PubMed · 14273998
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D DONIACH. 1964. AUTOIMMUNITY.. https://pubmed.ncbi.nlm.nih.gov/14273998/
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CONTEXT: Biomarkers that can accurately predict risk of type 1 diabetes (T1D) in genetically predisposed children can facilitate interventions to delay or prevent the disease. OBJECTIVE: This work aimed to determine if a combination of genetic, immunologic, and metabolic features, measured at infancy, can be used to predict the likelihood that a child will develop T1D by age 6 years. METHODS: Newborns with human leukocyte antigen (HLA) typing were enrolled in the prospective birth cohort of The Environmental Determinants of Diabetes in the Young (TEDDY). TEDDY ascertained children in Finland, Germany, Sweden, and the United States. TEDDY children were either from the general population or from families with T1D with an HLA genotype associated with T1D specific to TEDDY eligibility criteria. From the TEDDY cohort there were 702 children will all data sources measured at ages 3, 6, and 9 months, 11.4% of whom progressed to T1D by age 6 years. The main outcome measure was a diagnosis of T1D as diagnosed by American Diabetes Association criteria. RESULTS: Machine learning-based feature selection yielded classifiers based on disparate demographic, immunologic, genetic, and metabolite features. The accuracy of the model using all available data evaluated by the area under a receiver operating characteristic curve is 0.84. Reducing to only 3- and 9-month measurements did not reduce the area under the curve significantly. Metabolomics had the largest value when evaluating the accuracy at a low false-positive rate. CONCLUSION: The metabolite features identified as important for progression to T1D by age 6 years point to altered sugar metabolism in infancy. Integrating this information with classic risk factors improves prediction of the progression to T1D in early childhood.
BACKGROUND AND OBJECTIVES: Autoantibodies targeting the acetylcholine receptor (AChR), found in patients with myasthenia gravis (MG), mediate pathology through 3 mechanisms: complement-directed tissue damage, blocking of the acetylcholine binding site, and internalization of the AChR. Clinical assays, used to diagnose and monitor patients, measure only autoantibody binding. Consequently, they are limited in providing association with disease burden, understanding of mechanistic heterogeneity, and monitoring therapeutic response. The objective of this study was to develop a cell-based assay that measures AChR autoantibody-mediated complement membrane attack complex (MAC) formation. METHODS: An HEK293T cell line-modified using CRISPR/Cas9 genome editing to disrupt expression of the complement regulator genes (CD46, CD55, and CD59)-was used to measure AChR autoantibody-mediated MAC formation through flow cytometry. RESULTS: Serum samples (n = 155) from 96 clinically confirmed AChR MG patients, representing a wide range of disease burden and autoantibody titer, were tested along with 32 healthy donor (HD) samples. AChR autoantibodies were detected in 139 of the 155 (89.7%) MG samples through a cell-based assay. Of the 139 AChR-positive samples, autoantibody-mediated MAC formation was detected in 83 (59.7%), whereas MAC formation was undetectable in the HD group or AChR-positive samples with low autoantibody levels. MAC formation was positively associated with autoantibody binding in most patient samples; ratios (mean fluorescence intensity) of MAC formation to AChR autoantibody binding ranged between 0.27 and 48, with a median of 0.79 and an interquartile range of 0.43 (0.58-1.1). However, the distribution of ratios was asymmetric and included extreme values; 16 samples were beyond the 10-90 percentile, with high MAC to low AChR autoantibody binding ratio or the reverse. Correlation between MAC formation and clinical disease scores suggested a modest positive association (rho = 0.34, p = 0.0023), which included a subset of outliers that did not follow this pattern. MAC formation did not associate with exposure to immunotherapy, thymectomy, or MG subtypes defined by age-of-onset. DISCUSSION: A novel assay for evaluating AChR autoantibody-mediated complement activity was developed. A subset of patients that lacks association between MAC formation and autoantibody binding or disease burden was identified. The assay may provide a better understanding of the heterogeneous autoantibody molecular pathology and identify patients expected to benefit from complement inhibitor therapy.
This work aimed to assess the maturation of the humoral immune response to insulin in preclinical type 1 diabetes by observing the emergence of various isotypes of insulin autoantibodies (IAA) in children with HLA-DQB1-conferred disease susceptibility. The series was derived from the Finnish Type 1 Diabetes Prediction and Prevention Study and comprised 15 IAA-positive children who presented with type 1 diabetes during prospective observation (progressors) and 30 children who remained nondiabetic (nonprogressors). An isotype-specific radiobinding assay was used to determine isotype-specific IAA (IgG1-4 and IgA) from samples obtained with an interval of 3-12 mo. The progressors had IAA of subclass IgG3 in their first IAA-positive sample more often than did the nonprogressors (13 of 15 versus 12 of 30; p = 0.003). Nine progressors had a dominant IgG1-IAA response initially, and six had a dominant IgG3-IAA response. The corresponding distribution among the nonprogressors was that 20 had a dominant IgG1-IAA response, none had an IgG3-IAA response, and three had a dominant response other than IgG1- or IgG3-IAA (chi(2)(df = 2) = 12.02; p = 0.002). The progressors had higher integrated levels (area under the curve) of IgG1-IAA (p = 0.05) and IgG3-IAA (p = 0.002). Nine progressors had a dominant integrated IgG1-IAA response and six had a dominant IgG3-IAA response over the observation period, whereas 22 nonprogressors had a dominant IgG1-IAA response, six had a dominant IgG2-IAA response, and one an IgG3-IAA response (chi(2)(df = 2) = 11.23; p = 0.004). Genetically susceptible young children who progress rapidly to clinical type 1 diabetes are characterized by strong IgG1 and IgG3 responses to insulin, whereas a weak or absent IgG3 response is associated with relative protection from disease.