Incomplete immune response to Coxsackie B viruses. associates with early autoimmunity against insulin

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Incomplete immune response to Coxsackie B viruses associates with early autoimmunity against insulin Michelle P. Ashton 1, Anne Eugster 1, Denise Walther 1, Natalie Daehling 1, Stephanie Riethausen 2, Denise Kuehn 1, Karin Klingel 3, Andreas Beyerlein 2, Stephanie Zillmer 2, Anette-Gabriele Ziegler 2,4,5, Ezio Bonifacio 1,4,5,* 1 DFG-Center for Regenerative Therapies Dresden, Dresden, Germany 2 Institute of Diabetes Research, Helmholtz Zentrum München and Forschergruppe Diabetes, Klinikum rechts der Isar, Technische Universität München, Neuherberg, Germany 3 Department of Molecular Pathology, University Hospital Tübingen, Tübingen, Germany 4 Forschergruppe Diabetes e.v., Neuherberg, Germany 5 German Center for Diabetes Research (DZD), Neuherberg, Germany *ezio.bonifacio@crt-dresden.de 1

Supplementary Figure 1: Anti-VP1, anti-vp2, and anti-vp4 CVB antibodies can be detected in serum LIPS measurement of anti-vp1, anti-vp2, anti-vp3 and anti-vp4 antibodies in sera from children and adolescents with recent onset of type 1 diabetes (open circles; n=78) and healthy controls (filled circles; n=78). Each point is an individual and the line indicates the median. 2

3

Supplementary Figure 2: Correlations between antibodies to viral capsid antigens from CVB1-6. (a) Scatter plot matrix of anti-cvb3 and anti-cvb4 antibody titers in all sera analyzed in this study. Each dot represents a sample and the line represents the linear regression. Plots with the same VP (but different serotype) plotted on both the x and y axes are highlighted with a red border. (b) A matrix summarizing the Pearson correlation between antibody titers for each CVB antigen. The upper right panel lists the correlation co-efficient for each comparison and values greater than 0.4 are shaded. The bottom left panel shows ellipses representative of the magnitude of the correlation. Blue ellipses with a positive slope, indicate a positive correlation and red ellipses with a negative slope indicate negative correlations, where a greater intensity in color indicates a correlation-coefficient closer to 1 (blue) or -1 (red). 4

Supplementary Figure 3: Sera selected for analysis by plaque neutralization test. Anti-VP1 (filled symbols) and anti-vp2 (open symbols) antibody titers of sera selected to be analyzed by the plaque neutralization test as determined by the LIPS assay. Sera 1-4 have strong anti-vp1 and anti-vp2 antibody titers and sera 5-8 have strong anti-vp2 antibody titers. 5

Supplementary Figure 4: Anti-CVB antibodies in follow-up samples from children with early insulin autoimmunity. Anti-VP1 antibodies (y axis) in longitudinal serum samples from children who developed beta cell autoantibody seroconversion before age 3 years with IAA as the first detected autoantibodies. Titers are shown relative to the time of insulin autoantibody seroconversion (x axis). Each symbol and line represents a different child, each point represents the mean RLU for VP1 of all six CVB serotypes measured at a given time point, and error bars represent s.e.m. 6

Supplementary Figure 5: Anti-VP2 and anti-vp4 CVB antibodies in newborns are not associated with seroconversion. Anti-VP2 (a) and anti-vp4 (b) antibodies in cord blood serum of BABYDIAB study participants stratified as beta cell autoantibody negative throughout follow-up (no autoimmunity), beta cell autoantibody seroconversion before age 3 years with IAA as the first detected autoantibodies (early insulin), and beta cell autoantibody seroconversion with GAD as the first detected autoantibody target (GAD). Each point is an individual and the horizontal bar indicates the median. No significant differences based on comparison with early insulin autoimmunity group for the corresponding CVB serotype using the Mann Whitney U test. 7

Supplementary Figure 6: Maternal anti-cvb antibody profiles in newborns differ from those observed in adolescents. The LIPS assay was used to detect antibodies to viral capsid protein (VP) antigens of CVB1-6 in cord blood serum (Newborn), healthy control children and adolescents (Healthy controls), and children and adolescents with recent onset type 1 diabetes (Recent onset T1D). (a) Antibody titers against VPs of CBV1-6 are represented as a heat map where each vertical line is a sample and the intensity of the color corresponds to the RLU measured by the LIPS assay. Data is sorted based on the clusters that were identified as described in Fig. 1. (b) The proportion of sera within the 4 clusters defined in Fig. 1 is represented by a stacked bar chart for each cohort. A higher proportion of samples from newborns were observed in cluster 4 (p>0.001 Healthy controls; p=0.004 Recent onset T1D) and a lower proportion of samples from newborns were observed in cluster 1 (p=0.002 Healthy controls; p=0.027 Recent onset T1D) as compared to the children/adolescent groups using the Z-score test statistic and two-tailed test. 8

