Multi-omic analyses reveal antibody-dependent natural killer cell-mediated cytotoxicity in autoimmune thyroid diseases

The pathogenesis of autoimmune thyroid diseases (AITD) is poorly understood. We previously observed systemic depletion of IgG core fucosylation and antennary α1,2 fucosylation of peripheral blood mononuclear cells in AITD, correlated with thyroid peroxidase antibody (TPOAb) levels. We hypothesized that deficiency in IgG core fucose enhances antibody-dependent cell-mediated cytotoxicity of thyrocytes by TPOAb, contributing to thyroid autoimmunity. Multi-omic evaluations in 622 individuals (172 with AITD) from the TwinsUK cohort showed decreased IgG core fucosylation levels associated with a subpopulation of natural killer (NK) cells featuring CD335, CD314, and CD158b immunoreceptors, and increased levels of apoptosis-associated Caspase-2 and Interleukin-1α, positively associated with AITD. AITD-associated genetic variants rs1521 and rs3094228 alter expression of thyrocyte ligands of the CD314 and CD158b immunoreceptors on NK cells. The combination of low-core fucose IgG associated with an NK cell subpopulation and genetic variant-promoted ligand activation in thyrocytes may promote antibody-dependent NK cell-mediated cytotoxicity of thyrocytes in AITD.

[1]  É. Vivier,et al.  Natural killer cells and other innate lymphoid cells in cancer , 2018, Nature Reviews Immunology.

[2]  T. Spector,et al.  Decreased IgG core fucosylation, a player in antibody-dependent cell-mediated cytotoxicity, is associated with autoimmune thyroid diseases , 2018, bioRxiv.

[3]  Stephen Burgess,et al.  Genomic atlas of the human plasma proteome , 2018, Nature.

[4]  A. Bossowski,et al.  Role of the T and B lymphocytes in pathogenesis of autoimmune thyroid diseases , 2018, Thyroid Research.

[5]  Leland McInnes,et al.  UMAP: Uniform Manifold Approximation and Projection for Dimension Reduction , 2018, ArXiv.

[6]  C. Dayan,et al.  Management of hypothyroidism with combination thyroxine (T4) and triiodothyronine (T3) hormone replacement in clinical practice: a review of suggested guidance , 2018, Thyroid Research.

[7]  Steven J. M. Jones,et al.  Characterization of the human thyroid epigenome. , 2017, The Journal of endocrinology.

[8]  Nicola J. Rinaldi,et al.  Genetic effects on gene expression across human tissues , 2017, Nature.

[9]  Igor Rudan,et al.  Multivariate discovery and replication of five novel loci associated with Immunoglobulin G N-glycosylation , 2017, Nature Communications.

[10]  Z. Tian,et al.  NK cell subsets in autoimmune diseases. , 2017, Journal of autoimmunity.

[11]  Eleonore Fröhlich,et al.  Thyroid Autoimmunity: Role of Anti-thyroid Antibodies in Thyroid and Extra-Thyroidal Diseases , 2017, Front. Immunol..

[12]  G. Alter,et al.  The Immunoregulatory Roles of Antibody Glycosylation. , 2017, Trends in immunology.

[13]  Jin-an Zhang,et al.  The Emerging Role of Epigenetics in Autoimmune Thyroid Diseases , 2017, Front. Immunol..

[14]  Lai-Xi Wang,et al.  Modulating IgG effector function by Fc glycan engineering , 2017, Proceedings of the National Academy of Sciences.

[15]  T. Spector,et al.  Innate and adaptive immune traits are differentially affected by genetic and environmental factors , 2017, Nature Communications.

[16]  A. Bhardwaj,et al.  In situ click chemistry generation of cyclooxygenase-2 inhibitors , 2017, Nature Communications.

[17]  Camille Guillerey,et al.  Targeting natural killer cells in cancer immunotherapy , 2016, Nature Immunology.

[18]  G. Subedi,et al.  The immunoglobulin G1 N-glycan composition affects binding to each low affinity Fc γ receptor , 2016, mAbs.

[19]  L. Degroot,et al.  Autoimmunity to the Thyroid Gland , 2016 .

[20]  Manolis Kellis,et al.  HaploReg v4: systematic mining of putative causal variants, cell types, regulators and target genes for human complex traits and disease , 2015, Nucleic Acids Res..

[21]  F. Edfors,et al.  Immunocapture strategies in translational proteomics , 2015, Expert review of proteomics.

[22]  D. Bates,et al.  Linear Mixed-Effects Models using 'Eigen' and S4 , 2015 .

[23]  G. Subedi,et al.  The Structural Role of Antibody N-Glycosylation in Receptor Interactions. , 2015, Structure.

[24]  R. Childs,et al.  Therapeutic approaches to enhance natural killer cell cytotoxicity against cancer: the force awakens , 2015, Nature Reviews Drug Discovery.

[25]  C. Viswanathan,et al.  Natural killer cells: In health and disease. , 2015, Hematology/oncology and stem cell therapy.

[26]  S Lovestone,et al.  Plasma protein biomarkers of Alzheimer's disease endophenotypes in asymptomatic older twins: early cognitive decline and regional brain volumes , 2015, Translational Psychiatry.

[27]  Jun S. Liu,et al.  The Genotype-Tissue Expression (GTEx) pilot analysis: Multitissue gene regulation in humans , 2015, Science.

[28]  Tiphaine C. Martin,et al.  coMET: visualisation of regional epigenome-wide association scan results and DNA co-methylation patterns , 2015, BMC Bioinformatics.

