Mauro Congia - Academia.edu (original) (raw)

Papers by Mauro Congia

Research paper thumbnail of Primary Sequence of Coding Recion of Lactase-Phlorizin Hydrolase Gene in Congenital Human Lactase Deficiency

Journal of Pediatric Gastroenterology and Nutrition, Oct 1, 1991

Research paper thumbnail of Case 76: No Effect of Gluten-Free Diet in Prevention of Autoimmune Type 1 Diabetes and Other Autoimmune Disorders in a Child with Celiac Disease

American Diabetes Association eBooks, 2015

An 11-month-old Sardinian female infant was brought to our clinic in March 2000 for 3 weeks of di... more An 11-month-old Sardinian female infant was brought to our clinic in March 2000 for 3 weeks of diarrhea (4–5 bowel movements daily), associated with weight loss from 9.0 kg to 7.5 kg. She was naturally born at the 39th week of gestation and breast-fed until 1 month of age when baby formula milk was introduced. At the end of the sixth month, she started the weaning until the progressive onset of the diarrhea.

Research paper thumbnail of Studio DI Associazione Hla e Tiroidite Autoimmune in Una Casistica DI Pazienti Pediatrici

Research paper thumbnail of Determination of Glutamic Acid Decarboxylase 65 Peptides Presented by the Type I Diabetes-Associated HLA-DQ8 Class II Molecule Identifies an Immunogenic Peptide Motif

Journal of Immunology, Dec 1, 1999

Particular HLA class II allelic sequences are associated with susceptibility to type I diabetes. ... more Particular HLA class II allelic sequences are associated with susceptibility to type I diabetes. To understand the mechanism, knowledge of the molecular nature of the specific TCR/peptide/class II interactions involved in the disease process is required. To this end, we have introduced the diabetes-associated human class II HLA-DQ8 allele (DQA1*0301/DQB1*0302) as a transgene into mice and analyzed T cell responses restricted by this molecule to an important Ag in human diabetes, human glutamic acid decarboxylase 65. Hybridomas were used to determine the particular peptides from this Ag presented by HLA-DQ8 to T cells and to map the core minimal epitopes required for T cell stimulation. Analysis of these core epitopes reveals a motif and relevant features for peptides that are immunogenic to T cells when presented by HLA-DQ8. The major immunogenic epitopes of glutamic acid decarboxylase 65 do not contain a negatively charged residue that binds in the P9 pocket of the HLA-DQ8 molecule. PBMC from HLA-DQ8 ؉ diabetic and nondiabetic individuals respond to these peptides, confirming that the mouse model is a useful tool to define epitopes of autoantigens that are processed by human APC and recognized by human T cells.

Research paper thumbnail of Case 49: Glycemic Control in a Child with Type 1 Diabetes and Autoimmune Hepatitis

American Diabetes Association eBooks, 2015

A 5-year-old girl was brought to our clinic in July 2009 for increased values of liver transamina... more A 5-year-old girl was brought to our clinic in July 2009 for increased values of liver transaminases. She was naturally born at the 40th week of gestation and breast-fed for 6 months. At the 10th month of age after the last mandatory vaccine dose, she developed type 1 diabetes (T1D).

Research paper thumbnail of Identification of immunodominant T-cell epitopes of human glutamic acid decarboxylase 65 using HLA-DR4 transgenic mice

Experimental and Clinical Endocrinology & Diabetes, Jul 15, 2009

Research paper thumbnail of Genetic factors associated with levels of immune cell types

Research paper thumbnail of Dissecting T cell responses to cartilage antigens in HLA class II transgenic mice

Research paper thumbnail of DNA methylation of the TPMT gene and azathioprine pharmacokinetics in children with very early onset inflammatory bowel disease

Biomedicine & Pharmacotherapy

Research paper thumbnail of Peripheral blood mononuclear cells reactivity in recent-onset type I diabetes patients is directed against the leader peptide of preproinsulin, GAD65271-285 and GAD65431-450