Supplementary Figure 7: Gating strategy for isolation of peptide responsive CD45RO + T cells. CFSE-labeled CD45RO + T cells cultured with CVB4 p2c 30-51 or GAD65 247-266 peptide loaded monocyte-derived dendritic cells for 5 days. Antigen-responsive memory T cells were identified by flow cytometry as 7AAD - CD4 + CD25 hi CFSE lo CD45RO + CD45RA -. 9

Supplementary table 1: Anti-VP1 and anti-vp4 antibody titers increase with age. Group 1 Group 2 (mean ± s.e.m) (mean ± s.e.m) Age (years) 2.783 ± 0.039 12.01 ± 0.120 p-value* CVB1 0.272 ± 0.038 0.557 ± 0.031 >0.0001 CVB2 0.296 ± 0.062 0.339 ± 0.019 >0.0001 Relative light units (normalized) VP4 VP2 VP1 CVB3 0.281 ± 0.044 0.642 ± 0.041 >0.0001 CVB4 0.139 ± 0.025 0.584 ± 0.029 >0.0001 CVB5 0.312 ± 0.055 0.503 ± 0.029 >0.0001 CVB6 0.219 ± 0.031 0.623 ± 0.042 >0.0001 CVB1 0.507 ± 0.033 0.588 ± 0.021 0.0552 CVB3 0.448 ± 0.028 0.390 ± 0.019 0.0844 CVB4 0.662 ± 0.064 0.471 ± 0.027 0.1022 CVB5 0.816 ± 0.068 0.519 ± 0.031 0.0010 CVB6 0.551 ± 0.037 0.526 ± 0.027 0.5364 CVB1 0.067 ± 0.021 0.162 ± 0.025 >0.0001 CVB2 0.093 ± 0.023 0.124 ± 0.015 >0.0001 CVB3 0.100 ± 0.020 0.133 ± 0.017 0.0481 CVB4 0.083 ± 0.020 0.148 ± 0.017 >0.0001 CVB5 0.096 ± 0.034 0.141 ± 0.027 0.0002 CVB6 0.081 ± 0.017 0.171 ± 0.021 0.0002 *p-values calculated using Mann Whitney U Test 10

