CTLA4, SH2B3, and CLEC16A diversely affect the progression of early islet autoimmunity in relatives of Type 1 diabetes patients.

The HLA region is the major genetic risk determinant of Type 1 diabetes. How non-HLA loci contribute to the genetic risk is incompletely understood, but there are indications that at least some impact progression of asymptomatic autoimmunity. We examined whether SNPs in 7 susceptibility loci (INS, SH2B3, PTPN2, PTPN22, CTLA4, CLEC16A, and IL2RA) could improve prediction of the progression from single to multiple autoantibody positivity, and from there on to diagnosis.

Durvalumab-induced thyroiditis in a patient with non-small cell lung carcinoma: a case report and review of pathogenic mechanisms.

Background: Immune checkpoint inhibitors (ICI) targeting cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), programmed cell death protein 1 and its ligand (PD-1/PD-L1) have become the current standard-of-care for advanced cancers. This novel therapeutic approach comes with its costs in the form of immune-related adverse events (irAE), including endocrinopathy.

Case Presentation: A 63-year-old woman was diagnosed with a non-small cell lung carcinoma of the right superior lobe, cT3N2M0.

Genetic variation at ERBB3/IKZF4 and sexual dimorphism in epitope spreading in single autoantibody-positive relatives.

Aims/hypothesis: We examined whether the non-HLA susceptibility locus ERBB3/IKZF4 influences progression of type 1 diabetes stage specifically according to sex.

Methods: SNPs of ERBB3 (rs2292239 T/G) and IKZF4 (rs1701704 G/T) were screened by allelic discrimination quantitative PCR assay in first-degree relatives of type 1 diabetes patients who had developed at least one circulating autoantibody. The effect of ERBB3/IKZF4 genotypes and sex, on the progression of single autoantibody positivity to multiple autoantibody positivity and from multiple autoantibody positivity to diabetes, was studied by Kaplan-Meier analysis and multivariate Cox regression.

Insulitis in the pancreas of non-diabetic organ donors under age 25 years with multiple circulating autoantibodies against islet cell antigens.

Autoantibodies against islet cell antigens are routinely used to identify subjects at increased risk of symptomatic type 1 diabetes, but their relation to the intra-islet pathogenetic process that leads to positivity for these markers is poorly understood. We screened 556 non-diabetic organ donors (3 months to 24 years) for five different autoantibodies and found positivity in 27 subjects, 25 single- and two double autoantibody-positive donors. Histopathological screening of pancreatic tissue samples showed lesion characteristic for recent-onset type 1 diabetes in the two organ donors with a high-risk profile, due to their positivity for multiple autoantibodies and HLA-inferred risk.

Immune checkpoint inhibitors and type 1 diabetes mellitus: a case report and systematic review.

Objective: To better define the rare adverse event (AE) of diabetes mellitus associated with immune checkpoint inhibitors (ICIs).

Design And Methods: We report the case of a lung cancer patient with diabetic ketoacidosis (DKA) and autoimmune thyroiditis during pembrolizumab treatment. We provide a systematic review of all published cases (PubMed/Web of Science/Cochrane, through November 2018) of autoimmune diabetes mellitus related to blockade of the cytotoxic T-lymphocyte antigen 4 (CTLA-4)-, programmed cell death 1 (PD-1) receptor or its ligand (PD-L1) or combination (ICI) therapy.

SLC30A8 polymorphism and BMI complement HLA-A*24 as risk factors for poor graft function in islet allograft recipients.

Aims/hypothesis: HLA-A*24 carriership hampers achievement of insulin independence in islet allograft recipients. However, less than half of those who fail to achieve insulin independence carry the allele. We investigated whether genetic polymorphism at the recipients' zinc transporter 8-encoding SLC30A8 gene (rs13266634) could complement their HLA-A*24 status in predicting functional graft outcome.

Accelerated Progression to Type 1 Diabetes in the Presence of and Is Restricted to Multiple Islet Autoantibody-Positive Individuals With Distinct and Autoantibody Risk Profiles.

Objective: We investigated the effect of HLA class I risk alleles on disease progression in various phases of subclinical islet autoimmunity in first-degree relatives of patients with type 1 diabetes.

Research Design And Methods: A registry-based group of siblings/offspring (aged 0-39 years) was monitored from single- to multiple-autoantibody positivity ( = 267) and from multiple-autoantibody positivity to clinical onset ( = 252) according to , , , and status. Genetic markers were determined by PCR sequence-specific oligotyping.

HLA-A*24 Carrier Status and Autoantibody Surges Posttransplantation Associate With Poor Functional Outcome in Recipients of an Islet Allograft.

Objective: We investigated whether changes in islet autoantibody profile and presence of HLA risk markers, reported to predict rapid β-cell loss in pre-type 1 diabetes, associate with poor functional outcome in islet allograft recipients.

Research Design And Methods: Forty-one patients received ≥2.3 million β-cells/kg body wt in one to two intraportal implantations.

In antibody-positive first-degree relatives of patients with type 1 diabetes, HLA-A*24 and HLA-B*18, but not HLA-B*39, are predictors of impending diabetes with distinct HLA-DQ interactions.