Frontiers in Immunology

IntroductionT cell reactivity against pancreatic autoantigens is considered one of the main contr... more IntroductionT cell reactivity against pancreatic autoantigens is considered one of the main contributors to the destruction of insulin-producing cells in type 1 diabetes (T1D). Over the years, peptide epitopes derived from these autoantigens have been described in NOD mice and in both HLA class II transgenic mice and humans. However, which ones are involved in the early onset or in the progressive phases of the disease is still unclear.MethodsIn this work we have investigated, in early-onset T1D pediatric patients and HLA-matched controls from Sardinia, the potential of preproinsulin (PPI) and glutamate decarboxylase 65 (GAD65)-derived peptides to induce spontaneous T cell proliferation responses of peripheral blood mononuclear cells (PBMCs).ResultsSignificant T cell responses against PPI1-18, PPI7-19 and PPI31-49, the first two belonging to the leader sequence of PPI, and GAD65271-285 and GAD65431-450, were found in HLA-DR4, -DQ8 and -DR3, -DQ2 T1D children.ConclusionsThese data sh...

Research paper thumbnail of Low-Risk Human Leukocyte Antigen Genes and Mild Villous Atrophy Typify Celiac Disease With Immunoglobulin A Deficiency

Journal of Pediatric Gastroenterology & Nutrition, 2021

ABSTRACT Objectives: We aimed to establish if in celiac disease (CD) with immunoglobulin A defici... more ABSTRACT Objectives: We aimed to establish if in celiac disease (CD) with immunoglobulin A deficiency (IgAD) duodenal histopathology is influenced by human leukocyte antigen (HLA)-DQB1∗02 alleles dosage. Clinical differences between patients with CD and patients with CD and IgAD (CD-IgAD) were also evaluated. Methods: Five hundred and sixteen CD and 16 patients with CD-IgAD, enrolled over the time of 8 years, took part in this study. The severity of duodenal histopathology and frequency of CD at-risk HLA class II genes were compared in patients with CD versus patients with CD-IgAD. HLA class II genotypes were subdivided into two categories of genetic risk: high: HLA-DR3/DR7, -DR3/DR3, -DR4/DR4 -DR3/DR4 and low: HLA-DR5/DR7, -DR3/X, -DR4/X and X/X, where X means neither -DR3 nor -DR4. Then, they were compared with two types of duodenal histopathology: 0, 1, 2 and 3a of mild villous atrophy (MVA) and 3b and 3c of severe villous atrophy (SVA) according to the Marsh-Oberhuber classification. Clinical data concerning gender, number of esophagogastroduodenoscopies (EGDs) and association with other autoimmune diseases were obtained from medical records. Results: In comparison with CD, CD-IgAD showed an increased frequency of MVA (P < 0.0001). Furthermore, CD-IgAD with MVA showed an increase of HLA low-risk genotypes (P = 0.036) and half HLA-DQ2 heterodimers (P = 0.0443). Interestingly, CD-IgAD demanded an increased number of EGDs to reach the diagnosis of CD (P = 0.0104) and autoimmune liver diseases were more frequent compared to CD (P = 0.0049). Conclusions: CD-IgAD is associated with MVA, low-risk HLA class II genes, an increased number of EGDs and autoimmune liver diseases.

Research paper thumbnail of Toward the renal vesicle: Ultrastructural investigation of the cap mesenchyme splitting process in the developing kidney

Journal of Public Health Research

Background: A complex sequence of morphogenetic events leads to the development of the adult mous... more Background: A complex sequence of morphogenetic events leads to the development of the adult mouse kidney. In the present study, we investigated the morphological events that characterize the early stages of the mesenchymal-to-epithelial transition of cap mesenchymal cells, analyzing in depth the relationship between cap mesenchymal induction and ureteric bud (UB) branching. Design and methods: Normal kidneys of newborn non-obese diabetic (NOD) mice were excised and prepared for light and electron microscopic examination. Results: Nephrogenesis was evident in the outer portion of the renal cortex of all examined samples. This process was mainly due to the interaction of two primordial derivatives, the ureteric bud and the metanephric mesenchyme. Early renal developmental stages were initially characterized by the formation of a continuous layer of condensed mesenchymal cells around the tips of the ureteric buds. These caps of mesenchymal cells affected the epithelial cells of the un...

