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Affiliations Supplementary material Proteome-wide survey of the autoimmune target repertoire in autoimmune polyendocrine syndrome type 1 *Nils Landegren1,2, Donald Sharon3,4, Eva Freyhult2,5,6,, Åsa Hallgren1,2, Daniel Eriksson1,2, Per-Henrik Edqvist7, Sophie Bensing8, Jeanette Wahlberg9, Lawrence M. Nelson10, Jan Gustafsson11, Eystein S Husebye12, Mark S Anderson13, Michael Snyder3, Olle Kämpe1,2 Nils Landegren and Donald Sharon contributed equally to the work Affiliations 1Department of Medicine (Solna), Karolinska University Hospital, Karolinska Institutet, Sweden 2Science for Life Laboratory, Department of Medical Sciences, Uppsala University, Sweden 3Department of Genetics, Stanford University, California, USA 4Department of Molecular, Cellular, and Developmental Biology, Yale University, Connecticut, USA 1 5Department of Medical Sciences, Cancer Pharmacology and Computational Medicine, Uppsala University 6Bioinformatics Infrastructure for Life Sciences 7Department of Immunology, Genetics and Pathology, Uppsala University, Sweden and Science for Life Laboratory 8 Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden 9Department of Endocrinology and Department of Medical and Health Sciences and Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden 10Integrative Reproductive Medicine Group, Intramural Research Program on Reproductive and Adult Endocrinology, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA. 11Department of Women's and Children's Health, Uppsala University, Sweden 12Department of Clinical Science, University of Bergen, and Department of Medicine, Haukeland University Hospital, Bergen, Norway 2 13Diabetes Center, University of California San Francisco, USA *Correspondence should be addressed to Nils Landegren [email protected] Department of Medicine Solna, Karolinska Institute Experimental endocrinology Center for Molecular Medicine, L8:01, Karolinska University Hospital SE-171 76 Stockholm [email protected] phone: +46851779158 3 40000 All Patients count Healthy Controls Negative 20000 0 1e+01 1e+03 1e+05 Fig. S1. Distribution of log-intensities for arrays probed with patient sera, healthy control sera or without serum sample (Negative). DDC 100 50 Autoantibodyindex 3 SD 0 APS1 Healty Fig. S2. The proteome array results for DDC autoantibody detection were validated using a radio-ligand binding assay (RLBA) in the 51 patients from the APS1 discovery cohort and in 39 healthy controls. The upper limit of the normal range was defined as three standard deviations above the average of the healthy controls. 4 45000 40000 35000 30000 25000 cpm 20000 15000 10000 5000 0 Fig. S3. Representative raw data from the DDC autoantibody radio-ligand binding assay. All patient and control samples were analyzed in duplicate. Negative control (bar 1-4), positive control (bar 5-8), patients with APS1 (bar 9-68) and healthy control subjects (bar 69-96). Counts per minute (CPM). DDC Autoantibodies 60000 40000 20000 0 Proteomearray signal Positive in RLBA Negative in RLBA Fig. S4. The proteome array results for DDC were compared against the results from the radio-ligand binding assay (RLBA) for the 51 patients in the APS1 discovery cohort. Patients who were positive for DDC autoantibodies in the RLBA are grouped to the left (cut-off = average of the healthy + 3SD). Proteome array signals are 5 the array after subtraction of the background signal. represented as the average fluorescence signal intensities for signal. RLBA resul intensities for protein duplicates on the array after subtraction of the background the y cohort. Proteo the radio Fig. S5. The proteome array results for DDC were compared against the results from Height 100 120 140 160 -20 0.0 0.5 1.0 1.5 20 40 60 80 0 - 10 axis. Proteome array signals are represented as the average fluorescence signal R257X homozygotes R257X homozygotes - ligand binding assay (RLBA) for the 51 patients in the APS1 discovery R257X homozygotes Heterozygotes and rare AIRE mutations R257X homozygotes 100 R257X homozygotes me array signal results are shown on the x R257X homozygotes R257X homozygotes Heterozygotes and rare AIRE mutations ts are shown as autoantibody index values. R257X homozygotes R257X homozygotes 1000 c967−979del13 homozygotes R257X homozygotes c967−979del13 homozygotes Heterozygotes and rare AIRE mutations R257X homozygotes 10000 R257X homozygotes Heterozygotes and rare AIRE mutations R257X homozygotes R257X homozygotes R257X homozygotes R257X homozygotes 100000 Heterozygotes and rare AIRE mutations R257X homozygotes R257X homozygotes Healthy controls Healthy controls Healthy controls Healthy controls Heterozygotes and rare AIRE mutations Cluster Dendrogram hclust (*,"complete") Healthy controls Healthy