimmunity and beta-cell impairment, amplified this difference. The usefulness of autoantibody screening in adult-onset diabetes is further emphasized by these findings.

Aged↗
PubMed2005

Antibodies to recombinant human tissue-transglutaminase in coeliac disease: diagnostic effectiveness and decline pattern after gluten-free diet.

BACKGROUND/AIMS: To assess the sensitivity and specificity of IgA and IgG tissue-transglutaminase antibodies assay, the pattern of antibody decline after gluten withdrawal and their modifications with reference to dietary compliance. SUBJECTS: We studied sera from 143 untreated coeliac children and adolescents (8.8+/-6.1 years), 212 sera from 97 of those patients after gluten withdrawal, and 64 control subjects with non-coeliac intestinal disorders (6.8+/-4.8 years). METHODS: Samples were tested for IgA and IgG class tissue-transglutaminase antibodies by radiobinding assay, using human-derived tissue-transglutaminase, and for IgA anti-endomysium antibodies by indirect immunofluorescence on monkey oesophagus. RESULTS: Untreated coeliac patients had significantly higher titres of IgA and IgG tissue-transglutaminase antibodies than controls (p<0.00001); the diagnostic sensitivity was 95.8% and 99.3%, respectively, and the specificity was 95.3%. Three patients with selective IgA deficiency were positive for IgG tissue-transglutaminase antibodies. The concordance rate between IgA tissue-transglutaminase antibodies and anti-endomysium antibodies was 98.1%. Patients on gluten-free diet showed a significant decrease in IgA and IgG tissue-transglutaminase antibodies with respect to untreated patients (p<0.0001). Tissue-transglutaminase was more sensible than anti-endomysium antibodies to detect small amounts of gluten intake when the compliance was poor. CONCLUSIONS: The recombinant human tissue-transglutaminase antibodies assay is a highly sensitive and specific test for diagnosis of coeliac disease, and it is useful in monitoring the compliance to gluten-free diet.

Celiac Disease↗
PubMed2005

Effectiveness of frequency-modulated electromagnetic neural stimulation in the treatment of painful diabetic neuropathy.

AIMS/HYPOTHESIS: The largely unsatisfactory results reported for the pharmacological treatment of diabetic neuropathy has spurred the search for alternative therapies. The aim of this study was to evaluate the efficacy of frequency-modulated electromagnetic neural stimulation (FREMS) as a novel treatment for painful diabetic neuropathy. METHODS: Patients (n=31) with painful neuropathy associated with decreased nerve conduction velocity (<40 m/s) and increased vibration perception threshold (>25 V) were enrolled in a randomised, double-blind, crossover study designed to compare the effects of FREMS with those of placebo. Each patient received two series of ten treatments of either FREMS or placebo in random sequence, with each series lasting no more than 3 weeks. The primary efficacy end point was the change in pain measured by a visual analogue scale (VAS). RESULTS: FREMS induced a significant reduction in daytime and night-time VAS pain score (all p<0.02). Furthermore, FREMS induced a significant increase in sensory tactile perception, as assessed by monofilament; a decrease in foot vibration perception threshold, as measured by a biothesiometer; and an increase in motor nerve conduction velocity (all p<0.01). No significant changes were observed after placebo. Comparison of measurements at the 4-month follow-up with those at baseline revealed that a significant benefit persisted for all measures that showed an improvement at the end of treatment, with an additional improvement in quality of life evaluated by the Short Form-36 questionnaire (all p<0.05). No significant side effects were recorded during the study. CONCLUSIONS/INTERPRETATION: FREMS is a safe and effective therapy for neuropathic pain in patients with diabetes and is able to modify some parameters of peripheral nerve function.

Cross-Over Studies↗
PubMed2005

IA-2 antibody prevalence and risk assessment of early insulin requirement in subjects presenting with type 2 diabetes (UKPDS 71).