Aims/hypothesis: Secondary type 1 diabetes prevention trials require selection of participants with impending diabetes. HLA-A and -B alleles have been reported to promote disease progression. We investigated whether typing for HLA-B*18 and -B*39 may complement screening for HLA-DQ8, -DQ2 and -A*24 and autoantibodies (Abs) against islet antigen-2 (IA-2) and zinc transporter 8 (ZnT8) for predicting rapid progression to hyperglycaemia.

HLA-A*24 is an independent predictor of 5-year progression to diabetes in autoantibody-positive first-degree relatives of type 1 diabetic patients.

We investigated whether HLA-A*24 typing complements screening for HLA-DQ and for antibodies (Abs) against insulin, GAD, IA-2 (IA-2A), and zinc transporter-8 (ZnT8A) for prediction of rapid progression to type 1 diabetes (T1D). Persistently Ab(+) siblings/offspring (n = 288; aged 0-39 years) of T1D patients were genotyped for HLA-DQA1-DQB1 and HLA-A*24 and monitored for development of diabetes within 5 years of first Ab(+). HLA-A*24 (P = 0.

Validation of an enzyme-linked immunosorbent assay for C-peptide analysis in Cameroon.

Aims: To validate an ELISA method for C-peptide analysis in Cameroon.

Methods: We evaluated the linearity, detection limit, functional sensitivity, precision and accuracy, and further investigated for cross-reactivity by proinsulin, and interferences by lipids, bilirubin and hemoglobin. This method was compared with the Roche electrochemiluminescence immunoassay.

Association of IL-2RA/CD25 with type 1 diabetes in the Belgian population.

Our goals were to study the proposed association of IL-2RA /CD25 with type 1 diabetes in the Belgian population over a broad age range, and to explore possible correlations with disease phenotypes, immune markers, HLA-DQ, INS, and PTPN22. Patients (n = 1954), healthy controls (n = 2082), and families (n = 420) were genotyped for IL-2RA/CD25 rs41295061(C>A), HLA-DQ, INS-VNTR and PTPN22. IL-2RA/CD25 was associated with type 1 diabetes (χ(2) = 26.

Graves hyperthyroidism after stopping immunosuppressive therapy in type 1 diabetic Islet cell recipients with pretransplant TPO autoantibodies.

Objective: After an initially successful islet cell transplantation, a number of patients return to C-peptide negativity, and therefore immunosuppressive therapy is discontinued. Some are then found to have developed Graves disease. We examined the risk of Graves disease after immunosuppression.

IFIH1 gene polymorphisms in type 1 diabetes: genetic association analysis and genotype-phenotype correlation in the Belgian population.

The evaluation of susceptibility loci in a registry-based setting could be an important addition to the current predictive and screening models in T1D. Therefore, the aim of this study was to evaluate the importance of one of these loci, IFIH1. T1D patients (n=1981), control subjects (n=2092) and 430 families were genotyped for HLA-DQ and IFIH1 nsSNP rs1990760 (Ala946Thr).

Association of KIR2DL2 polymorphism rs2756923 with type 1 diabetes and preliminary evidence for lack of inhibition through HLA-C1 ligand binding.

Killer cell immunoglobulin-like receptors (KIRs) on chromosome 19q13.4 regulate the function of not only human natural killer (NK) cells but also T cells. An increase in activating KIR- human leucocyte antigen ligand pairs has been associated with an additional risk to develop type 1 diabetes (T1D).

TNFa microsatellite polymorphism modulates the risk of type 1 diabetes in the Belgian population, independent of HLA-DQ.

To determine the contribution of the tumor necrosis factor alpha gene (TNFA) to the immunogenetic risk prediction of type 1 diabetes (T1D) in the Belgian population, well-characterized antibody-positive patients with type 1 diabetes (T1D), nondiabetic control subjects, and nuclear families were analyzed for HLA-DQA1-DQB1, TNFA -308 G/A promoter single nucleotide polymorphism (SNP) and TNFa microsatellite markers in both case-control and transmission studies. A total of 1,029 patients (mean age at onset, 18 years; male/female ratio, 1.2), 575 control subjects and 179 nuclear families were analyzed for the -308 SNP and 1,082 patients (mean age at onset, 17 years; and male/female ratio, 1.

Screening for insulitis in adult autoantibody-positive organ donors.

Antibodies against islet cell antigens are used as predictive markers of type 1 diabetes, but it is unknown whether they reflect an ongoing autoimmune process in islet tissue. We investigated whether organs from adult donors that are positive for autoantibodies (aAbs) against islet cell antigens exhibit insulitis and/or a reduced beta-cell mass. Serum from 1,507 organ donors (age 25-60 years) was analyzed for islet cell antibodies (ICAs), glutamate decarboxylase aAbs (GADAs), insulinoma-associated protein 2 aAbs (IA-2As), and insulin aAbs.

Neither an intronic CA repeat within the CD48 gene nor the HERV-K18 polymorphisms are associated with type 1 diabetes.

