HLA-DRB1*15:01-DQA1*01:02-DQB1*06:02 Haplotype Protects Autoantibody-Positive Relatives From Type 1 Diabetes Throughout the Stages of Disease Progression.

The HLA-DRB1*15:01-DQA1*01:02-DQB1*06:02 haplotype is linked to protection from the development of type 1 diabetes (T1D). However, it is not known at which stages in the natural history of T1D development this haplotype affords protection. We examined a cohort of 3,358 autoantibody-positive relatives of T1D patients in the Pathway to Prevention (PTP) Study of the Type 1 Diabetes TrialNet.

Genetics of Autoimmune Thyroiditis in Type 1 Diabetes Reveals a Novel Association With DPB1*0201: Data From the Type 1 Diabetes Genetics Consortium.

Background: Autoimmune thyroiditis occurs in 10-25% of patients with type 1 diabetes (T1D). Most of these patients are also positive for thyroid peroxidase (TPO) antibodies. Thyroid dysfunction complicates T1D metabolic control and is a component of the autoimmune polyglandular syndrome (APS, type 2 or 3).

Novel Association Between Immune-Mediated Susceptibility Loci and Persistent Autoantibody Positivity in Type 1 Diabetes.

Islet autoantibodies detected at disease onset in patients with type 1 diabetes are signs of an autoimmune destruction of the insulin-producing β-cells. To further investigate the genetic determinants of autoantibody positivity, we performed dense immune-focused genotyping on the Immunochip array and tested for association with seven disease-specific autoantibodies in a large cross-sectional cohort of 6,160 type 1 diabetes-affected siblings. The genetic association with positivity for GAD autoantibodies (GADAs), IA2 antigen (IA-2A), zinc transporter 8, thyroid peroxidase, gastric parietal cells (PCAs), tissue transglutaminase, and 21-hydroxylase was tested using a linear mixed-model regression approach to simultaneously control for population structure and family relatedness.

HLA similarities indicate shared genetic risk in 21-hydroxylase autoantibody positive South African and United States Addison's disease.

Genetic similarities between patients from the United States and South African (SA) Addison's Disease (AD) strengthen evidence for genetic association. SA-AD (n = 73), SA healthy controls (N = 78), and US-AD patients (N = 83) were genotyped for DQA1, DQB1, DRB1, and HLA-B alleles. Serum was tested for the quantity of 21OH-AA and IFNα-AA at the Barbara Davis Center.

Risk of pediatric celiac disease according to HLA haplotype and country.

Background: The presence of HLA haplotype DR3-DQ2 or DR4-DQ8 is associated with an increased risk of celiac disease. In addition, nearly all children with celiac disease have serum antibodies against tissue transglutaminase (tTG).

Methods: We studied 6403 children with HLA haplotype DR3-DQ2 or DR4-DQ8 prospectively from birth in the United States, Finland, Germany, and Sweden.

γδ T cells recognize the insulin B:9-23 peptide antigen when it is dimerized through thiol oxidation.

The insulin peptide B:9-23 is a natural antigen in the non-obese diabetic (NOD) mouse model of type 1 diabetes (T1D). In addition to αβ T cells and B cells, γδ T cells recognize the peptide and infiltrate the pancreatic islets where the peptide is produced within β cells. The peptide contains a cysteine in position 19 (Cys19), which is required for the γδ but not the αβ T cell response, and a tyrosine in position 16 (Tyr16), which is required for both.

MAS-1 adjuvant immunotherapy generates robust Th2 type and regulatory immune responses providing long-term protection from diabetes in late-stage pre-diabetic NOD mice.

MAS-1, a nanoparticular, emulsion-based adjuvant, was evaluated for its ability to promote Th2 and regulatory immune responses and prevent type 1 diabetes progression when given alone or as antigen-specific immunotherapy (ASI) using insulin B chain (IBC; MER3101) and its analog B:9-23(19Ala) (MER3102). MAS-1 formulations were administered to NOD mice at age 9 and 13 weeks and followed through 52 weeks. MER3101 and MER3102 provided long-term protection with 60% and 73% of mice remaining diabetes-free at week 35, and 60% and 47% at week 52.

Monoclonal antibody blocking the recognition of an insulin peptide-MHC complex modulates type 1 diabetes.

