TY  - JOUR
AB  - Human herpesvirus-6 (HHV-6) is a ubiquitous pathogen associated with nervous and endocrine autoimmune disorders. The aim of this study was to investigate the presence of HHV-6 in pancreatic tissue sections from nondiabetic, auto-antibody positive (AAB +), and donors with type 1 diabetes (T1D) and explore whether there is any association between HHV-6 and MHC class I hyperexpression and CD8 T cell infiltration.HHV-6 DNA was detected by PCR and its protein was examined by indirect immunofluorescence assay followed by imaging using high-resolution confocal microscopy. Viral DNA (U67) was found in most pancreata of non-diabetic (3 out of 4), AAB+ (3 out of 5) and T1D donors (6 out of 7). Interestingly, HHV-6 glycoprotein B (gB) was more expressed in islets and exocrine pancreas of donors with T1D. However, gB expression was not directly associated with other pathologies. Out of 20 islets with high gB expression, only 3 islets (15%) showed MHC class I hyperexpression. Furthermore, no correlation was found between gB expression and CD8 T cell infiltration on a per-islet basis in any of the groups.Our observations indicate that HHV-6 DNA and protein are present in the pancreas of non-diabetic subjects but gB expression is higher in the pancreas of donors with T1D. The possible role of HHV-6 as a contributory factor for T1D should therefore be further investigated.
AU  - Sabouri, S.*
AU  - Benkahla, M.A.*
AU  - Kiosses, W.B.*
AU  - Rodriguez-Calvo, T.
AU  - Zapardiel-Gonzalo, J.
AU  - Castillo, E.*
AU  - Von Herrath, M.G.*
C1  - 57654
C2  - 47983
CY  - 24-28 Oval Rd, London Nw1 7dx, England
TI  - Human herpesvirus-6 is present at higher levels in the pancreatic tissues of donors with type 1 diabetes.
JO  - J. Autoimmun.
VL  - 107
PB  - Academic Press Ltd- Elsevier Science Ltd
PY  - 2020
SN  - 0896-8411
ER  - 

TY  - JOUR
AB  - The susceptibility to autoimmune diseases is influenced by genes encoding major histocompatibility complex (MHC) proteins. By examining the epigenetic methylation maps of cord blood samples, we found marked differences in the methylation status of CpG sites within the MHC genes (cis-metQTLs) between carriers of the type 1 diabetes risk haplotypes HLA-DRB1*03-DQA1*0501-DQB1*0201 (DR3-DQ2) and HLA-DRB1*04-DQA1*0301-DQB1*0302 (DR4-DQ8). These differences were found in children and adults, and were accompanied by reduced HLA-DR protein expression in immune cells with the HLA-DR3-DQ2 haplotype. Extensive cis-metQTLs were identified in all 45 immune and non-immune type 1 diabetes susceptibility genes analyzed in this study. We observed and validated a novel association between the methylation status of CpG sites within the LDHC gene and the development of insulin autoantibodies in early childhood in children who are carriers of the highest type 1 diabetes risk genotype. Functionally relevant epigenetic changes in susceptibility genes may represent therapeutic targets for type 1 diabetes.
AU  - Kindt, A.
AU  - Fuerst, R.W.
AU  - Knoop, J.
AU  - Laimighofer, M.
AU  - Telieps, T.
AU  - Hippich, M.
AU  - Woerheide, M.A.
AU  - Wahl, S.
AU  - Wilson, R.
AU  - Sedlmeier, E.-M.
AU  - Hommel, A.*
AU  - Todd, J.A.*
AU  - Krumsiek, J.
AU  - Ziegler, A.-G.
AU  - Bonifacio, E.
C1  - 52522
C2  - 44046
SP  - 63-74
TI  - Allele-specific methylation of type 1 diabetes susceptibility genes.
JO  - J. Autoimmun.