Type 1 diabetes is an autoimmune heterogeneous disease that is determined by environmental and genetic factors. A possible retroviral etiology has been inferred from the observation that human endogenous retrovirus (HERV)-K18 encoding a superantigen (SAg) has a polymorphism associated with this disease. Type 1 diabetes families from Germany and Belgium were genotyped for the novel HERV-8914 (303 families) and for the known HERV-8594 (284 families) polymorphisms within the SAg-coding region on the HERV-K18.

MICA is associated with type 1 diabetes in the Belgian population, independent of HLA-DQ.

To ascertain association of MICA with type 1 diabetes (T1D) in the Belgian population, well-characterized antibody-positive patients were analyzed for MICA transmembrane gene polymorphism in both an association study and a nuclear family study. The frequency of MICA5 was significantly increased in the T1D patient group (18%) compared with the control population (12%, OR=1.6, pc<10(-3)), whereas MICA9 was decreased (11% versus 16%, OR=0.

Sex- and season-dependent differences in C-peptide levels at diagnosis of immune-mediated type 1 diabetes.

Aims/hypothesis: The incidence of type 1 diabetes varies according to age, sex and season of diagnosis. We investigated whether these and other clinical, biological and anthropometric parameters were correlated with residual beta cell function in newly diagnosed patients, since it is possible that the nature of external and/or genetic disease accelerators may be (partly) reflected in the inaugural disease presentation.

Materials And Methods: The correlates of random C-peptide levels sampled shortly after diagnosis (median [interquartile range]: 3 [0-14] days) were studied by multivariate analysis in 1,883 islet-antibody-positive diabetic patients aged <40 years who were diagnosed between 1989 and 2000.

Combined positivity for HLA DQ2/DQ8 and IA-2 antibodies defines population at high risk of developing type 1 diabetes.

Aims/hypothesis: Prevention trials in first-degree relatives of type 1 diabetic patients are hampered by large interindividual differences in progression rate to diabetes. We investigated whether specific combinations of immune and genetic markers can identify subgroups with more homogeneous progression to clinical onset.

Methods: Antibodies against islet cell cytoplasm (ICA), insulin (IAA), glutamate decarboxylase (GADA) and IA-2 protein (IA-2A) were measured in 790 non-diabetic control subjects and 4,589 first-degree relatives under age 40.

The rare HLA-DQA1*03-DQB1*02 haplotype confers susceptibility to type 1 diabetes in whites and is preferentially associated with early clinical disease onset in male subjects.

The heterozygous combination of DQA1*03-DQB1*0302 (DQ8) and DQA1*05-DQB1*0201 (DQ2) confers the highest known HLA-DQ-linked risk for type 1 diabetes, suggesting a role for transcomplementation. The trans-heterodimer encoded by DQA1*03 and DQB1*02 is also rarely observed in cis in whites. Islet antibody-positive diabetic patients (P; n = 2,238) and control subjects (C; n = 2,223) of white descent were genotyped by a HLA-DQA1-DQB1 dot-blot method.

Seasonality in clinical onset of type 1 diabetes in belgian patients above the age of 10 is restricted to HLA-DQ2/DQ8-negative males, which explains the male to female excess in incidence.

Aims/hypothesis: Type 1 diabetes arises from an interplay between environmental and genetic factors. The reported seasonality at diagnosis supports the hypothesis that currently unknown external triggers play a role in the onset of the disease. We investigated whether a seasonal pattern is observed at diagnosis in Belgian Type 1 diabetic patients, and if so whether seasonality varies according to age, sex and genetic risk, all known to affect the incidence of Type 1 diabetes.

[Preventative biology of type 1 diabetes: implications for clinical preventative studies].

Type 1 diabetes is a multifactorial disease caused by an interplay of poorly known environmental factors and partially characterized genetic factors. Focal infiltration of the endocrine pancreas by mononuclear cells and a strikingly decreased functional beta cell mass constitute the histopathological hallmarks of the disease at diagnosis, but there is a marked interindividual variability in terms of the extent of the lesions. The disease process is triggered long before clinical onset as testified by the appearance of circulating islet cell autoantibodies years before the development of hyperglycemia.

Non-transmitted maternal HLA DQ2 or DQ8 alleles and risk of Type I diabetes in offspring: the importance of foetal or post partum exposure to diabetogenic molecules.

Aims/hypothesis: Type I (insulin-dependent) diabetes mellitus results from an immune-mediated destruction of pancreatic beta cells for which HLA haplotypes DR3-DQ2 and DR4-DQ8 represent the strongest genetic risk markers. Mothers of patients with rheumatoid arthritis carry more frequently the HLA DR4-DQ8 haplotype as non-transmitted haplotype than mothers of healthy control subjects. As maternal cells have been shown to persist in their offspring up to 30 years after birth, we investigated whether the association of HLA DR3-DQ2 and DR4-DQ8 with Type I diabetes is purely a genetic effect acting through inheritance or whether it can also act as an environmental factor, for example through foetal exposure in utero to maternal circulating cells.