Research paper thumbnail of McDevitt: Chronic tumor necrosis factor alters T cell responses by attenuating T cell receptor signaling

Repeated injections of adult mice with recombinant murine TNF prolong the survival of NZB/W F1 mi... more Repeated injections of adult mice with recombinant murine TNF prolong the survival of NZB/W F1 mice, and suppress type I insulin-dependent diabetes mellitus (IDDM) in nonobese diabetic (NOD) mice. To determine whether repeated TNF injections suppress T cell function in adult mice, we studied the responses of influenza hemagglutinin-specific T cells derived from T cell receptor (HNT-TCR) transgenic mice. Treatment of adult mice with murine TNF for 3 wk suppressed a broad range of T cell responses, including proliferation and cytokine production. Furthermore, T cell responses of HNT-TCR transgenic mice also expressing the human TNF-globin transgene were markedly reduced compared to HNT-TCR single transgenic littermates, indicating that sustained p55 TNF-R signaling is sufficient to suppress T cell function in vivo. Using a model of chronic TNF exposure in vitro, we demonstrate that (a) chronic TNF effects are dose and time dependent, (b) TNF suppresses the responses of both Th1 and Th...

Research paper thumbnail of Phenotype and Natural History of Children With Coexistent Inflammatory Bowel Disease and Celiac Disease

Inflammatory Bowel Diseases, 2021

Background Adult patients with both inflammatory bowel disease (IBD) and celiac disease (CeD) hav... more Background Adult patients with both inflammatory bowel disease (IBD) and celiac disease (CeD) have peculiar phenotypic features. This study aimed at describing the characteristics and natural history of children with both IBD and CeD. Methods This was a case-control study based on a national registry. Cases included children diagnosed with both IBD and CeD. Two matched IBD controls without CeD, and 2 matched CeD controls were selected for each case. Inflammatory bowel disease phenotype and natural history, comprising growth and pubertal development, were compared between groups. Results Forty-nine (1.75%) patients with IBD and CeD were identified out of 2800 patients with IBD. Compared with patients with IBD alone, patients with IBD and CeD presented more frequently with autoimmune diseases (odds ratio, 2.81; 95% CI, 0.97–8.37; P = 0.04). Ileocolonic localization (46.1% vs 73.1%), treatment with azathioprine (46.2% vs 71.2%), and anti-TNF biologics (46.2% vs 69.2%) were less common ...

Research paper thumbnail of Early effects of gliadin on enterocyte intracellular signalling involved in intestinal barrier function

Gut, 2003

Background and aims: Despite the progress made in understanding the immunological aspects of the ... more Background and aims: Despite the progress made in understanding the immunological aspects of the pathogenesis of coeliac disease (CD), the early steps that allow gliadin to cross the intestinal barrier are still largely unknown. The aim of this study was to establish whether gliadin activates a zonulin dependent enterocyte intracellular signalling pathway(s) leading to increased intestinal permeability. Methods: The effect of gliadin on the enterocyte actin cytoskeleton was studied on rat intestinal epithelial (IEC-6) cell cultures by fluorescence microscopy and spectrofluorimetry. Zonulin concentration was measured on cell culture supernatants by enzyme linked immunosorbent assay. Transepithelial intestinal resistance (Rt) was measured on ex vivo intestinal tissues mounted in Ussing chambers. Results: Incubation of cells with gliadin led to a reversible protein kinase C (PKC) mediated actin polymerisation temporarily coincident with zonulin release. A significant reduction in Rt was observed after gliadin addition on rabbit intestinal mucosa mounted in Ussing chambers. Pretreatment with the zonulin inhibitor FZI/0 abolished the gliadin induced actin polymerisation and Rt reduction but not zonulin release. Conclusions: Gliadin induces zonulin release in intestinal epithelial cells in vitro. Activation of the zonulin pathway by PKC mediated cytoskeleton reorganisation and tight junction opening leads to a rapid increase in intestinal permeability.