controls as.dist(1 as.dist(1 Healthy controls Healthy controls Healthy controls − c) Healthy controls Healthy controls Healthy controls Healthy controls Healthy controls Healthy controls Healthy controls - Healthy controls axis and RLBA results on Healthy controls Healthy controls Healthy controls Healthy controls protein duplicates on R257X homozygotes R257X homozygotes Heterozygotes and rare AIRE mutations R257X homozygotes c967−979del13 homozygotes R257X homozygotes c967−979del13 homozygotes R257X homozygotes R257X homozygotes R257X homozygotes c967−979del13 homozygotes R257X homozygotes R257X homozygotes R257X homozygotes c967−979del13 homozygotes c967−979del13 homozygotes 6 Heterozygotes and rare AIRE mutations Heterozygotes and rare AIRE mutations c967−979del13 homozygotes R257X homozygotes R257X homozygotes Fig. S6. Patients with APS1 and healthy controls were clustered based on Spearman correlations for the known autoantigens; glutamate decarboxylase 2 (GAD2), glutamate decarboxylase 1 (GAD1), tryptophan hydroxylase (TPH1), aromatic L- amino acid decarboxylase (DDC), gastric intrinsic factor (GIF), cytochrome P450, family 1, subfamily A, polypeptide 2 (CYP1A2), potassium channel regulator (KCNRG), testis specific 10 (TSGA10), interleukin 22 (IL22), interleukin 17A (IL17A), interferon omega (IFNW1) and interferon alpha 1 (IFNA1). Distance = 1 – correlation. 7 value 60000 40000 20000 0 IL1B IL32 TSLP IL3 IL24 IL36B IL20 IL26 IL12A IL1RN IL1F10 IL34 LIF IL21 IL9 IL23A IL16 IL25 IL4 IFNK IL19 OSM IL36G IL13 CLCF1 IL10 IL7 IL2 IL15 IL5 IL27 IL17A IL22 IFNA16 IFNW1 IL36A IFNA17 IFNA1 IFNA13 IFNA4 IFNA21 IFNA2 IFNA5 IFNA6 IFNA8 IFNA14 IFNG IL6 IL8 P1 P2 P3 P4 P5 P6 P7 P8 P9 P10 P11 P12 P13 P14 P15 P16 P17 P18 P19 P20 P21 P22 P23 P24 P25 P26 P27 P28 P29 P30 P31 P32 P33 P34 P35 P36 P37 P38 P39 P40 P41 P42 P43 P44 P45 P46 P47 P48 P49 P50 P51 HC1 HC2 HC3 HC4 HC5 HC6 HC7 HC8 HC9 HC10 HC11 HC12 HC13 HC14 HC15 HC16 HC17 HC18 HC19 HC20 HC21 Fig. S7. Focused investigation of 49 interferons, interleukins and other closely related cytokines. High autoantibody signals were seen specifically for the previously 8 established immune targets, including multiple alpha interferon specifies, IFNW1, IL22 and IL17A (IL17F was not present in the array panel) 60000 40000 DDC CORO2A C1orf137 Intensity EPDR1 20000 0 ● ● ● ● ● ● ● ● ●● ● ● ● 10000 ● ● ● ● ● ● ● ● ● ● ● ● ● ●● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●● ● ● ● ● ● ● CORO2A ● ● ● ● ● C1orf137 ● ● ● ● ● Intensity ● ● EPDR1 ● ●● ● ● ● ● ● ● ● ● ● ● ● ● ● ●● ● ● ● ● ● ● ● ● ● ● ● ● ●● ●●● ● ● ● ● ● ● ● ● ●● ● ● 100 ● ● ● ● ●● ● ● ● ● ● ● ● ● ● ●● ●● ● ● ●●●● ●● ● ● ●●● ●●●● ● ●● ● ● ● ● ● ●● ●● ●●● ● ● ● ● ● ●● ● ● ● ● ● ●● ● ● ●● ●● ● ● ● ● ● ● ● ● 100 1000 10000 Intensity DDC Fig. S8. Printing contamination artifacts exemplified by DDC and adjacent targets. Correlated protein array signals between DCC, an established APS1 autoantigen, and 9 TPH1 10 CCDC40 MOBK1B IGSF21 PDILT WDR45L MAGEB2 MAGEB4 FAM70A IFNA13 IFNA6 y screen before FAM71F1 IFNA14 IFNA8 IFNA5 IFNA2 IFNA17 IFNA4 IFNA1 IFNA21 IFNA4 IFNW1 al intensities for protein duplicates on the array IL22 TGM4 EPDR1 C1orf137 CORO2A DDC GIF GAD1 GAD1 IL1RN IQCG GAD2 . Identification of printing contamination artifacts in the proteome array data ATP5G3 1 0.5 0.75 0.25 Absolute correlation Absolute annotation are shown. Unexpected strong correlations between targets closely located on the array were identified as artifacts (marked in Italic) and excluded from the analyses. Fig. S9 set. Correlations between the top targets in the protein arra are grouped to the left and patients with APS1 (n=51) to the right in the upper image. Average fluorescence sign after subtraction of the background signal are shown. nearby located proteins; CORO2AA, C1orf137 and EPDR1. Healthy subjects (n=21) PDILT 30000 20000 10000 0 Proteomearray signal Positive in RLBA Negative in RLBA Fig. S10. Validation of PDILT autoantibodies in the APS1 discovery cohort (n=51) using a radio-ligand binding assay (RLBA). Patients that were positive for PDILT autoantibodies in the RLBA are grouped to the left. The cut-off in the RLBA was defined as an index-value of 15. Proteome array signals are shown as the average fluorescence signal intensities for protein duplicates on the array after subtraction of the background signal. MAGEB2 60000 40000 20000 0 Proteomearray signal Positive in RLBA Negative in RLBA Fig. S11. Validation of MAGEB2 autoantibodies in the APS1 discovery cohort (n=51) using a radio-ligand binding assay (RLBA). Patients that were positive for MAGEB2 11 autoantibodies in the RLBA are grouped to the left. The cut-off in the RLBA was defined as an index-value of 15. Proteome array signals are
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