VL  - 89
PY  - 2018
SN  - 0896-8411
ER  - 

TY  - JOUR
AB  - beta-cell autoantibodies against insulin (IAA), GAD65 (GADA) and IA-2 (IA-2A) precede onset of childhood type 1 diabetes (T1D). Incidence of the first appearing beta-cell autoantibodies peaks at a young age and is patterned by T1D-associated genes, suggesting an early environmental influence. Here, we tested if gestational infections and interactions with child's human leukocyte antigen (HLA) and non-HLA genes affected the appearance of the first beta-cell autoantibody. Singletons of mothers without diabetes (n = 7472) with T1D-associated HLA-DR-DQ genotypes were prospectively followed quarterly through the first 4 years of life, then semiannually until age 6 years, using standardized autoantibody analyses. Maternal infections during pregnancy were assessed via questionnaire 3-4.5 months post-delivery. Polymorphisms in twelve non-HLA genes associated with the first appearing beta-cell autoantibodies were included in a Cox regression analysis. IAA predominated as the first appearing beta-cell autoantibody in younger children (n = 226, median age at seroconversion 1.8 years) and GADA (n = 212; 3.2 years) in children aged >= 2 years. Gestational infections were not associated with the first appearing beta-cell autoantibodies overall. However, gestational respiratory infections (G-RI) showed a consistent protective influence on IAA (HR 0.64, 95% CI 0.45-0.91) among CTLA4-(AG, GG) children (G-RI*CTLA4 interaction, p = 0.002). The predominant associations of HLA-DR-DQ4-8/8-4 with IAA and HLA-DR-DQ 3-2/3-2 with GADA were not observed if a G-RI was reported (G-RI*HLA-DR-DQ interaction, p = 0.03). The role of G-RI may depend on offspring HLA and CTLA-4 alleles and supports a bidirectional trigger for IAA or GADA as a first appearing beta-cell autoantibody in early life. (C) 2017 Elsevier Ltd. All rights reserved.
AU  - Lynch, K.F.*
AU  - Lee, H.S.*
AU  - Törn, C.*
AU  - Vehik, K.*
AU  - Krischer, J.P.*
AU  - Larsson, H.E.*
AU  - Haller, M.J.*
AU  - Hagopian, W.A.*
AU  - Rewers, M.J.*
AU  - She, J.X.*
AU  - Simell, O.G.*
AU  - Toppari, J.*
AU  - Ziegler, A.-G.
AU  - Akolkar, B.*
AU  - Hyöty, H.*
AU  - Bonifacio, E.*
AU  - Lernmark, A.*
C1  - 51974
C2  - 43623
CY  - London
SP  - 93-103
TI  - Gestational respiratory infections interacting with offspring HLA and CTLA-4 modifies incident beta-cell autoantibodies.
JO  - J. Autoimmun.
VL  - 86
PB  - Academic Press Ltd- Elsevier Science Ltd
PY  - 2018
SN  - 0896-8411
ER  - 

TY  - JOUR
AB  - Traditional linkage analysis and genome-wide association studies have identified HLA and a number of non-HLA genes as genetic factors for islet autoimmunity (IA) and type 1 diabetes (T1D). However, the relative risk associated with previously identified non-HLA genes is usually very small as measured in cases/controls from mixed populations. Genetic associations for IA and T1D may be more accurately assessed in prospective cohorts. In this study, 5806 subjects from the TEDDY (The Environmental Determinants of Diabetes in the Young) study, an international prospective cohort study, were genotyped for 176,586 SNPs on the ImmunoChip. Cox proportional hazards analyses were performed to discover the SNPs associated with the risk for IA, T1D, or both. Three regions were associated with the risk of developing any persistent confirmed islet autoantibody: one known region near SH2B3 (HR = 1.35, p = 3.58 x 10(-7)) with Bonferroni-corrected significance and another known region near PTPN22 (HR = 1.46, p = 2.17 x 10(-6)) and one novel region near PPIL2 (HR = 2.47, p = 9.64 x 10(-7)) with suggestive evidence (p < 10(-5)). Two known regions (PTPN22: p = 2.25 x 10(-6), INS; p = 1.32 x 10(-7)) and one novel region (PXK/PDHB: p = 8.99 x 10(-6)) were associated with the risk for multiple islet autoantibodies. First appearing islet autoantibodies differ with respect to association. Two regions (INS: p = 5.67 x 10(-6) and TTC34/PROM16: 6.45 x 10(-6)) were associated if the fist appearing autoantibody was IAA and one region (RBFOXI: p = 8.02 x 10(-6)) was associated if the first appearing autoantibody was GADA. The analysis of T1D identified one region already known to be associated with T1D (INS: p = 3.13 x 10(-7)) and three novel regions (RNASET2, PLEKHA1, and PPIL2; 5.42 x 10(-6) > p > 2.31 x 10(-6)). These results suggest that a number of low frequency variants influence the risk of developing IA and/or T1D and these variants can be identified by large prospective cohort studies using a survival analysis approach. (C) 2017 Elsevier Ltd. All rights reserved.