AIMS/HYPOTHESIS: Established autoimmune markers of type 1 diabetes, including islet cell autoantibodies (ICA) and autoantibodies to glutamic acid decarboxylase (GADA) have been used to screen people presenting with type 2 diabetes for latent autoimmune diabetes in adults. We have examined the prevalence of autoantibodies to protein tyrosine phosphatase isoforms IA-2 (IA-2A) and IA-2beta/phogrin (IA-2betaA) in a cohort of adult UKPDS patients thought to have type 2 diabetes, and investigated the possible role of these autoantibodies in predicting requirement for insulin therapy. METHODS: IA-2A and IA-2betaA were measured by a validated radioimmunoassay with human recombinant autoantigens in 4,169 white Caucasian patients aged 25-65 years and newly diagnosed with type 2 diabetes. The clinical requirement for insulin therapy within 6 years was examined in 2,556 patients not randomised to insulin. RESULTS: IA-2A and IA-2betaA were present in 2.2 and 1.4%, respectively, of these patients. IA-2A were more prevalent in younger patients (p for trend <0.00001), more often associated with the HLA-DR4 allele (26.3 vs 8.0%, p<0.0001), and their presence increased the likelihood of insulin therapy requirement within 6 years from diagnosis [relative risk (95%CI) 12.2 (9.8-15.3)]. The presence of IA-2A together with GADA increased the relative risk of requiring insulin therapy from 5.4 (4.1-7.1) for GADA alone to 8.3 (3.7-18.8) and the corresponding positive predictive value from 33 to 50%. CONCLUSIONS/INTERPRETATION: In type 2 diabetes, the presence of IA-2A is infrequent, associated with the HLA-DR4 haplotype, and highly predictive of future need for insulin therapy. The measurement of IA-2betaA does not provide additional information.

Adult↗
PubMed2005

Islet autoantibodies in clinically diagnosed type 2 diabetes: prevalence and relationship with metabolic control (UKPDS 70).

AIMS/HYPOTHESIS: We examined the prevalence of islet autoantibodies and their relationship to glycaemic control over 10 years in patients diagnosed clinically with new-onset type 2 diabetes. METHODS: Patient clinical characteristics and autoantibody status were determined at entry to the UK Prospective Diabetes Study (UKPDS) before randomisation to different glucose control policies. Patients were followed for 10 years. RESULTS: Data available on 4,545 of the 5,102 UKPDS patients showed that 11.6% had antibodies to at least one of three antigens: islet cell cytoplasm, glutamic acid decarboxylase and islet autoantibody 2A (IA-2A). Autoantibody-positive patients were younger, more often Caucasian and leaner, with lower beta cell function and higher insulin sensitivity than autoantibody-negative patients. They also had higher HbA1c, and HDL-cholesterol levels, and lower blood pressure, total cholesterol and plasma triglyceride levels. Despite relative hyperglycaemia, autoantibody-positive patients were less likely to have the metabolic syndrome (as defined by the National Cholesterol Education Program Adult Treatment Program III), reflecting a more beneficial overall risk factor profile. Of 3,867 patients with post-dietary run-in fasting plasma glucose (FPG) values between 6.0 and 14.9 mmol/l and no hyperglycaemic symptoms, 9.4% were autoantibody-positive, compared with 25.1% of 678 patients with FPG values of 15.0 mmol/l or higher, or hyperglycaemic symptoms. In both groups, no differences were seen between those with and without autoantibodies in changes to HbA1c over time, but autoantibody-positive patients required insulin treatment earlier, irrespective of the allocated therapy (p<0.0001). CONCLUSIONS/INTERPRETATION: Autoantibody-positive patients can be treated initially with sulphonylurea, but are likely to require insulin earlier than autoantibody-negative patients.

Adult↗
PubMed2005

Insulin aspart improves meal time glycaemic control in patients with Type 2 diabetes: a randomized, stratified, double-blind and cross-over trial.

