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OBJECTIVE - This study investigated the temporal dynamics of pancreas volume and microstructure in children and adolescents with recent-onset type 1 diabetes (T1D) and individuals without diabetes, including a subset expressing autoantibodies associated with the early stages of T1D.
RESEARCH DESIGN AND METHODS - MRI was performed in individuals with recent-onset stage 3 T1D ( = 51; median age 13 years) within 100 days after diagnosis (mean 67 days), 6 months, and 1 year postdiagnosis. Longitudinal MRI measurements were also made in similarly aged control participants ( = 57) and in autoantibody-positive individuals without diabetes ( = 20). The MRI protocol consisted of anatomical imaging to determine pancreas volume and quantitative MRI protocols interrogating tissue microstructure and composition.
RESULTS - Within 100 days of diabetes onset, individuals with T1D had a smaller pancreas (median volume 28.6 mL) than control participants (median volume 48.4 mL; < 0.001), including when normalized by individual weight ( < 0.001). Longitudinal measurements of pancreas volume increased in control participants over the year, consistent with adolescent growth, but pancreas volume declined over the first year after T1D diagnosis ( < 0.001). In multiple autoantibody-positive individuals, the pancreas volume was significantly larger than that of the T1D cohort ( = 0.017) but smaller than that of the control cohort ( = 0.04). Diffusion-weighted MRI showed that individuals with recent-onset T1D had a higher apparent diffusion coefficient ( = 0.012), suggesting a loss of cellular structural integrity, with heterogeneous pancreatic distribution.
CONCLUSIONS - These results indicate that pancreas volume is decreased in stages 1, 2, and 3 of T1D and decreases during the first year after diabetes onset and that this loss of pancreatic volume is accompanied by microstructural changes.
© 2018 by the American Diabetes Association.
OBJECTIVE - There are variable reports of risk of concordance for progression to islet autoantibodies and type 1 diabetes in identical twins after one twin is diagnosed. We examined development of positive autoantibodies and type 1 diabetes and the effects of genetic factors and common environment on autoantibody positivity in identical twins, nonidentical twins, and full siblings.
RESEARCH DESIGN AND METHODS - Subjects from the TrialNet Pathway to Prevention Study ( = 48,026) were screened from 2004 to 2015 for islet autoantibodies (GAD antibody [GADA], insulinoma-associated antigen 2 [IA-2A], and autoantibodies against insulin [IAA]). Of these subjects, 17,226 (157 identical twins, 283 nonidentical twins, and 16,786 full siblings) were followed for autoantibody positivity or type 1 diabetes for a median of 2.1 years.
RESULTS - At screening, identical twins were more likely to have positive GADA, IA-2A, and IAA than nonidentical twins or full siblings (all < 0.0001). Younger age, male sex, and genetic factors were significant factors for expression of IA-2A, IAA, one or more positive autoantibodies, and two or more positive autoantibodies (all ≤ 0.03). Initially autoantibody-positive identical twins had a 69% risk of diabetes by 3 years compared with 1.5% for initially autoantibody-negative identical twins. In nonidentical twins, type 1 diabetes risk by 3 years was 72% for initially multiple autoantibody-positive, 13% for single autoantibody-positive, and 0% for initially autoantibody-negative nonidentical twins. Full siblings had a 3-year type 1 diabetes risk of 47% for multiple autoantibody-positive, 12% for single autoantibody-positive, and 0.5% for initially autoantibody-negative subjects.
CONCLUSIONS - Risk of type 1 diabetes at 3 years is high for initially multiple and single autoantibody-positive identical twins and multiple autoantibody-positive nonidentical twins. Genetic predisposition, age, and male sex are significant risk factors for development of positive autoantibodies in twins.
© 2018 by the American Diabetes Association.
OBJECTIVE - We tested the ability of a type 1 diabetes (T1D) genetic risk score (GRS) to predict progression of islet autoimmunity and T1D in at-risk individuals.