AU  - Sharma, A.*
AU  - Liu, X.*
AU  - Hadley, D.*
AU  - Hagopian, W.*
AU  - Chen, W.M.*
AU  - Onengut-Gumuscu, S.*
AU  - Törn, C.*
AU  - Steck, A.K.*
AU  - Frohnert, B.I.*
AU  - Rewers, M.*
AU  - Ziegler, A.-G.
AU  - Lernmark, A.*
AU  - Toppari, J.*
AU  - Krischer, J.P.*
AU  - Akolkar, B.*
AU  - Rich, S.S.*
AU  - She, J.X.*
AU  - TEDDY Study Group (The Teddy Study Group*)
C1  - 52706
C2  - 44291
CY  - London
SP  - 90-100
TI  - Identification of non-HLA genes associated with development of islet autoimmunity and type 1 diabetes in the prospective TEDDY cohort.
JO  - J. Autoimmun.
VL  - 89
PB  - Academic Press Ltd- Elsevier Science Ltd
PY  - 2018
SN  - 0896-8411
ER  - 

TY  - JOUR
AB  - Anti-neutrophil cytoplasmic antibodies (ANCA) with proteinase 3 (PR3) specificity are a useful laboratory biomarker for the diagnosis of Granulomatosis with Polyangiitis (GPA) and are believed to be implicated in the pathogenesis. It has been repeatedly suggested that disease activity of GPA is more closely related to the appearance and rise of PR3-inhibiting ANCA than to an increase of total ANCA. Previous studies on a limited number of patient samples, however, have yielded inconclusive results. To overcome the previous methodological limitations, we established a new ultrasensitive method to quantify the inhibitory capacity of PR3-ANCA using small volumes of plasma from patients with GPA. A large collection of longitudinally-collected samples from the Wegener Granulomatosis Etanercept Trial (WGET) became available to us to determine the functional effects of ANCA on PR3 in comparison to clinical disease manifestations. In these patient samples we not only detected PR3-ANCA with inhibitory capacity, but also PR3-ANCA with enhancing effects on PR3 activity. However no correlation of these activity-modulating PR3-ANCA with disease activity at either the time of enrollment or over the course of disease was found. Only patients with pulmonary involvement, especially patients with nodule formation in the respiratory tract, showed a slight, but not significant, decrease of inhibitory capacity. Epitope mapping of the activity-modulating PR3-ANCA revealed a binding on the active site surface of PR3. Yet these ANCA were able to bind to PR3 with an occupied active site cleft, indicating an allosteric mechanism of inhibition. The recently described signal ratio between the MCPR3-3 and MCPR3-2 capture ELISA was consistent with the binding of activity-modulating ANCA to the active site surface. Evidence for a shared epitope between activity-modulating PR3-ANCA and MCPR3-7, however, was very limited, suggesting that a majority of PR3-ANCA species do not inhibit PR3 by the same mechanism as previously reported for MCPR3-7.
AU  - Hinkofer, L.C.
AU  - Hummel, A.M.*
AU  - Stone, J.H.*
AU  - Hoffman, G.S.*
AU  - Merkel, P.A.*
AU  - Spiera, E.R.*
AU  - St. Clair, W.*
AU  - McCune, J.W.*
AU  - Davis, J.C.*
AU  - Specks, U.*
AU  - Jenne, D.
C1  - 43658
C2  - 36664
CY  - London
SP  - 43-52
TI  - Allosteric modulation of proteinase 3 activity by anti-neutrophil cytoplasmic antibodies in granulomatosis with polyangiitis.
JO  - J. Autoimmun.
