The regenerative capacity of Schwann cells in the PNS underlies functional repair after injury. In this study, Mindos et al. show a new function for the tumor suppressor Merlin and Hippo/YAP signaling in the generation of repair-competent Schwann cells after injury.

The only strategy to select individuals at increased risk for type 1 diabetes for primary prevention trials is through genetic risk assessment. While genome-wide association studies have identified more than 40 loci associated with type 1 diabetes, the single most important genetic determinants lie within the human leucocyte antigen gene family on chromosome 6.In this chapter we describe a protocol for a straightforward, cheap strategy to determine HLA class II mediated risk of type 1 diabetes. This method has proved robust for genotyping whole-genome-amplified DNA as well as DNA extracted directly from human tissues.

Background Maternal microchimerism (MMc), the transmission of small quantities of maternal cells to the fetus, is relatively common and persistent. MMc has been detected with increased frequency in the circulation and pancreas of type 1 diabetes (T1D) patients. We investigated for the first time whether MMc levels at birth predict future T1D risk. We also tested whether cord blood MMc predicted MMc in samples taken at T1D diagnosis. Methods Participants in the Norwegian Mother and Child Cohort study were human leukocyte antigen (HLA) class II typed to determine non‐inherited, non‐shared maternal alleles (NIMA). Droplet digital (dd) polymerase chain reaction (PCR) assays specific for common HLA class II NIMA (HLADQB1*03:01, *04:02, and *06:02/03) were developed and validated. MMc was estimated as maternal DNA quantity in the fetal circulation, by NIMA specific ddPCR, measured in cord blood DNA from 71 children who later developed T1D and 126 controls within the cohort. Results We found detectable quantities of MMc in 34/71 future T1D cases (48%) and 53/126 controls (42%) (adjusted odds ratio [aOR] 1.27, 95% confidence interval (CI) 0.68‐2.36), and no significant difference in ranks of MMc quantities between cases and controls (Mann‐Whitney P = .46). There was a possible association in the NIMA HLA‐DQB1*03:01 subgroup with later T1D (aOR 3.89, 95%CI 1.05‐14.4). MMc in cord blood was not significantly associated with MMc at T1D diagnosis. Conclusions Our findings did not support the hypothesis that the degree of MMc in cord blood predict T1D risk. The potential subgroup association with T1D risk should be replicated in a larger cohort.

Purpose of Review An increased frequency of autoimmunity in children with Down syndrome (DS) is well described but few studies have investigated the underlying mechanisms. Recent immune system investigation of individuals with DS may shed light on the increased risk of autoimmune conditions including type 1 diabetes. Recent Findings Diagnosis of type 1 diabetes is accelerated in children with DS with 17% diagnosed at, or under, the age of 2 years compared with only 4% in the same age group in the general population. Counterintuitively, children with DS and diabetes have less human leukocyte antigen (HLA)-mediated susceptibility than age-matched children with autoimmune diabetes from the general population. Early onset of diabetes in DS is further highlighted by the recent description of neonatal cases of diabetes which is autoimmune but not HLA associated. There are two potential explanations for this accelerated onset: (1) an additional chromosome 21 increases the genetic and immunological risk of autoimmune diabetes or (2) there are two separate aetiologies in children with DS and diabetes. Summary Autoimmunity in DS is an under-investigated area. In this review, we will draw on recent mechanistic studies in individuals with DS which shed some light on the increased risk of autoimmunity in children with DS and consider the current support for and against two aetiologies underlying diabetes in children with DS.