Supplementary table 2: Paired TCR sequences not shared between CVB4 p2c peptide and GAD65 peptide responsive CD4 + CD45RO + T cells. Subject Antigen # cells TRAV TRAJ JunctionA TRBV TRBJ TRBD JunctionB BC928 CVB4 1 36/DV7*02 42*01 CAVEA#YGGSQGNLIF 20-1*01 2-7*01 2*02 CSARDLRELEQYF p2c30-51 1 36/DV7*02 42*01 CAVEANMEXAK#NLIF 20-1*01 2-7*01 2*02 CSARDLRELEQYF 1 9-2*01 30*01 CALT#NRDDKIIF 28*01 2-3*01 1*01 CASSLAGQTPDTQ#F 1 9-2*01 30*01 CALTGTEMTRSS# 9*01 2-3*01 1*01 CASSLAGQTPDTQ#F 1 9-2*01 34*01 CVVSVGNTDKLIF 10-3*01 2-3*01 1*01 CASSLAGQTPDTQ#F 1 9-2*01 29*01 CAVGARGSGNTPLVF 30*01 2-3*01 1*01 CASSLAGQTPDTQ#F 1 26-1*01 42*01 CIVRG#YGGSQGNLIF 10-3*01 2-1*01 1*01 CASSIGGTFGPYNEQFF 1 22*01 28*01 CAVSGAGSYQLTF 5-1*01 2-5*01 2*01 CASSLSTSVAQETQYF 1 8-2*01 34*01 CVVSVGNTDKLIF 28*01 1-5*01 1*01 VPSVPRQE#QPQHF 1 26-1*01 58*01 CIVSKETSGSRLTF 6-1*01 2-1*01 1*01 CATRSTGNIYNEQFF 1 26-1*01 33*01 CIVRFGP#MDSNYQLIW 6-1*01 2-3*01 2*01 CRARVSATSTDTQ#F 1 36/DV7*02 54*01 CAVEAVIQGAQKLVF 2*01 2-3*01 2*02 CASSQDGASGRAYTQYF 1 36/DV7*02 42*01 CAVEXNMEEAXX#LIF 27*01 2-7*01 2*02 CRARDLRELXEQYF 1 9-2*01 21*01 CALLSYNFNKFYF 28*01 2-1*01 2*01 CASXKRD*RGGLQ*A#FF 1 23/DV6*01 13*02 CAASRTSGGYQKVTF 5-4*01 1-6*02 1*01 CASRGQGAASPLHF 1 17*01 56*01 CATDYTGANSKLTF 4-2*01 2-1*01 2*01 CSAQXTPRPVSS#F 1 23/DV6*01 29*01 CAARYSGNTPLVF 5-6*01 2-7*01 1*01 CRANGAR#EQYF 1 8-6*01 49*01 CAVILL#NQFYF 14*01 2-1*01 1*01 FTSSAARYEQFF 1 36/DV7*02 40*01 CAVEG#YKYIF 3-1*01 2-3*01 1*01 CRXGDRGTDTQ#F 1 9-2*01 52*01 CALSQNAGGTSYGKLTF 19*01 2-5*01 1*01 CASSSRDRPTQYF 1 9-2*01 30*01 CALTGTEMTSSS# 28*01 2-3*01 1*01 CASSLAGRPQIR##F 1 41*01 49*01 CADHTNTGNQFYF 2*01 2-5*01 2*01 CASSALSSVKKETQYF 1 17*01 23*01 CATLNVGNQGGKLIF 7-6*01 2-6*01 1*01 CASXEGQGLGGWVNXLTF 1 17*01 23*01 CATLNXGNQGGKLIF 5-5*01 2-6*01 1*01 CAXXEGRGWALGPTAX#F 1 8-6*02 52*01 CAVSYAGGTSYGKLTF 6-6*01 1-5*01 1*01 CASSGXGGQPQHF 266 1 26-1*01 26*01 CIVRVSHN*G#RDNYGQNFVF 10-3*01 2-5*01 1*01 CAS*GQGQETQNF 1 29/DV5*01 33*01 CAASDGSNYQLIW 27*01 2-7*01 1*01 CASSLPRTGKDEQYF 1 29/DV5*01 6*01 CAASGSGGSYIPTF 27*01 2-3*01 2*01 CARQGD*RKXDTQ#F 1 6*03 [] 4*01 CALDPGGYNKLFF 7-9*01 2-1*01 2*01 CSARTSGGYNEQFF 1 2*01 39*01 CAVEDHILLXNLLPF 5-1*01 2-1*01 2*01 CASSLVFTGSGYNEQFF 1 8-6*02 50*01 CAVRRASYDKVIF 7-9*01 2-2*01 2*02 CASKSSGRLTGELFF 1 3*01 6*01 CAVRVLGGSYIPTF 5-1*01 2-1*01 2*01 CTGTREYNEQFF 1 8-6*01 31*01 CAVSEGX#RLMF 28*01 2-2*01 2*01 CASTPRGRETGGLFF 1 8-2*01 56*01 CAVSGAA*GLX#NSKLTF 29-1*01 2-7*01 2*01 CASSERGGS#EQYF 1 26-1*01 42*01 CIVLRL#GSQGNLIF 28*01 2-2*01 2*02 CASRGLAGATGELFF 1 26-1*01 33*01 CIVRFGPKWI#NYQLIW 2*01 2-3*01 1*01 CSARVSATSTDTQYF 1 26-1*01 38*01 CIVRG*CWQQPYAEL# 6-5*01 2-3*01 2*01 CRAKLGLEATDTQ#F 1 26-1*01 38*01 CIVRG*CWQQPYPEP# 20-1*01 2-3*01 2*01 CSARLGLEATDTQYF 1 8-4*03 49*01 CVASLNTGNQFYF 20-1*03 2-5*01 1*01 CASSLDRVQETQYF 1 29/DV5*01 30*01 VQQE#DDKIIF 20-1*01 2-1*01 2*01 CASSVGLAKTIGEQFF 1 25*01 39*01 CAALVGWAGNMLTF 5-6*01 2-7*01 2*01 CVPAIIRGGGXYEEYF 1 2*01 29*01 CAASRNSGNTPLVF 1*01 2-3*01 1*01 CARSWEDTQXF B858 GAD65247- GAD65247-266 5 8-3*02 20*01 CAVGSNDYKLSF 20-1*04 1-2*01 1*01 CSAPSGPP#NYGYTF 2 41*01 42*01 CAVMNYGGSQGNLIF 11-1*01 2-2*01 2*01 CASDRGGKPGGVVF D161 CVB4 p2c30-51 2 29/DV5*01 31*01 CAAFRNNNARLMF 5-5*01 1-3*01 1*01 CASSLFSSGNTIYF 1 36/DV7*01 44*01 CAVEAAGTASKLTF 30*01 1-1*01 2*01 CAWGHSGGPTNTEAFF 11

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