RESEARCH DESIGN AND METHODS - We studied the 1,244 TrialNet Pathway to Prevention study participants (T1D patients' relatives without diabetes and with one or more positive autoantibodies) who were genotyped with Illumina ImmunoChip (median [range] age at initial autoantibody determination 11.1 years [1.2-51.8], 48% male, 80.5% non-Hispanic white, median follow-up 5.4 years). Of 291 participants with a single positive autoantibody at screening, 157 converted to multiple autoantibody positivity and 55 developed diabetes. Of 953 participants with multiple positive autoantibodies at screening, 419 developed diabetes. We calculated the T1D GRS from 30 T1D-associated single nucleotide polymorphisms. We used multivariable Cox regression models, time-dependent receiver operating characteristic curves, and area under the curve (AUC) measures to evaluate prognostic utility of T1D GRS, age, sex, Diabetes Prevention Trial-Type 1 (DPT-1) Risk Score, positive autoantibody number or type, HLA DR3/DR4-DQ8 status, and race/ethnicity. We used recursive partitioning analyses to identify cut points in continuous variables.
RESULTS - Higher T1D GRS significantly increased the rate of progression to T1D adjusting for DPT-1 Risk Score, age, number of positive autoantibodies, sex, and ethnicity (hazard ratio [HR] 1.29 for a 0.05 increase, 95% CI 1.06-1.6; = 0.011). Progression to T1D was best predicted by a combined model with GRS, number of positive autoantibodies, DPT-1 Risk Score, and age (7-year time-integrated AUC = 0.79, 5-year AUC = 0.73). Higher GRS was significantly associated with increased progression rate from single to multiple positive autoantibodies after adjusting for age, autoantibody type, ethnicity, and sex (HR 2.27 for GRS >0.295, 95% CI 1.47-3.51; = 0.0002).
CONCLUSIONS - The T1D GRS independently predicts progression to T1D and improves prediction along T1D stages in autoantibody-positive relatives.
© 2018 by the American Diabetes Association.
Early breaches in B cell tolerance are central to type 1 diabetes progression in mouse and man. Conventional BCR transgenic mouse models (VH125.Tg NOD) reveal the power of B cell specificity to drive disease as APCs. However, in conventional fixed IgM models, comprehensive assessment of B cell development is limited. To provide more accurate insight into the developmental and functional fates of anti-insulin B cells, we generated a new NOD model (V125NOD) in which anti-insulin VDJH125 is targeted to the IgH chain locus to generate a small (1-2%) population of class switch-competent insulin-binding B cells. Tracking of this rare population in a polyclonal repertoire reveals that anti-insulin B cells are preferentially skewed into marginal zone and late transitional subsets known to have increased sensitivity to proinflammatory signals. Additionally, IL-10 production, characteristic of regulatory B cell subsets, is increased. In contrast to conventional models, class switch-competent anti-insulin B cells proliferate normally in response to mitogenic stimuli but remain functionally silent for insulin autoantibody production. Diabetes development is accelerated, which demonstrates the power of anti-insulin B cells to exacerbate disease without differentiation into Ab-forming or plasma cells. Autoreactive T cell responses in V125NOD mice are not restricted to insulin autoantigens, as evidenced by increased IFN-γ production to a broad array of diabetes-associated epitopes. Together, these results independently validate the pathogenic role of anti-insulin B cells in type 1 diabetes, underscore their diverse developmental fates, and demonstrate the pathologic potential of coupling a critical β cell specificity to predominantly proinflammatory Ag-presenting B cell subsets.
Copyright © 2018 by The American Association of Immunologists, Inc.