Research paper thumbnail of Hla Class-II Genes and Insulin-Dependent Diabetes-Mellitus (Iddm) in Sardinia

Research paper thumbnail of Gene-Frequency and Mechanism of Generation of a Novel HLA-DQB1 Allele

American Journal of Human Genetics, 1993

Research paper thumbnail of Enterocyte actin autoantibody detection: A new diagnostic tool in celiac disease diagnosis: Results of a multicenter study

American Journal of Gastroenterology, 2004

This study describes a new method to detect autoantibodies against actin filaments (AAA) as a ser... more This study describes a new method to detect autoantibodies against actin filaments (AAA) as a serological marker of intestinal villous atrophy (IVA) in celiac disease (CD), and reports the results of an Italian double-blind multicenter study. IgA-AAA were analyzed by immunofluorescence using a newly developed method based on intestinal epithelial cells cultured in presence of colchicine. IgA-AAA were blindly evaluated prospectively in 223 antiendomysial antibody (AEA) and/or antitransglutaminase antibody (TGA) positive subjects and in 78 AEA and TGA negative subjects. IgA-AAA positive patients underwent an intestinal biopsy to confirm the diagnosis. Moreover, IgA-AAA were retrospectively investigated in 84 biopsy-proven CD patients and in 2,000 new consecutively collected serum samples from AEA and TGA negative nonbiopsied subjects. IgA-AAA were positive in 98.2% of the CD patients with flat mucosa, in 89% with subtotal villous atrophy, and in 30% with partial villous atrophy. IgA-AAA were present in none of the AEA and TGA negative nonbiopsied controls. In AEA and/or TGA positive CD patients IgA-AAA positivity significantly correlated with IVA (p &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.000 in the prospective study, p = 0.005 in the retrospective study). In the prospective study, the values of sensitivity, specificity, the positive predictive value, the negative predictive value, and the efficiency of the IgA-AAA test to identify patients with IVA were, respectively, 83.9%, 95.1%, 97.8%, 69.2%, and 87.0%. Furthermore, a significant correlation (p &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.0001) was found between the IgA-AAA serum titre and the degree of IVA (rs 0.56). The results of this multicenter study show that the new method for IgA-AAA detection could represent a practical diagnostic tool in AEA and/or TGA positive subjects, which would be especially useful when IVA shows a patchy distribution, when the histological picture is difficult to interpret, or when a biopsy could represent a life-threatening risk.

Research paper thumbnail of Autoimmune Polyendocrine Syndrome Type 1: An Extensive Longitudinal Study in Sardinian Patients

The Journal of Clinical Endocrinology & Metabolism, 2012

Context: Autoimmune polyendocrine syndrome type 1 (APS1) is a childhood-onset monogenic disorder ... more Context: Autoimmune polyendocrine syndrome type 1 (APS1) is a childhood-onset monogenic disorder caused by mutations in the autoimmune regulator (AIRE) gene, including the distinctive R139X in Sardinia. Its rarity and great variability in manifestations/onset ages make early diagnosis difficult. To date, very few longitudinal studies of APS1 patients have been reported. Objective: The aim of this study was to describe the features and clinical course of APS1 and correlate them with AIRE and HLA class II genotypes in a large homogeneous cohort of Sardinian patients followed for up to 25 yr. Patients: Twenty-two pediatric APS1 patients were studied prospectively. Results: This Sardinian series (female/male ratio, 1.44; median current age, 30.7 yr; range, 1.8-46 yr) showed early disease onset (age range, 0.3-10 yr; median, 3.5 yr) and severe phenotype (on average, seven manifestations per patient). Besides the classic triad of chronic mucocutaneous candidiasis, hypoparathyroidism, and Addison's disease, autoimmune hepatitis was a serious and surprisingly common/early/presenting feature (27%; two deaths), with a 5:1 female bias (median age, 6 yr; range, 2.5-11 yr). By contrast, type 1 diabetes was rare (one patient), and hypothyroidism was not seen. Additional disease components (several of them potentially life-threatening) appeared in adulthood. The major nonsense mutation, R139X, was found in 93% of the mutant AIRE alleles. High-titer interferon (IFN)-and IFN-␣ autoantibodies were detected in all patients tested, even preclinically at 4 months of age in one sibling. HLA alleles appear to influence the exact phenotype-the most interesting apparent association being between HLA-DRB1*0301-DQB1*0201, liver-kidney microsome autoantibodies (anti-CYP1A2), and autoimmune hepatitis. Conclusion: APS1 in Sardinia is characterized by severe phenotype, marked clinical heterogeneity, and relative genetic homogeneity. The single AIRE mutation, R139X, and the anti-IFN-and IFN-␣ autoantibodies are helpful for earlier diagnosis, especially when APS1 presents unusually. HLA genotypes can modify the phenotype.