VL  - 59
PB  - Academic Press Ltd- Elsevier Science Ltd
PY  - 2015
SN  - 0896-8411
ER  - 

TY  - JOUR
AB  - Optic neuritis is a common inflammatory manifestation of multiple sclerosis (MS). In experimental autoimmune encephalomyelitis (EAE), the optic nerve is affected as well. Here, we investigated whether autoimmune inflammation in the optic nerve is distinct from inflammation in other parts of the central nervous system (CNS). In our study, inflammatory infiltrates in the optic nerve and the brain were characterized by a high fraction of Ly6G(+) granulocytes whereas in the spinal cord, macrophage infiltrates were predominant. At the peak of disease, IL-17 mRNA abundance was highest in the optic nerve as compared with other parts of the CNS. The ratio of IL-17 vs IFN-γ producing CD4(+) T cells was higher in the optic nerve and brain than in the spinal cord and more effector CD4(+) T cells were committed to the Th17 transcriptional program in the optic nerve than in the spinal cord. IL-17 producing γδ T cells but rather not Ly6G(+) granulocytes themselves contributed to IL-17 production. Optical coherence tomography (OCT) studies on murine eyes revealed a decline in thickness of the retinal nerve fiber layer (RNFL) and the common layer of ganglion cells and inner plexiform layer (GCL+) after the recovery from motor symptoms indicating that autoimmune inflammation induced a significant atrophy of optic nerve fibers during EAE. Neutralization of IL-17 by treatment with anti-IL-17 antibodies reduced but did not abrogate motor symptoms of EAE. However, RNFL and GCL+ atrophy were completely prevented by blocking IL-17. Thus, the optic nerve compartment is particularly prone to support IL-17 mediated inflammatory responses during CNS autoimmunity and structural integrity of the retina can be preserved by neutralizing IL-17.
AU  - Knier, B.*
AU  - Rothhammer, V.*
AU  - Heink, S.*
AU  - Puk, O.
AU  - Graw, J.
AU  - Hemmer, B.*
AU  - Korn, T.*
C1  - 32468
C2  - 35066
CY  - London
SP  - 34-44
TI  - Neutralizing IL-17 protects the optic nerve from autoimmune pathology and prevents retinal nerve fiber layer atrophy during experimental autoimmune encephalomyelitis.
JO  - J. Autoimmun.
VL  - 56
PB  - Academic Press Ltd- Elsevier Science Ltd
PY  - 2015
SN  - 0896-8411
ER  - 

TY  - JOUR
AB  - The incidence of type 1 diabetes is rising worldwide, particularly in young children. Since type 1 diabetes is preceded by autoimmunity to islet antigens, there must be a consequent increase in the incidence of islet autoimmunity in young children or a more rapid rate of progression to diabetes once islet autoimmunity initiates. This study was to determine whether the incidence of islet autoimmunity or the rate of progression from autoimmunity to diabetes onset has changed over a 20-year period in children genetically predisposed to type 1 diabetes. Between 1989 and 2010, children who were first-degree relatives of patients with type 1 diabetes and who were born in Germany were prospectively followed from birth without intervention. A total of 324 children (BABYDIAB study) born between 1989 and 2000 and 216 children (TEDDY study) born between 2004 and 2010 with matched HLA genotypes were recruited before age 3 months and included for analysis. Children were followed for the development of autoantibodies to insulin, GAD, and IA-2, and for progression to diabetes. The cumulative frequency of diabetes by age 4 years was 2.5% (95% CI 0.8-4.2%) in BABYDIAB children and 6.2% (95% CI 2.3-10.1%) in TEDDY children (p = 0.03). The cumulative frequency of islet autoantibodies by age 4 years was similar in the children from both studies (11.3% vs 13.9%). Progression to diabetes from the development of islet autoantibodies was markedly increased in autoantibody-positive children from the more recently recruited TEDDY cohort (50% progression within 85.2 months for BABYDIAB children vs 9.6 months for TEDDY children; p = 0.009), also if children were further selected on the basis of high-risk HLA genotypes or the development of autoantibodies to multiple islet antigens (p = 0.01). The findings suggest that recent increasing incidence of type 1 diabetes in young children could be due to weakening of mechanisms that normally regulate autoimmune destruction of islet beta cells.
AU  - Ziegler, A.-G.
AU  - Pflueger, M.*
AU  - Winkler, C.*
AU  - Achenbach, P.
AU  - Akolkar, B.*
AU  - Krischer, J.P.*
AU  - Bonifacio, E.*
C1  - 6745
C2  - 29201
CY  - London, UK
SP  - 3-7
TI  - Accelerated progression from islet autoimmunity to diabetes is causing the escalating incidence of type 1 diabetes in young children.
JO  - J. Autoimmun.
VL  - 37
IS  - 1
PB  - Academic Press
PY  - 2011
SN  - 0896-8411
ER  -