We report a case of severe type I hyperlipoproteinemia caused by autoimmunity against lipoprotein lipase (LPL) in the context of presymptomatic Sjögren's syndrome. A 7-year-old mixed race (Caucasian/African American) girl was admitted to the intensive care unit at Vanderbilt Children's Hospital with acute pancreatitis and shock. She was previously healthy aside from asthma and history of Hashimoto's thyroiditis. Admission triglycerides (TGs) were 2191 mg/dL but returned to normal during the hospital stay and in the absence of food intake. At discharge, she was placed on a low-fat, low-sugar diet. She did not respond to fibrates, prescription fish oil, metformin, or orlistat, and during the following 2 years, she was hospitalized several times with recurrent pancreatitis. Except for a heterozygous mutation in the promoter region of LPL, predicted to have no clinical significance, she had no further mutations in genes known to affect TG metabolism and to cause inherited type I hyperlipoproteinemia, such as APOA5, APOC2, GPIHBP1, or LMF1. When her TG levels normalized after incidental use of prednisone, an autoimmune mechanism was suspected. Immunoblot analyses showed the presence of autoantibodies to LPL in the patient's plasma. Autoantibodies to LPL decreased by 37% while patient was on prednisone, and by 68% as she subsequently transitioned to hydroxychloroquine monotherapy. While on hydroxychloroquine, she underwent a supervised high-fat meal challenge and showed normal ability to metabolize TG. For the past 3 years and 6 months, she has had TG consistently <250 mg/dL, and no symptoms of, or readmissions for, pancreatitis.
Copyright © 2017 National Lipid Association. Published by Elsevier Inc. All rights reserved.
PURPOSE OF REVIEW - Laboratory criteria for the classification of antiphospholipid syndrome include the detection of a lupus anticoagulant and/or anticardiolipin and anti-β2-glycoprotein I antibodies. However, the majority of patients who test positive in these assays do not have thrombosis. Current risk-stratification tools are largely limited to the antiphospholipid antibody profile and traditional thrombotic risk factors.
RECENT FINDINGS - Novel biomarkers that correlate with disease activity and potentially provide insight into future clinical events include domain 1 specific anti-βGPI antibodies, antibodies to other phospholipids or phospholipid/protein antigens (such as anti-PS/PT), and functional/biological assays such as thrombin generation, complement activation, levels of circulating microparticles, and annexin A5 resistance. Clinical risk scores may also have value in predicting clinical events. Biomarkers that predict thrombosis risk in patients with antiphospholipid antibodies have been long sought, and several biomarkers have been proposed. Ultimately, integration of biomarkers with established assays and clinical characteristics may offer the best chance of identifying patients at highest risk of APS-related complications.
BACKGROUND - A protein that is expressed on capillary endothelial cells, called GPIHBP1 (glycosylphosphatidylinositol-anchored high-density lipoprotein binding protein 1), binds lipoprotein lipase and shuttles it to its site of action in the capillary lumen. A deficiency in GPIHBP1 prevents lipoprotein lipase from reaching the capillary lumen. Patients with GPIHBP1 deficiency have low plasma levels of lipoprotein lipase, impaired intravascular hydrolysis of triglycerides, and severe hypertriglyceridemia (chylomicronemia). During the characterization of a monoclonal antibody-based immunoassay for GPIHBP1, we encountered two plasma samples (both from patients with chylomicronemia) that contained an interfering substance that made it impossible to measure GPIHBP1. That finding raised the possibility that those samples might contain GPIHBP1 autoantibodies.
METHODS - Using a combination of immunoassays, Western blot analyses, and immunocytochemical studies, we tested the two plasma samples (as well as samples from other patients with chylomicronemia) for the presence of GPIHBP1 autoantibodies. We also tested the ability of GPIHBP1 autoantibodies to block the binding of lipoprotein lipase to GPIHBP1.
RESULTS - We identified GPIHBP1 autoantibodies in six patients with chylomicronemia and found that these autoantibodies blocked the binding of lipoprotein lipase to GPIHBP1. As in patients with GPIHBP1 deficiency, those with GPIHBP1 autoantibodies had low plasma levels of lipoprotein lipase. Three of the six patients had systemic lupus erythematosus. One of these patients who had GPIHBP1 autoantibodies delivered a baby with plasma containing maternal GPIHBP1 autoantibodies; the infant had severe but transient chylomicronemia. Two of the patients with chylomicronemia and GPIHBP1 autoantibodies had a response to treatment with immunosuppressive agents.
CONCLUSIONS - In six patients with chylomicronemia, GPIHBP1 autoantibodies blocked the ability of GPIHBP1 to bind and transport lipoprotein lipase, thereby interfering with lipoprotein lipase-mediated processing of triglyceride-rich lipoproteins and causing severe hypertriglyceridemia. (Funded by the National Heart, Lung, and Blood Institute and the Leducq Foundation.).