AIMS: This randomized, multi-centre, double-blind, stratified, two period, cross-over trial was undertaken to assess the pharmacokinetics and pharmacodynamics of insulin aspart injected immediately before compared with regular human insulin injected 30 min before a Mediterranean-style meal in 37 (23 M, 14 F) patients with Type 2 diabetes. METHODS: Insulin aspart or regular human insulin was given subcutaneously (0.15 U/kg) in random sequence, using a double-dummy technique (at one visit: human regular insulin at t=-30 min and placebo at t=0; at the other visit: placebo at t=-30 min and aspart insulin at t=0). Serum glucose and insulin concentrations (15 points) were measured after each meal for 240 min. RESULTS: Post-prandial glycaemic excursions were 20% lower with insulin aspart (IAsp) compared with regular human insulin (HI) treatment [ratio (Iasp/HI)=0.80, CI=(0.66-0.98), P=0.034]. The maximum serum glucose (SG) concentration was similar for the two treatments (P=NS). The (median) time to maximum SG was 25 min shorter for IAsp compared with HI (P=0.048). Maximum serum insulin concentration was higher after IAsp compared with HI (P=0.023) as well as the area under the 4-h serum insulin curve (P=0.006). Furthermore, the time to maximum serum insulin concentration was 27 min shorter after IAsp (P=0.039), even though IAsp was injected 30 min after HI. No adverse events occurred during the trial. CONCLUSIONS: In patients with Type 2 diabetes a more favourable insulin profile and a better glycaemic control were found with IAsp injected immediately before compared with HI injected 30 min before a Mediterranean-style meal.

Aged↗
PubMed2004

Cytokine profile and insulin antibody IgG subclasses in patients with recent onset type 1 diabetes treated with oral insulin.

AIMS/HYPOTHESIS: Tolerance to orally administered antigens may be generated through the induction of T helper cell type 2 and 3 (Th2/Th3) regulatory cells. We previously reported that treatment of recent onset type 1 diabetes with oral insulin had no effect on residual beta cell function. The aim of this study was to evaluate whether this treatment produces a deviation in the immune response, with polarisation of the cytokine pattern and the induction of a Th2-like antibody response. METHODS: Mononuclear cells were collected from a total of 20 patients with type 1 diabetes before and after 12 months of treatment with oral insulin (n=11) or placebo (n=9). Following stimulation of the cells with insulin or phytohaemagglutinin, levels of Th2 and Th3 cytokines (including TGF-beta, IFN-gamma, IL-4 and IL-5) in the culture supernatants were assessed by ELISA. In addition, levels of total and specific insulin antibody IgG subclasses were measured by radioimmunoassay in serum samples drawn from 33 patients with type 1 diabetes before and after 3, 6 and 12 months of therapy with oral insulin (n=18) or placebo (n=15). RESULTS: After 12 months of treatment, the release of TGF-beta was significantly higher in patients who received oral insulin compared with those who received placebo (p=0.025 and p=0.006 for lymphocytes challenged with insulin and phytohaemagglutinin respectively). The two groups had similar levels of IL-4 and IL-5 both at baseline and after 12 months of treatment. The release of IFN-gamma was markedly reduced in patients treated with oral insulin compared with those who received placebo at the 12-month follow-up. Circulating levels of IgG1 and IgG3 subclasses directed against insulin were significantly lower in the oral insulin group than in the placebo group after 12 months of treatment (p=0.05 for IgG1 and p=0.014 for IgG3). CONCLUSIONS/INTERPRETATION: The increased TGF-beta release observed in patients treated with oral insulin suggests that a regulatory response can be induced in vivo by this treatment. The lower levels of insulin antibody IgG1 and IgG3 subclasses present in patients exposed to oral insulin are consistent with a Th2 deviation of the immune response. The failure of oral insulin treatment to provide any measurable clinical benefit may be due to the timing of treatment initiation.

Administration, Oral↗
PubMed2002

Autoantibodies against a 72-kDa ductal cell membrane glycoprotein in a patient affected by Sjögren's syndrome and gastric MALT lymphoma.