The clinical usefulness of post-diagnosis islet autoantibody levels is unclear and factors that drive autoantibody persistence are poorly defined in type 1 diabetes (T1D). Our aim was to characterise longitudinal loss of islet autoantibody responses after diagnosis in a large, prospectively sampled UK cohort. Participants with T1D [n=577] providing a diagnosis sample [range -1.0-2.0 years] and at least one post-diagnosis sample (<32.0 years) were tested for autoantibodies to glutamate decarboxylase 65 (GADA), islet antigen-2 (IA-2A), and zinc transporter 8 (ZnT8A). Select HLA and non-HLA SNPs were considered. Non-genetic and genetic factors were assessed by multivariable logistic regression models for autoantibody positivity at initial sampling and autoantibody loss at final sampling. For GADA, IA-2A, and ZnT8A, 70.8%, 76.8% and 40.1%, respectively, remained positive at final sampling. Non-genetic predictors of autoantibody loss were low baseline autoantibody titres (p<0.0001), longer diabetes duration (p<0.0001), and age-at-onset under 8 years (p<0.01-0.05). Adjusting for non-genetic covariates, GADA loss was associated with low-risk HLA class II genotypes (p=0.005), and SNPs associated with autoimmunity RELA/11q13 (p=0.017), LPP/3q28 (p=0.004), and negatively with IFIH1/2q24 (p=0.018). IA-2A loss was not associated with genetic factors independent of other covariates, while ZnT8A loss was associated with the presence of HLA A*24 (p=0.019) and weakly negatively with RELA/11q13 (p=0.049). The largest longitudinal study of islet autoantibody responses from diagnosis of T1D shows that autoantibody loss is heterogeneous and influenced by low titres at onset, longer duration, earlier age-at-onset, and genetic variants. These data may inform clinical trials where post-diagnosis participants are recruited.

A case of parathyroiditis with epithelial hyperplasia is reported in which the histological features suggest an autoimmune process analogous to Hashimoto's disease.

Aims Some childhood type 1 diabetes cases are islet autoantibody negative at diagnosis. Potential explanations include misdiagnosis of genetic forms of diabetes or insufficient islet autoantibody testing. Many NHS laboratories offer combinations of three autoantibody markers. We sought to determine the benefit of testing for additional islet autoantibodies, including insulin (IAA) and tetraspanin 7 (TSPAN7A). Methods Radiobinding assays (RBAs) were used to test for four islet autoantibodies in children with newly diagnosed type 1 diabetes (n = 486; 54.1% male; median age 10.4 years [range 0.7–18.0]; median duration 1 day [range −183 to 14]). Islet autoantibody negative children were tested for TSPAN7A using a luminescence‐based test. Where available, islet cell antibody (ICA) and human leucocyte antigen (HLA) data were considered. Results Using three autoantibody markers, 21/486 (4.3%) children were autoantibody negative. Testing for IAA classified a further 9/21 (42.9%) children as autoantibody positive. Of the remaining 12 (2.5%) autoantibody negative children, all were TPAN7A negative, seven were ICA negative and one was positive for the protective variant DQB1*0602. One was subsequently diagnosed with Maturity Onset of Diabetes in the Young, but follow‐up was not available in all cases. Conclusions Using highly sensitive assays, testing for three autoantibodies fails to detect islet autoimmunity in approximately 1/20 children diagnosed with type 1 diabetes. Testing for IAA in children <5 years and GADA in those >10 years was the most effective strategy for detecting islet autoimmunity. The ability to test for all islet autoantibodies should inform clinical decisions and make screening for monogenic diabetes more cost‐effective.

Recent success in clinical trials to delay the onset of type 1 diabetes has heralded a new era of type 1 diabetes research focused on the most accurate methods to predict risk and progression rate in the general population. Risk prediction for type 1 diabetes has been ongoing since the 1970s and 1980s when human leucocyte antigen (HLA) variants and islet autoantibodies associated with type 1 diabetes were first described. Development of prediction methodologies has relied on well-characterised cohorts and samples. The Bart's Oxford (BOX) study of type 1 diabetes has been recruiting children with type 1 diabetes and their first (and second)-degree relatives since 1985. In this review, we use the timeline of the study to review the accompanying basic science developments which have facilitated improved prediction by genetic (HLA analysis through to genetic risk scores) and biochemical strategies (islet cell autoantibodies through to improved individual tests for antibodies to insulin, glutamate decarboxylase, the tyrosine phosphatase IA-2, zinc transporter 8 and tetraspanin 7). The type 1 diabetes community are poised to move forward using the best predictive markers to predict and delay the onset of type 1 diabetes K E Y W O R D S genetic risk score, genetics, HLA, islet autoantibodies, type 1 diabetes How to cite this article: Gillespie KM, Fareed R, Mortimer GL. Four decades of the Bart's Oxford study: Improved tests to predict type 1 diabetes.