INTRODUCTION - The incidence of pulmonary nodules is increasing with the movement toward screening for lung cancer by low-dose computed tomography. Given the large number of benign nodules detected by computed tomography, an adjunctive test capable of distinguishing malignant from benign nodules would benefit practitioners. The ability of the EarlyCDT-Lung blood test (Oncimmune Ltd., Nottingham, United Kingdom) to make this distinction by measuring autoantibodies to seven tumor-associated antigens was evaluated in a prospective registry.
METHODS - Of the members of a cohort of 1987 individuals with Health Insurance Portability and Accountability Act authorization, those with pulmonary nodules detected, imaging, and pathology reports were reviewed. All patients for whom a nodule was identified within 6 months of testing by EarlyCDT-Lung were included. The additivity of the test to nodule size and nodule-based risk models was explored.
RESULTS - A total of 451 patients (32%) had at least one nodule, leading to 296 eligible patients after exclusions, with a lung cancer prevalence of 25%. In 4- to 20-mm nodules, a positive test result represented a greater than twofold increased relative risk for development of lung cancer as compared with a negative test result. Also, when the "both-positive rule" for combining binary tests was used, adding EarlyCDT-Lung to risk models improved diagnostic performance with high specificity (>92%) and positive predictive value (>70%).
CONCLUSIONS - A positive autoantibody test result reflects a significant increased risk for malignancy in lung nodules 4 to 20 mm in largest diameter. These data confirm that EarlyCDT-Lung may add value to the armamentarium of the practitioner in assessing the risk for malignancy in indeterminate pulmonary nodules.
Copyright © 2016 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.
PURPOSE - No biomarker is available for pancreatic cancer early detection, but a small prospective European study involving 16 cases and 32 controls raised the possibility that anti-Ezrin autoantibodies may be associated with risk of pancreatic cancer. We aimed to validate this finding in a case-control study nested within a prospective study in the USA.
METHODS - Levels of anti-Ezrin autoantibodies were examined using ELISA in pre-diagnostic plasma samples of 73 cases and 145 matched controls. Paired t test and paired signed rank tests were used to determine the difference between two groups, and conditional logistic regression was used to evaluate the association between anti-Ezrin autoantibody levels and risk of developing pancreatic cancer.
RESULTS - No association was found between levels of anti-Ezrin plasma autoantibodies and subsequent risk of developing pancreatic cancer.
CONCLUSION - Anti-Ezrin autoantibodies did not appear to be useful as a plasma biomarker for early detection of pancreatic cancer.
Autoantibody against glomerular basement membrane (GBM) plays a direct role in the initiation and development of Goodpasture's (GP) disease. The principal autoantigen is the non-collagenous domain 1 (NC1) of α3 chain of collagen IV, with two immunodominant epitopes, EA-α3 and EB-α3. We recently demonstrated that antibodies targeting α5NC1 are bound to kidneys in GP patients, suggesting their pathogenic relevance. In the present study, we sought to assess the pathogenicity of the α5 autoantibody with clinical and animal studies. Herein, we present a special case of GP disease with circulating autoantibody reactive exclusively to the α5NC1 domain. This autoantibody reacted with conformational epitopes within GBM collagen IV hexamer and produced a linear IgG staining on frozen sections of human kidney. The antibody binds to the two regions within α5NC1 domain, EA and EB, and inhibition ELISA indicates that they are targeted by distinct sub-populations of autoantibodies. Sequence analysis highlights five residues that determine specificity of antibody targeting EA and EB epitopes of α5NC1 over homologous regions in α3NC1. Furthermore, immunization with recombinant α5NC1 domain induced crescentic glomerulonephritis and alveolar hemorrhage in Wistar-Kyoto rats. Thus, patient data and animal studies together reveal the pathogenicity of α5 antibodies. Given previously documented cases of GP disease with antibodies selectively targeting α3NC1 domain, our data presents a conundrum of why α3-specific antibodies developing in majority of GP patients, with α5-specific antibodies emerged in isolated cases, the answer for which is critical for understanding of etiology and progression of the GP disease.
Copyright © 2016 Elsevier Ltd. All rights reserved.