Sjögren's syndrome is a chronic autoimmune disease affecting exocrine glands, resulting in xerostomia and xerophthalmia. Lymphocytic infiltration and fibrosis of exocrine glands as well as the presence of autoantibodies against organ-specific and non-organ-specific antigens are the hallmarks of the disease. We investigated whether some patients affected by Sjögren's syndrome might have autoantibodies directed against epithelial duct cell membrane proteins. We screened sera from patients affected by Sjögren's syndrome by indirect immunofluorescence on monkey salivary gland sections and FG-Met-2 cells (a pancreatic carcinoma cell line with ductal features) for the presence of antisalivary duct antibodies. Positive sera were employed in immunoprecipitation experiments on (35)S-methionine in vivo labeled and surface-biotinylated FG-Met-2 cells. The serum of a patient affected by Sjögren's syndrome and gastric mucosa-associated lymphoid tissue (MALT) lymphoma gave positive and distinct membrane immunostaining on FG-Met-2 cells. Immunoprecipitation with the patient's serum from (35)S-methionine-labeled cell extracts followed by sodium dodecyl sulfate (SDS) polyacrylamide gel electrophoresis (PAGE) and autoradiography showed the presence of autoantibodies against a 72-kDa protein. After biotin-surface labeling of FG-Met-2 cells, a band with identical electrophoretic mobility was immunoprecipitated by the serum, demonstrating that the 72-kDa band is a membrane glycoprotein. We demonstrated by three complementary approaches, i.e., immunocytochemistry, (35)S-methionine in vivo labeling, and cell surface biotinylation, the presence of autoantibodies directed against a duct cell membrane protein of 72-kDa in a patient affected by Sjögren's syndrome and gastric MALT lymphoma. Autoantibodies directed against this novel membrane autoantigen may be an additional serological marker in some cases of Sjögren's syndrome.

Aged↗
PubMed2001

Fulminant autoimmune Type 1 diabetes during interferon-alpha therapy: a case of Th1-mediated disease?

AIM: A case of autoimmune Type 1 diabetes with some unique characteristics developing in a 29-year-old male during treatment with interferon-alpha (IFN-alpha) for chronic hepatitis C virus (HCV) hepatitis is reported. PATIENT AND METHODS: In this patient IFN-alpha treatment was well tolerated and successful in the cure of hepatitis with eradication of HCV infection within 3 months, but at 8.5 months Type 1 diabetes appeared and insulin therapy was started and maintained thereafter. HLA class II molecular typing was determined and retrospective measurement of islet cell (ICA), glutamate decarboxylase (GADA), tyrosin phosphatase IA-2 (IA-2A) and insulin (IAA) antibodies was performed in serum samples obtained before and at 0.5, 1, 2, 3, 4, 5, 6, 8.5, 10 and 13 months after the beginning of IFN-alpha treatment. RESULTS: Complete HLA class II typing was consistent with homozygosity for the HLA DRB *03011, DQA1 *0501, DQB1 *0201 haplotype. All autoantibodies were undetectable prior to IFN-alpha therapy and remained undetectable up to 6 months of treatment; at 8.5 months, at the time of diabetes onset, ICA were detectable at low titre while GADA were present at high titre. Both ICA and GADA persisted at high levels in subsequent samples. IA-2A remained undetectable in all serum samples, while IAA appeared only after treatment with exogenous insulin. DISCUSSION: This appears to be a case of autoimmune Type 1 diabetes induced by IFN-alpha treatment and developing on a predisposed genetic background with an unusually rapid development of the autoimmune process as reflected by the absence of detectable autoantibodies up to 2.5 months prior to disease onset. In this example of fulminant Type 1 diabetes a pathogenic process unbalanced towards a Th1-mediated autoimmune response is hypothesized. Diabet. Med. 18, 329-332 (2001)

Adult↗
PubMed2001

Macroamylasemia attributable to gluten-related amylase autoantibodies: a case report.

