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Early Detection of Peripheral Blood Cell Signature in Children Developing B-Cell Autoimmunity at a Young Age

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Early Detection of Peripheral Blood Cell Signature in Children Developing B-Cell Autoimmunity at a Young Age 2024 Diabetes Volume 68, October 2019 Early Detection of Peripheral Blood Cell Signature in Children Developing b-Cell Autoimmunity at a Young Age Henna Kallionpää,1 Juhi Somani,2 Soile Tuomela,1 Ubaid Ullah,1 Rafael de Albuquerque,1 Tapio Lönnberg,1 Elina Komsi,1 Heli Siljander,3,4 Jarno Honkanen,3,4 Taina Härkönen,3,4 Aleksandr Peet,5,6 Vallo Tillmann,5,6 Vikash Chandra,3,7 Mahesh Kumar Anagandula,8 Gun Frisk,8 Timo Otonkoski,3,7 Omid Rasool,1 Riikka Lund,1 Harri Lähdesmäki,2 Mikael Knip,3,4,9,10 and Riitta Lahesmaa1 Diabetes 2019;68:2024–2034 | https://doi.org/10.2337/db19-0287 The appearance of type 1 diabetes (T1D)-associated function before T1D and suggest a potential role for IL32 autoantibodies is the first and only measurable param- in the pathogenesis of T1D. eter to predict progression toward T1D in genetically susceptible individuals. However, autoantibodies indi- cate an active autoimmune reaction, wherein the im- Family and sibling studies in type 1 diabetes (T1D) have mune tolerance is already broken. Therefore, there is implicated a firm genetic predisposition to a locus con- a clear and urgent need for new biomarkers that predict taining HLA class I and class II genes on chromosome the onset of the autoimmune reaction preceding auto- 6 suggesting a role for CD4+ as well as CD8+ T cells in T1D fl antibody positivity or re ect progressive b-cell destruc- pathogenesis (1–3). As much as 30–50% of the genetic risk – tion. Here we report the mRNA sequencing based is conferred by HLA class II molecules, which are crucial in analysis of 306 samples including fractionated samples antigen presentation to CD4+ T cells. Further, CD4+ cells of CD4+ and CD8+ T cells as well as CD42CD82 cell reactive to b-cell antigen peptides are found in peripheral fractions and unfractionated peripheral blood mono- blood and the pancreas and typically secrete the cytokine nuclear cell samples longitudinally collected from g + seven children who developed b-cell autoimmunity IFN (4,5). CD4 cells orchestrate adaptive immune responses, including that of antibody-secreting B cells as (case subjects) at a young age and matched control + subjects. We identified transcripts, including interleukin well as cytotoxic CD8 T cells. Indeed, circulating autoanti- 32 (IL32), that were upregulated before T1D-associated bodies against b-cell antigens may appear years before the + autoantibodies appeared. Single-cell RNA sequencing clinical onset. Further, a cytolytic CD4 subtype might studies revealed that high IL32 in case samples was directly contribute to target cell killing (6). GENETICS/GENOMES/PROTEOMICS/METABOLOMICS contributed mainly by activated T cells and NK cells. Although HLA class II is associated with the develop- Further, we showed that IL32 expression can be in- ment of autoantibodies, HLA class I seems to be more duced by a virus and cytokines in pancreatic islets strongly linked to disease progression (7). Histological and b-cells, respectively. The results provide a basis analysis of pancreatic sections of cadaveric donors with for early detection of aberrations in the immune system T1D revealed that HLA class I is highly expressed in islets 1Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku, 10Tampere Center for Child Health Research, Tampere University Hospital, Finland Tampere, Finland 2 Department of Computer Science, Aalto University School of Science, Espoo, Corresponding author: Riitta Lahesmaa, riitta.lahesmaa@utu.fi Finland Received 17 April 2019 and accepted 10 July 2019 3Children’s Hospital, University of Helsinki, and Helsinki University Hospital, Helsinki, Finland This article contains Supplementary Data online at http://diabetes 4Research Programs Unit, Diabetes and Obesity, University of Helsinki, Helsinki, .diabetesjournals.org/lookup/suppl/doi:10.2337/db19-0287/-/DC1. Finland H.K., J.S., S.T., and U.U. contributed equally to this work. 5Department of Pediatrics, University of Tartu, Tartu, Estonia H.K., M.K., and R.L. share senior authorship. 6Children’s Clinic of Tartu, Tartu University Hospital, Tartu, Estonia 7Research Programs Unit, Molecular Neurology and Biomedicum Stem Cell Centre, © 2019 by the American Diabetes Association. Readers may use this article as fi Faculty of Medicine, University of Helsinki, Helsinki, Finland long as the work is properly cited, the use is educational and not for pro t, and the 8Department of Immunology, Genetics and Pathology, Uppsala University, Sweden work is not altered. More information is available at http://www.diabetesjournals 9Folkhälsan Research Center, Helsinki, Finland .org/content/license. diabetes.diabetesjournals.org Kallionpää and Associates 2025 (8,9). Moreover, CD8+ cells are the most abundant cell type Sample Collections during insulitis (10), and the islets contain CD8+ cells At each study visit, 8 mL blood was drawn in sodium- specific for T1D autoantigens (11). Thus, the autoimmune heparin tubes (368480, Vacutainer; BD Biosciences). Pe- cascade in T1D might be initiated by self-reactive CD4+ ripheral blood mononuclear cells (PBMCs) were isolated by cells that activate B cells to produce autoantibodies that Ficoll-Paque centrifugation (17-1440-03; GE Healthcare) target the b-cells and unleash the cytotoxic activity of the and were suspended in RPMI-1640 medium (42401-018; autoreactive CD8+ cells. The environmental factors trig- Gibco) supplemented with 10% DMSO (cat. no. 0231, gering and driving the autoimmunity in T1D are poorly 500 mL, Thermo Fisher Scientific), 5% Human AB Serum defined, but the disease has been associated with viral (cat. no. IPLA-SERAB-OTC; Innovative Research), 2 infections (12), diet in early childhood (13), and reduced mmol/L L-glutamine (G7513; Sigma-Aldrich), and 25 mmol/L diversity of gut microbiota (14). gentamicin (G-1397; Sigma-Aldrich). After overnight Currently, the appearance of T1D-associated autoanti- incubation at 280°C, samples were stored in liquid nitro- bodies is the first and only measurable parameter to gen (2180°C). For fractionation, PBMC samples were predict progression toward T1D in genetically susceptible thawed quickly in a 37°C water bath and quantitated individuals. Although the disease progression rate varies for cell numbers and viability. On average, 90% of cells considerably, children with genetic HLA risk expressing at were viable. Magnetic antibody-coupled beads were used least two T1D autoantibodies will very likely progress to for sequential positive enrichment of CD4+ and CD8+ cells clinical disease during the next 15 years (15). However, (11331D and 11333D; Invitrogen). RNA was isolated autoantibodies are poor prognostic markers for the timing from the samples with an AllPrep kit (80224; QIAGEN), of the clinical presentation of T1D. The appearance of and quantity and quality were determined using a Qubit autoantibodies indicates an active autoimmune reaction, RNA assay (Q32852; Invitrogen) and Bioanalyzer 2100 wherein the immune tolerance is already broken. There- (Agilent), respectively. fore, there is a clear and urgent need for new biomarkers that predict the onset of the autoimmune reaction pre- Bulk RNA Sequencing of PBMCs and Other Fractions ceding autoantibody positivity or reflect progressive b-cell At least 80 ng total RNA was processed for RNA sequenc- destruction. Such markers would present a window for ing (RNA-seq) with the TruSeq Stranded mRNA Library early intervention aimed at complete disease prevention. Prep kit (RS-122-2101; Illumina). The sequencing was Previously, we reported changes in whole-blood transcripts carried out with the Illumina HiSeq2500 instrument using and serum proteins before the detection of diabetes- TruSeq v3 (2 3 100 base pairs [bp] chemistry). The average associated antibodies in children who later progressed to T1D sequencing depth was ;51 million reads. Quality control (16,17). Therefore, we hypothesized that a comprehensive was performed using FastQC (version 0.10.0). All the analysis of the transcriptome of longitudinal cellular sam- samples passed the quality criteria. The reads were aligned ples including CD4+ and CD8+ T cells will lead to the to the human reference transcriptome, GRCh37 assembly identification of new early biomarkers. version 75, using TopHat (version 2.0.10) (20). Average mapping percentage was 93. The concordant pairs per- RESEARCH DESIGN AND METHODS centage was ;89. The aligned reads were counted with Study Cohort htseq-count (HTSEq. 0.6.1; overlap mode of “intersection- Samples were collected as part of the DIABIMMUNE study strict”) (21). The read counts of genes were normalized from Finnish (n = 10) and Estonian (n = 4) participants using the trimmed means of the M values (TMM imple- (Supplementary Table 1). The HLA-DR-DQ genotypes were mented in edgeR [22]). Coding, noncoding information analyzed as previously described (18). A total of 836 children were taken from Ensembl. Differential expression analyses with HLA-DR-DQ risk allele were monitored and sampled at were conducted separately for coding and noncoding 3, 6, 12, 18, 24, and 36 months of age. The study protocols genes, using edgeR (22). The variance of the data was were approved by the ethics committees of the participating estimated using the trended dispersion method. A further hospitals, and the parents gave written informed consent. filtering step retained only those genes as differentially Autoantibodies against insulin (IAA), glutamic acid decar- expressed (DE) that had |median log2 fold change (FC)| boxylase (GADA), islet antigen-2 (IA-2A), and zinc trans- .0.5 and had .65% samples across all individuals regu- porter 8 (ZnT8A) were measured from serum with specific lated in the same direction (i.e., up- or downregulated). radiobinding assays (19). Islet cell antibodies (ICAs) were These filtering steps were added to discard false positives analyzed with immunofluorescence in autoantibody-positive that may arise due to the heterogeneity of the samples subjects. The cutoff values were based on the 99th per- resulting from normal variation, which is unrelated to T1D centile in children without diabetes, which were 2.80 as well as to discard the outliers.
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