Research paper thumbnail of HLA class II genes in chronic hepatitis C virus-infection and associated immunological disorders

Research paper thumbnail of Primary Sequence of Coding Recion of Lactase-Phlorizin Hydrolase Gene in Congenital Human Lactase Deficiency

Journal of Pediatric Gastroenterology and Nutrition, Oct 1, 1991

Research paper thumbnail of Case 76: No Effect of Gluten-Free Diet in Prevention of Autoimmune Type 1 Diabetes and Other Autoimmune Disorders in a Child with Celiac Disease

American Diabetes Association eBooks, 2015

An 11-month-old Sardinian female infant was brought to our clinic in March 2000 for 3 weeks of di... more An 11-month-old Sardinian female infant was brought to our clinic in March 2000 for 3 weeks of diarrhea (4–5 bowel movements daily), associated with weight loss from 9.0 kg to 7.5 kg. She was naturally born at the 39th week of gestation and breast-fed until 1 month of age when baby formula milk was introduced. At the end of the sixth month, she started the weaning until the progressive onset of the diarrhea.

Research paper thumbnail of Studio DI Associazione Hla e Tiroidite Autoimmune in Una Casistica DI Pazienti Pediatrici

Research paper thumbnail of Determination of Glutamic Acid Decarboxylase 65 Peptides Presented by the Type I Diabetes-Associated HLA-DQ8 Class II Molecule Identifies an Immunogenic Peptide Motif

Journal of Immunology, Dec 1, 1999

Particular HLA class II allelic sequences are associated with susceptibility to type I diabetes. ... more Particular HLA class II allelic sequences are associated with susceptibility to type I diabetes. To understand the mechanism, knowledge of the molecular nature of the specific TCR/peptide/class II interactions involved in the disease process is required. To this end, we have introduced the diabetes-associated human class II HLA-DQ8 allele (DQA1*0301/DQB1*0302) as a transgene into mice and analyzed T cell responses restricted by this molecule to an important Ag in human diabetes, human glutamic acid decarboxylase 65. Hybridomas were used to determine the particular peptides from this Ag presented by HLA-DQ8 to T cells and to map the core minimal epitopes required for T cell stimulation. Analysis of these core epitopes reveals a motif and relevant features for peptides that are immunogenic to T cells when presented by HLA-DQ8. The major immunogenic epitopes of glutamic acid decarboxylase 65 do not contain a negatively charged residue that binds in the P9 pocket of the HLA-DQ8 molecule. PBMC from HLA-DQ8 ؉ diabetic and nondiabetic individuals respond to these peptides, confirming that the mouse model is a useful tool to define epitopes of autoantigens that are processed by human APC and recognized by human T cells.

Research paper thumbnail of Case 49: Glycemic Control in a Child with Type 1 Diabetes and Autoimmune Hepatitis

American Diabetes Association eBooks, 2015

A 5-year-old girl was brought to our clinic in July 2009 for increased values of liver transamina... more A 5-year-old girl was brought to our clinic in July 2009 for increased values of liver transaminases. She was naturally born at the 40th week of gestation and breast-fed for 6 months. At the 10th month of age after the last mandatory vaccine dose, she developed type 1 diabetes (T1D).

Research paper thumbnail of Identification of immunodominant T-cell epitopes of human glutamic acid decarboxylase 65 using HLA-DR4 transgenic mice

Experimental and Clinical Endocrinology & Diabetes, Jul 15, 2009

Research paper thumbnail of Genetic factors associated with levels of immune cell types

Research paper thumbnail of Dissecting T cell responses to cartilage antigens in HLA class II transgenic mice

Research paper thumbnail of DNA methylation of the TPMT gene and azathioprine pharmacokinetics in children with very early onset inflammatory bowel disease

Biomedicine & Pharmacotherapy

Research paper thumbnail of Peripheral blood mononuclear cells reactivity in recent-onset type I diabetes patients is directed against the leader peptide of preproinsulin, GAD65271-285 and GAD65431-450