BACKGROUND: Macroamylasemia (MA) is a benign condition caused by circulating macroamylase complexes of pancreatic or salivary amylase bound to plasma proteins, which cannot be cleared by the renal glomeruli. In most cases, the macromolecular amylase represents a complex of normal amylase and either immunoglobulin A or G and may be a specific antigen-antibody complex. Celiac disease (CD) is a permanent intolerance to ingested gluten that results in immunologically mediated inflammatory damage of the small intestinal mucosa. Several recent population-based serologic surveys have shown CD to be a common disorder, possibly affecting 1 in 200 to 250 individuals in most countries studied, including the United States, where overt CD is rare, indicating a high proportion of subclinical disease. The diagnosis of CD currently rests on the histological demonstration of the characteristic lesion in the small intestine and the subsequent clinical response to the introduction of a gluten-free diet. MA associated with CD has been described in adult patients, and in a few cases, MA decreased or resolved after a strict gluten-free diet. A few single cases of MA have been described in childhood, but no association with CD has been reported so far. We report a girl with CD, autoimmune thyroiditis, and MA, in whom CD-related antibodies to amylase and to exocrine pancreas tissue resolved with a gluten-free diet. CASE REPORT: An 11-year-old girl was referred for chronic abdominal pain and growth retardation associated with persistent hyperamylasemia and suspected chronic pancreatitis. We confirmed elevated serum amylase, normal serum lipase, and very low 24-hour urine amylase and amylase clearance/creatinine clearance ratio, consistent with MA. Serologic tests for CD were positive, and the diagnosis was confirmed by small bowel biopsy showing subtotal villous atrophy. Thyroid function tests showed a pronounced hypothyroidism, associated with high titers of thyroid microsomal and thyroglobulin antibodies. Screening for other autoantibodies-including antinuclear, islet cell, glutamic acid decarboxylase, protein tyrosine phosphatase islet antigen 512, adrenal gland, and cytoplasmic neutrophil granulocyte antibodies-was negative. A diagnosis of CD, MA, and hypothyroidism attributable to autoimmune thyroiditis was made. A gluten-free diet and oral replacement with L-thyroxine was started with clinical improvement. Serum amylase and amylase clearance/creatinine clearance ratio normalized, consistent with resolution of MA. STUDY DESIGN AND METHODS: The patient's serum samples were obtained at the time of CD diagnosis and at 3 and 12 months after instituting a gluten-free diet. Serum samples from 10 consecutive untreated celiac children were disease controls, and 39 participants with no gastrointestinal symptoms and no family history of CD served as healthy controls. The origin of MA as determined by complexes of amylase with circulating immunoglobulins was tested by the measurement of amylase on supernatants after precipitation of immune complexes with either protein A Sepharose or polyethylene glycol. The precipitation of >60% of amylase activity was consistent with the presence of MA. Immunoglobulin G (IgG) and immunoglobulin A (IgA) circulating autoantibodies to amylase were measured using recently developed enzyme-linked immunosorbent assay (ELISA), using porcine amylase as antigen. Results were expressed as arbitrary units (AUs). Statistical analysis was performed by Student's t test for unpaired data. IgA and IgG antibodies to exocrine pancreas tissue were detected by indirect immunofluorescence on human pancreas cryosections. RESULTS: Serum immunoprecipitation with either protein A Sepharose or polyethylene glycol reduced amylase activity from 1698 to 89 U/L (94.8%) and to 75 U/L (95.6%), with only marginal reduction in control serum samples. The ELISA for autoantibodies to amylase detected high values, both IgA (3531 AU) and IgG (1855 AU), in the serum sample from the patient at CD diagnosis. IgA autoantibodies (mean +/- standard deviation) were 3.4 +/- 2.5 AU in healthy controls, and 2.1 +/- 1.2 AU in celiac controls; IgG autoantibodies were 10 +/- 4.8 AU in healthy controls and 8.5 +/- 3.2 AU, respectively. Autoantibodies to exocrine pancreas tissue were documented in patient sera at the time of CD diagnosis, both IgA and IgG, but not in control groups. Preincubation of patient's serum with excess of alpha-amylase specifically inhibited antibody binding to coated amylase in the ELISA, and partially inhibited immunoreactivity to exocrine pancreas. Autoantibodies to alpha-amylase and to exocrine pancreas declined in CD patients after institution of a gluten-free diet. CONCLUSIONS: Few cases of MA have been described in children, and in all amylase determination was part of the clinical investigation for abdominal pain or trauma. (ABSTRACT TRUNCATED)

Amylases↗
PubMed2001

Autoantibody response to islet transplantation in type 1 diabetes.