The primary autoantigen triggering spontaneous type 1 diabetes mellitus in nonobese diabetic (NOD) mice is insulin. The major T-cell insulin epitope lies within the amino acid 9-23 peptide of the β-chain (B:9-23). This peptide can bind within the peptide binding groove of the NOD MHC class II molecule (MHCII), IA(g7), in multiple positions or "registers.

Use of the Diabetes Prevention Trial-Type 1 Risk Score (DPTRS) for improving the accuracy of the risk classification of type 1 diabetes.

OBJECTIVE We studied the utility of the Diabetes Prevention Trial-Type 1 Risk Score (DPTRS) for improving the accuracy of type 1 diabetes (T1D) risk classification in TrialNet Natural History Study (TNNHS) participants. RESEARCH DESIGN AND METHODS The cumulative incidence of T1D was compared between normoglycemic individuals with DPTRS values >7.00 and dysglycemic individuals in the TNNHS (n = 991).

GAD65 autoantibodies detected by electrochemiluminescence assay identify high risk for type 1 diabetes.

The identification of diabetes-relevant islet autoantibodies is essential for predicting and preventing type 1 diabetes (T1D). The aim of the current study was to evaluate a newly developed electrochemiluminescence (ECL)-GAD antibody (GADA) assay and compare its sensitivity and disease relevance with standard radioassay. The assay was validated with serum samples from 227 newly diagnosed diabetic children; 68 prediabetic children who were prospectively followed to T1D; 130 nondiabetic children with confirmed islet autoantibodies to insulin, GAD65, IA-2, and/or ZnT8 longitudinally followed for 12 ± 3.

Type 1 diabetes.

Over the past decade, knowledge of the pathogenesis and natural history of type 1 diabetes has grown substantially, particularly with regard to disease prediction and heterogeneity, pancreatic pathology, and epidemiology. Technological improvements in insulin pumps and continuous glucose monitors help patients with type 1 diabetes manage the challenge of lifelong insulin administration. Agents that show promise for averting debilitating disease-associated complications have also been identified.

Infant exposures and development of type 1 diabetes mellitus: The Diabetes Autoimmunity Study in the Young (DAISY).

Importance: The incidence of type 1 diabetes mellitus (T1DM) is increasing worldwide, with the most rapid increase among children younger than 5 years of age.

Objective: To examine the associations between perinatal and infant exposures, especially early infant diet, and the development of T1DM.

Design: The Diabetes Autoimmunity Study in the Young (DAISY) is a longitudinal, observational study.

The prediction of type 1 diabetes by multiple autoantibody levels and their incorporation into an autoantibody risk score in relatives of type 1 diabetic patients.

Objective: We assessed whether a risk score that incorporates levels of multiple islet autoantibodies could enhance the prediction of type 1 diabetes (T1D).

Research Design And Methods: TrialNet Natural History Study participants (n = 784) were tested for three autoantibodies (GADA, IA-2A, and mIAA) at their initial screening. Samples from those positive for at least one autoantibody were subsequently tested for ICA and ZnT8A.

Plasmid-encoded proinsulin preserves C-peptide while specifically reducing proinsulin-specific CD8⁺ T cells in type 1 diabetes.

In type 1 diabetes (T1D), there is an intense inflammatory response that destroys the β cells in the pancreatic islets of Langerhans, the site where insulin is produced and released. A therapy for T1D that targets the specific autoimmune response in this disease while leaving the remainder of the immune system intact, has long been sought. Proinsulin is a major target of the adaptive immune response in T1D.

Seroconversion to multiple islet autoantibodies and risk of progression to diabetes in children.

Importance: Type 1 diabetes usually has a preclinical phase identified by circulating islet autoantibodies, but the rate of progression to diabetes after seroconversion to islet autoantibodies is uncertain.

Objective: To determine the rate of progression to diabetes after islet autoantibody seroconversion.

Design, Setting, And Participants: Data were pooled from prospective cohort studies performed in Colorado (recruitment, 1993-2006), Finland (recruitment, 1994-2009), and Germany (recruitment, 1989-2006) examining children genetically at risk for type 1 diabetes for the development of insulin autoantibodies, glutamic acid decarboxylase 65 (GAD65) autoantibodies, insulinoma antigen 2 (IA2) autoantibodies, and diabetes.

Improving coeliac disease risk prediction by testing non-HLA variants additional to HLA variants.

Background: The majority of coeliac disease (CD) patients are not being properly diagnosed and therefore remain untreated, leading to a greater risk of developing CD-associated complications. The major genetic risk heterodimer, HLA-DQ2 and DQ8, is already used clinically to help exclude disease. However, approximately 40% of the population carry these alleles and the majority never develop CD.