Frontiers in Immunology

IntroductionT cell reactivity against pancreatic autoantigens is considered one of the main contr... more IntroductionT cell reactivity against pancreatic autoantigens is considered one of the main contributors to the destruction of insulin-producing cells in type 1 diabetes (T1D). Over the years, peptide epitopes derived from these autoantigens have been described in NOD mice and in both HLA class II transgenic mice and humans. However, which ones are involved in the early onset or in the progressive phases of the disease is still unclear.MethodsIn this work we have investigated, in early-onset T1D pediatric patients and HLA-matched controls from Sardinia, the potential of preproinsulin (PPI) and glutamate decarboxylase 65 (GAD65)-derived peptides to induce spontaneous T cell proliferation responses of peripheral blood mononuclear cells (PBMCs).ResultsSignificant T cell responses against PPI1-18, PPI7-19 and PPI31-49, the first two belonging to the leader sequence of PPI, and GAD65271-285 and GAD65431-450, were found in HLA-DR4, -DQ8 and -DR3, -DQ2 T1D children.ConclusionsThese data sh...

Research paper thumbnail of Low-Risk Human Leukocyte Antigen Genes and Mild Villous Atrophy Typify Celiac Disease With Immunoglobulin A Deficiency

Journal of Pediatric Gastroenterology & Nutrition, 2021

ABSTRACT Objectives: We aimed to establish if in celiac disease (CD) with immunoglobulin A defici... more ABSTRACT Objectives: We aimed to establish if in celiac disease (CD) with immunoglobulin A deficiency (IgAD) duodenal histopathology is influenced by human leukocyte antigen (HLA)-DQB1∗02 alleles dosage. Clinical differences between patients with CD and patients with CD and IgAD (CD-IgAD) were also evaluated. Methods: Five hundred and sixteen CD and 16 patients with CD-IgAD, enrolled over the time of 8 years, took part in this study. The severity of duodenal histopathology and frequency of CD at-risk HLA class II genes were compared in patients with CD versus patients with CD-IgAD. HLA class II genotypes were subdivided into two categories of genetic risk: high: HLA-DR3/DR7, -DR3/DR3, -DR4/DR4 -DR3/DR4 and low: HLA-DR5/DR7, -DR3/X, -DR4/X and X/X, where X means neither -DR3 nor -DR4. Then, they were compared with two types of duodenal histopathology: 0, 1, 2 and 3a of mild villous atrophy (MVA) and 3b and 3c of severe villous atrophy (SVA) according to the Marsh-Oberhuber classification. Clinical data concerning gender, number of esophagogastroduodenoscopies (EGDs) and association with other autoimmune diseases were obtained from medical records. Results: In comparison with CD, CD-IgAD showed an increased frequency of MVA (P < 0.0001). Furthermore, CD-IgAD with MVA showed an increase of HLA low-risk genotypes (P = 0.036) and half HLA-DQ2 heterodimers (P = 0.0443). Interestingly, CD-IgAD demanded an increased number of EGDs to reach the diagnosis of CD (P = 0.0104) and autoimmune liver diseases were more frequent compared to CD (P = 0.0049). Conclusions: CD-IgAD is associated with MVA, low-risk HLA class II genes, an increased number of EGDs and autoimmune liver diseases.

Research paper thumbnail of Toward the renal vesicle: Ultrastructural investigation of the cap mesenchyme splitting process in the developing kidney

Journal of Public Health Research

Background: A complex sequence of morphogenetic events leads to the development of the adult mous... more Background: A complex sequence of morphogenetic events leads to the development of the adult mouse kidney. In the present study, we investigated the morphological events that characterize the early stages of the mesenchymal-to-epithelial transition of cap mesenchymal cells, analyzing in depth the relationship between cap mesenchymal induction and ureteric bud (UB) branching. Design and methods: Normal kidneys of newborn non-obese diabetic (NOD) mice were excised and prepared for light and electron microscopic examination. Results: Nephrogenesis was evident in the outer portion of the renal cortex of all examined samples. This process was mainly due to the interaction of two primordial derivatives, the ureteric bud and the metanephric mesenchyme. Early renal developmental stages were initially characterized by the formation of a continuous layer of condensed mesenchymal cells around the tips of the ureteric buds. These caps of mesenchymal cells affected the epithelial cells of the un...