Islet allotransplantation into patients with autoimmune type 1 diabetes represents a reexposure to autoantigen. Here, measurement of antibodies to GAD and IA-2 autoantigens before and after islet transplantation in 36 patients (33 receiving islet plus kidney grafts with cyclosporin and steroid-based immunosuppression, and 3 receiving solitary islet transplants with mycophenolate but cyclosporin-free immunosuppression) demonstrated marked rises in GAD antibodies within 7 days posttransplantation in 5 patients (3 receiving islet after kidney transplants, and 2 receiving solitary islet transplants) and within 30 days in the third patient receiving solitary islet transplantation. GAD antibodies were of the IgG1 subclass, against major autoantigenic epitopes, and in cases of islet after kidney transplants, the responses were short-lived and not accompanied by HLA antibodies. Two of these patients had subsequent marked rises of IA-2 antibodies, and an additional patient had a marked rise in IgM-GAD antibodies 3 years after transplantation. Insulin independence was not achieved in patients with autoantibody elevations and was significantly less frequent in these patients. These data are consistent with a reactivation of autoimmunity that may be dependent on immunosuppression therapy and is associated with impaired graft function.

Adult↗
PubMed2000

Modulation of humoral islet autoimmunity by pancreas allotransplantation influences allograft outcome in patients with type 1 diabetes.

Pancreas transplantation in patients with type 1 diabetes presents allogeneic beta-cell autoantigens to the immune system long after the initial beta-cell destruction that leads to diabetes has occurred. The aims of this study were to determine whether re-exposure to beta-cell autoantigen through transplantation affect the humoral autoimmune response and whether its modulation correlates with graft outcome. Antibodies to the major autoantigens GAD (GADA) and protein tyrosine phosphatase IA-2 (IA-2A) were measured before and after transplantation in patients with type 1 diabetes who received pancreas and kidney allografts. In the 110 cases studied, pancreas graft survival was not significantly associated with the presence of GADA or IA-2A before transplantation. In the 75 patients with sequential follow-up samples up to 11.2 years after transplantation, autoantibodies were persistently undetectable in 44 cases (59%) and remained at stable detectable levels in 13 cases (17%). Substantial changes in antibody levels were found in 18 cases (24%), of which 13 cases (17%) had declining levels and 5 cases (7%) had marked increments after transplantation. Rising GADA and IA-2A levels in these five patients were predominantly of the IgG1 subclass, with progressive spreading of epitope reactivity. Pancreas graft function was lost 0.7-2.3 years after rising autoantibody levels in four of these five patients, and a significantly lower pancreas graft survival was found in patients with major rises in either GADA or IA-2A levels (P < 0.0001 vs. the remainder) and in patients having persistently high levels of IA-2A (P = 0.002 vs. stable antibody-negative patients). Kidney graft survival was not associated with islet autoantibody status. In conclusion, a minority of patients receiving pancreas allografts under generalized immunosuppression show a stimulation of islet autoantibody reactivity characteristic of that found in preclinical type 1 diabetes, which is almost invariably followed by graft function failure and resumption of insulin therapy.

Adult↗
PubMed2000

Autoimmunity against pancreatic islets and other tissues before and after interferon-alpha therapy in patients with hepatitis C virus chronic infection.

OBJECTIVE: The aim of the study was to investigate the prevalence of clinical and latent autoimmune diseases in Italian patients with hepatitis C virus (HCV) chronic infection before and after treatment with interferon-alpha (IFN-alpha). RESEARCH DESIGN AND METHODS: The evidence of clinical autoimmune disease and the presence of autoantibodies were assessed in 70 patients with HCV chronic infection. Autoantibodies to islet cell (ICA), glucagon-producing cells (GCA), parietal cell (PCA), adrenal cortex (ACA), adrenal medulla (AdMA), nuclei (ANA), liver-kidney microsomal (LKM-Ab), mitochondrial, and smooth muscle (SMA) were tested using the classic indirect immunofluorescence technique. Autoantibodies to GAD (GADAb), second islet cell autoantigen (IA2-Ab), and insulin (IAA) were tested by radioimmunoassay and thyroid microsomal autoantibodies (TMHA) and thyroglobulin autoantibodies (TGHA) were assessed by hemoagglutination test. RESULTS: None of the 70 patients studied showed evidence of clinical disease before treatment with IFN-alpha. However, 1 (1.4%) patient was positive for ICA, 2 (2.8%) were positive for GCA, 2 (2.8%) for GADAb, 5 (7.1%) for PCA, 2 (2.8%) for ANA, 3 (3.7%) for SMA, 4 (5.7%) for TMHA, and 2 (2.8%) for TGHA. These frequencies were not significantly different when compared with healthy control subjects. There were 29 (41%) patients who were positive for IAA at low titers compared with 2% of the control subjects (significantly different P < 0.0001). ICA titers of one patient positive for ICA/GADAb increased during the IFN-alpha therapy, and the patient developed type 1 diabetes 5 months after the beginning of treatment. IAA levels did not change during the course of treatment, and none of the IAA+ patients developed diabetes. Thyroid autoantibody titers increased in 3 of the 4 initially positive patients, with 1 patient becoming positive and 2 thyroid antibody-positive patients developing overt hypothyroidism during IFN-alpha treatment. PCA titers increased in 1 of 5 positive patients. Antibodies to other autoantigens did not change during the course of treatment. CONCLUSIONS: We have not found an increased frequency of clinical or latent autoimmune diseases in patients with chronic HCV infection. However, this study suggests that screening patients for autoantibodies (in particular, thyroid and pancreas) before and during IFN-alpha therapy may be useful in assessing the risk of patients developing autoimmune disease.