Humoral autoimmunity in type 1 diabetes: prediction, significance, and detection of distinct disease subtypes.

Type 1 diabetes mellitus (T1D) is an autoimmune disease encompassing the T-cell-mediated destruction of pancreatic β cells and the production of autoantibodies against islet proteins. In humoral autoimmunity in T1D, the detection of islet autoantibodies and the examination of their associations with genetic factors and cellular autoimmunity constitute major areas in both basic research and clinical practice. Although insulin is a key autoantigen and may be primus inter pares in importance among T1D autoantigens, an abundant body of research has also revealed other autoantigens associated with the disease process.

Investigation of the vitamin D receptor gene (VDR) and its interaction with protein tyrosine phosphatase, non-receptor type 2 gene (PTPN2) on risk of islet autoimmunity and type 1 diabetes: the Diabetes Autoimmunity Study in the Young (DAISY).

The present study investigated the association between variants in the vitamin D receptor gene (VDR) and protein tyrosine phosphatase, non-receptor type 2 gene (PTPN2), as well as an interaction between VDR and PTPN2 and the risk of islet autoimmunity (IA) and progression to type 1 diabetes (T1D). The Diabetes Autoimmunity Study in the Young (DAISY) has followed children at increased risk of T1D since 1993. Of the 1692 DAISY children genotyped for VDR rs1544410, VDR rs2228570, VDR rs11568820, PTPN2 rs1893217, and PTPN2 rs478582, 111 developed IA, defined as positivity for GAD, insulin or IA-2 autoantibodies on 2 or more consecutive visits, and 38 IA positive children progressed to T1D.

Type 1 diabetes: primary antigen/peptide/register/trimolecular complex.

Type 1A diabetes (autoimmune) is now immunologically predictable in man, but preventable only in animal models. What triggers the development of autoimmunity in genetically susceptible individuals remains unknown. Studies of non-obese diabetic (NOD) mice reveal that interactions between T-cell receptors of diabetogenic T cell and an MHC class II loaded with an autoantigen are key determinates of the disease.

Evidence of gene-gene interaction and age-at-diagnosis effects in type 1 diabetes.

The common genetic loci that independently influence the risk of type 1 diabetes have largely been determined. Their interactions with age-at-diagnosis of type 1 diabetes, sex, or the major susceptibility locus, HLA class II, remain mostly unexplored. A large collection of more than 14,866 type 1 diabetes samples (6,750 British diabetic individuals and 8,116 affected family samples of European descent) were genotyped at 38 confirmed type 1 diabetes-associated non-HLA regions and used to test for interaction of association with age-at-diagnosis, sex, and HLA class II genotypes using regression models.

Genetic determinants of 21-hydroxylase autoantibodies amongst patients of the Type 1 Diabetes Genetics Consortium.

Background: Autoantibodies to 21-hydroxylase (21OH-AA) precede the onset of autoimmune Addison's disease (AD) and are found in 1.5% of individuals with type 1 diabetes mellitus (T1DM). The greatest genetic risk for both disorders is found in the major histocompatibility complex (MHC), suggesting a common pathophysiology between AD and T1DM.

Autoimmune diabetes inflames the heart.

Patients with type 1 diabetes tend to suffer subsequent and persistent inflammation of cardiac tissue after a heart attack.

Network for Pancreatic Organ Donors with Diabetes (nPOD): developing a tissue biobank for type 1 diabetes.

Background: The Network for Pancreatic Organ Donors with Diabetes (nPOD) was established to recover and characterize pancreata and related organs from cadaveric organ donors with various risk levels for type 1 diabetes (T1D). These biospecimens are available to investigators for collaborative studies aimed at addressing questions related to T1D natural history and pathogenesis.

Research Design And Methods: Organ donors included T1D patients (new onset to long term), non-diabetic autoantibody-positive subjects, non-diabetic controls and individuals with disorders relevant to β-cell function.

Prevention of type 1A diabetes mellitus.

Objective: To review prediction of type 1 diabetes mellitus in light of current trials for prevention and novel preclinical therapies.

Methods: The stages in the development of type 1A diabetes are reviewed and strategies for prevention are discussed.

Results: From islet autoantibody testing of random cadaveric donors, it is apparent that approximately one-half million persons in the United States express multiple islet autoantibodies and are in the process of developing type 1A (immune-mediated) diabetes.