Research paper thumbnail of McDevitt: Chronic tumor necrosis factor alters T cell responses by attenuating T cell receptor signaling

Repeated injections of adult mice with recombinant murine TNF prolong the survival of NZB/W F1 mi... more Repeated injections of adult mice with recombinant murine TNF prolong the survival of NZB/W F1 mice, and suppress type I insulin-dependent diabetes mellitus (IDDM) in nonobese diabetic (NOD) mice. To determine whether repeated TNF injections suppress T cell function in adult mice, we studied the responses of influenza hemagglutinin-specific T cells derived from T cell receptor (HNT-TCR) transgenic mice. Treatment of adult mice with murine TNF for 3 wk suppressed a broad range of T cell responses, including proliferation and cytokine production. Furthermore, T cell responses of HNT-TCR transgenic mice also expressing the human TNF-globin transgene were markedly reduced compared to HNT-TCR single transgenic littermates, indicating that sustained p55 TNF-R signaling is sufficient to suppress T cell function in vivo. Using a model of chronic TNF exposure in vitro, we demonstrate that (a) chronic TNF effects are dose and time dependent, (b) TNF suppresses the responses of both Th1 and Th...

Research paper thumbnail of Phenotype and Natural History of Children With Coexistent Inflammatory Bowel Disease and Celiac Disease

Inflammatory Bowel Diseases, 2021

Background Adult patients with both inflammatory bowel disease (IBD) and celiac disease (CeD) hav... more Background Adult patients with both inflammatory bowel disease (IBD) and celiac disease (CeD) have peculiar phenotypic features. This study aimed at describing the characteristics and natural history of children with both IBD and CeD. Methods This was a case-control study based on a national registry. Cases included children diagnosed with both IBD and CeD. Two matched IBD controls without CeD, and 2 matched CeD controls were selected for each case. Inflammatory bowel disease phenotype and natural history, comprising growth and pubertal development, were compared between groups. Results Forty-nine (1.75%) patients with IBD and CeD were identified out of 2800 patients with IBD. Compared with patients with IBD alone, patients with IBD and CeD presented more frequently with autoimmune diseases (odds ratio, 2.81; 95% CI, 0.97–8.37; P = 0.04). Ileocolonic localization (46.1% vs 73.1%), treatment with azathioprine (46.2% vs 71.2%), and anti-TNF biologics (46.2% vs 69.2%) were less common ...

Research paper thumbnail of Early effects of gliadin on enterocyte intracellular signalling involved in intestinal barrier function

Gut, 2003

Background and aims: Despite the progress made in understanding the immunological aspects of the ... more Background and aims: Despite the progress made in understanding the immunological aspects of the pathogenesis of coeliac disease (CD), the early steps that allow gliadin to cross the intestinal barrier are still largely unknown. The aim of this study was to establish whether gliadin activates a zonulin dependent enterocyte intracellular signalling pathway(s) leading to increased intestinal permeability. Methods: The effect of gliadin on the enterocyte actin cytoskeleton was studied on rat intestinal epithelial (IEC-6) cell cultures by fluorescence microscopy and spectrofluorimetry. Zonulin concentration was measured on cell culture supernatants by enzyme linked immunosorbent assay. Transepithelial intestinal resistance (Rt) was measured on ex vivo intestinal tissues mounted in Ussing chambers. Results: Incubation of cells with gliadin led to a reversible protein kinase C (PKC) mediated actin polymerisation temporarily coincident with zonulin release. A significant reduction in Rt was observed after gliadin addition on rabbit intestinal mucosa mounted in Ussing chambers. Pretreatment with the zonulin inhibitor FZI/0 abolished the gliadin induced actin polymerisation and Rt reduction but not zonulin release. Conclusions: Gliadin induces zonulin release in intestinal epithelial cells in vitro. Activation of the zonulin pathway by PKC mediated cytoskeleton reorganisation and tight junction opening leads to a rapid increase in intestinal permeability.

Research paper thumbnail of Hla Class-II Genes and Insulin-Dependent Diabetes-Mellitus (Iddm) in Sardinia

Research paper thumbnail of Gene-Frequency and Mechanism of Generation of a Novel HLA-DQB1 Allele

American Journal of Human Genetics, 1993

Research paper thumbnail of Enterocyte actin autoantibody detection: A new diagnostic tool in celiac disease diagnosis: Results of a multicenter study