Adrenal Glands↗
PubMed1999

Comparison of tissue transglutaminase-specific antibody assays with established antibody measurements for coeliac disease.

Tissue transglutaminase C has recently been identified as one of the auto-antigens of endomysial antibodies found in coeliac disease. In this study we have cloned the human autoantigen and developed immunoassays measuring antibodies to transglutaminase in order to compare their diagnostic performance to that of established markers of the disease. A radiobinding assay using in vitro transcribed and translated 35S-methionine-labelled transglutaminase detected IgG antibodies in 110 and IgA antibodies in 109 of 112 patients at diagnosis of coeliac disease and in three and four of 92 control subjects, respectively. A radiobinding assay measuring both IgG and IgA transglutaminase antibodies identified 111 (99.1%) of the patients and 4 (4.3%) control subjects. Concordance of this assay with the IgA endomysial antibody test was found in 108 patients and 89 control subjects: two patients who had IgA deficiency and a third patient without IgA deficiency were only detected in the radiobinding assay; one patient had weak IgA endomysial antibodies only, and three of the control subjects with weak transglutaminase antibodies by radiobinding assay were undetectable in the IgA endomysial antibody assay. IgA and IgG ELISA using guinea pig transglutaminase and commercial ELISA measuring anti-gliadin antibodies had lower sensitivity and specificity than the radiobinding assays or the IgA endomysial antibody assay. This study confirms tissue transglutaminase C as a major autoantigen in coeliac disease and describes novel radiobinding assays for large scale testing to identify cases of coeliac disease.

Adolescent↗
PubMed1999

Antibodies to tissue transglutaminase C in type I diabetes.

AIMS/HYPOTHESIS: Silent coeliac disease is a gluten driven autoimmune disease which is relatively frequent in patients with Type I (insulin-dependent) diabetes mellitus. To determine the extent of gluten associated autoimmunity in Type I diabetes, autoantibodies to tissue transglutaminase C, a major autoantigen in coeliac disease, were measured in patients with new-onset Type I diabetes. METHODS: We measured IgG and IgA tissue transglutaminase C autoantibodies using human recombinant antigen and radio-binding assays in a cohort of 287 patients with new-onset Type I diabetes, 119 with Type II (non-insulin-dependent) diabetes mellitus and in 213 control subjects. RESULTS: We found IgA and IgG tissue transglutaminase C antibodies in 24 (8 %) patients with Type I diabetes; 97 (33 %) patients had IgG antibodies only and 1 IgA antibodies only. Antibody concentrations were highest in those with both IgA and IgG antibodies. Only 2 (2 %) patients with Type II diabetes and 2 (1 %) control subjects had either IgG or IgA tissue transglutaminase C antibodies. Patients with HLA DRB1(*)04 alleles had the highest prevalence of IgG tissue transglutaminase C antibodies. CONCLUSION/INTERPRETATION: These data show that almost 10 % of patients have autoimmunity typical of coeliac disease and that another 30 % have low level tissue transglutaminase C antibody binding. This high prevalence suggests either involvement of the gut in the pathogenesis of Type I diabetes or that transglutaminase is a secondary autoantigen resulting from beta-cell destruction. [Diabetologia (1999) 42: 1195-1198]

Adolescent↗