American Journal of Gastroenterology, 2004

This study describes a new method to detect autoantibodies against actin filaments (AAA) as a ser... more This study describes a new method to detect autoantibodies against actin filaments (AAA) as a serological marker of intestinal villous atrophy (IVA) in celiac disease (CD), and reports the results of an Italian double-blind multicenter study. IgA-AAA were analyzed by immunofluorescence using a newly developed method based on intestinal epithelial cells cultured in presence of colchicine. IgA-AAA were blindly evaluated prospectively in 223 antiendomysial antibody (AEA) and/or antitransglutaminase antibody (TGA) positive subjects and in 78 AEA and TGA negative subjects. IgA-AAA positive patients underwent an intestinal biopsy to confirm the diagnosis. Moreover, IgA-AAA were retrospectively investigated in 84 biopsy-proven CD patients and in 2,000 new consecutively collected serum samples from AEA and TGA negative nonbiopsied subjects. IgA-AAA were positive in 98.2% of the CD patients with flat mucosa, in 89% with subtotal villous atrophy, and in 30% with partial villous atrophy. IgA-AAA were present in none of the AEA and TGA negative nonbiopsied controls. In AEA and/or TGA positive CD patients IgA-AAA positivity significantly correlated with IVA (p &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.000 in the prospective study, p = 0.005 in the retrospective study). In the prospective study, the values of sensitivity, specificity, the positive predictive value, the negative predictive value, and the efficiency of the IgA-AAA test to identify patients with IVA were, respectively, 83.9%, 95.1%, 97.8%, 69.2%, and 87.0%. Furthermore, a significant correlation (p &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.0001) was found between the IgA-AAA serum titre and the degree of IVA (rs 0.56). The results of this multicenter study show that the new method for IgA-AAA detection could represent a practical diagnostic tool in AEA and/or TGA positive subjects, which would be especially useful when IVA shows a patchy distribution, when the histological picture is difficult to interpret, or when a biopsy could represent a life-threatening risk.

Research paper thumbnail of Autoimmune Polyendocrine Syndrome Type 1: An Extensive Longitudinal Study in Sardinian Patients

The Journal of Clinical Endocrinology & Metabolism, 2012

Context: Autoimmune polyendocrine syndrome type 1 (APS1) is a childhood-onset monogenic disorder ... more Context: Autoimmune polyendocrine syndrome type 1 (APS1) is a childhood-onset monogenic disorder caused by mutations in the autoimmune regulator (AIRE) gene, including the distinctive R139X in Sardinia. Its rarity and great variability in manifestations/onset ages make early diagnosis difficult. To date, very few longitudinal studies of APS1 patients have been reported. Objective: The aim of this study was to describe the features and clinical course of APS1 and correlate them with AIRE and HLA class II genotypes in a large homogeneous cohort of Sardinian patients followed for up to 25 yr. Patients: Twenty-two pediatric APS1 patients were studied prospectively. Results: This Sardinian series (female/male ratio, 1.44; median current age, 30.7 yr; range, 1.8-46 yr) showed early disease onset (age range, 0.3-10 yr; median, 3.5 yr) and severe phenotype (on average, seven manifestations per patient). Besides the classic triad of chronic mucocutaneous candidiasis, hypoparathyroidism, and Addison's disease, autoimmune hepatitis was a serious and surprisingly common/early/presenting feature (27%; two deaths), with a 5:1 female bias (median age, 6 yr; range, 2.5-11 yr). By contrast, type 1 diabetes was rare (one patient), and hypothyroidism was not seen. Additional disease components (several of them potentially life-threatening) appeared in adulthood. The major nonsense mutation, R139X, was found in 93% of the mutant AIRE alleles. High-titer interferon (IFN)-and IFN-␣ autoantibodies were detected in all patients tested, even preclinically at 4 months of age in one sibling. HLA alleles appear to influence the exact phenotype-the most interesting apparent association being between HLA-DRB1*0301-DQB1*0201, liver-kidney microsome autoantibodies (anti-CYP1A2), and autoimmune hepatitis. Conclusion: APS1 in Sardinia is characterized by severe phenotype, marked clinical heterogeneity, and relative genetic homogeneity. The single AIRE mutation, R139X, and the anti-IFN-and IFN-␣ autoantibodies are helpful for earlier diagnosis, especially when APS1 presents unusually. HLA genotypes can modify the phenotype.

Research paper thumbnail of HLA class II genes in chronic hepatitis C virus-infection and associated immunological disorders