[29]  Mario Roederer,et al.  The Genetic Architecture of the Human Immune System: A Bioresource for Autoimmunity and Disease Pathogenesis , 2015, Cell.

[30]  田原 康玄,et al.  生活習慣病とgenome-wide association study , 2015 .

[31]  Sharad Kumar,et al.  Old, new and emerging functions of caspases , 2014, Cell Death and Differentiation.

[32]  C. Lebrilla,et al.  Glycans in the immune system and The Altered Glycan Theory of Autoimmunity: a critical review. , 2015, Journal of autoimmunity.

[33]  Ruedi Aebersold,et al.  Quantitative variability of 342 plasma proteins in a human twin population , 2015 .

[34]  M. Daly,et al.  Genetic and Epigenetic Fine-Mapping of Causal Autoimmune Disease Variants , 2014, Nature.

[35]  Magda Tsolaki,et al.  Circulating Proteomic Signatures of Chronological Age , 2014, The journals of gerontology. Series A, Biological sciences and medical sciences.

[36]  Rbcafe.  The Force Awakens , 2015 .

[37]  M. Niedziela,et al.  The clinical role of serum concentrations of selected cytokines: IL-1β, TNF-α and IL-6 in diagnosis of autoimmune thyroid disease (AITD) in children , 2014, Autoimmunity.

[38]  Larry Gold,et al.  Nucleic Acid Ligands With Protein-like Side Chains: Modified Aptamers and Their Use as Diagnostic and Therapeutic Agents , 2014, Molecular therapy. Nucleic acids.

[39]  M. Hammouda,et al.  Immunoregulatory T cells, LFA-3 and HLA-DR in autoimmune thyroid diseases , 2014, Indian journal of endocrinology and metabolism.

[40]  U. Olsson‐Strömberg,et al.  The use of multiplex platforms for absolute and relative protein quantification of clinical material , 2014 .

[41]  W. Wiersinga,et al.  Mechanisms in endocrinology: autoimmune thyroid disease: old and new players. , 2014, European journal of endocrinology.

[42]  Chapelle,et al.  University of Birmingham Identification of novel genetic Loci associated with thyroid peroxidase antibodies and clinical thyroid disease , 2014 .

[43]  Peggy Hall,et al.  The NHGRI GWAS Catalog, a curated resource of SNP-trait associations , 2013, Nucleic Acids Res..

[44]  W. Wiersinga,et al.  Autoimmune thyroid disease : old and new players , 2014 .

[45]  J. Koch,et al.  New prospects on the NKG2D/NKG2DL system for oncology , 2013, Oncoimmunology.

[46]  M. Peters,et al.  Systematic identification of trans eQTLs as putative drivers of known disease associations , 2013, Nature Genetics.

[47]  Alireza Moayyeri,et al.  COHORT PROFILE Cohort Profile : TwinsUK and Healthy Ageing Twin Study , 2013 .

[48]  Jeanine J. Houwing-Duistermaat,et al.  Loci Associated with N-Glycosylation of Human Immunoglobulin G Show Pleiotropy with Autoimmune Diseases and Haematological Cancers , 2013, PLoS genetics.

[49]  William Stafford Noble,et al.  Integrative annotation of chromatin elements from ENCODE data , 2012, Nucleic acids research.

[50]  P. Parham,et al.  Diverse functionality among human NK cell receptors for the C1 epitope of HLA-C: KIR2DS2, KIR2DL2, and KIR2DL3 , 2012, Front. Immun..

[51]  W. Cho,et al.  Association of MICA Alleles with Autoimmune Thyroid Disease in Korean Children , 2012, International journal of endocrinology.

[52]  Y. Li,et al.  Antibody-Dependent Cell-Mediated Cytotoxicity Overcomes NK Cell Resistance in MLL-Rearranged Leukemia Expressing Inhibitory KIR Ligands but Not Activating Ligands , 2012, Clinical Cancer Research.

[53]  D. Cooper,et al.  The incidence and prevalence of thyroid autoimmunity , 2012, Endocrine.

[54]  W. Scherbaum,et al.  Evidence of a combined cytotoxic thyroglobulin and thyroperoxidase epitope-specific cellular immunity in Hashimoto's thyroiditis. , 2012, The Journal of clinical endocrinology and metabolism.

[55]  C. Dinarello,et al.  Sterile inflammation of endothelial cell-derived apoptotic bodies is mediated by interleukin-1α , 2011, Proceedings of the National Academy of Sciences.

[56]  E. Pamer,et al.  Monocyte recruitment during infection and inflammation , 2011, Nature Reviews Immunology.

[57]  F. Shi,et al.  Organ-specific features of natural killer cells , 2011, Nature Reviews Immunology.

[58]  L. Liang,et al.  A genome-wide association study identifies two new risk loci for Graves' disease , 2011, Nature Genetics.

[59]  A. Syed,et al.  The role of TSH receptor antibodies in the management of Graves' disease. , 2011, European journal of internal medicine.

[60]  N. Stanietsky,et al.  Paired NK cell receptors controlling NK cytotoxicity , 2010, FEBS letters.

[61]  B. Robert,et al.  Human recombinant anti-thyroperoxidase autoantibodies: in vitro cytotoxic activity on papillary thyroid cancer expressing TPO , 2010, British Journal of Cancer.

[62]  P. Parham,et al.  Co-evolution of KIR2DL3 with HLA-C in a human population retaining minimal essential diversity of KIR and HLA class I ligands , 2009, Proceedings of the National Academy of Sciences.

[63]  R. Jefferis,et al.  Recombinant antibody therapeutics: the impact of glycosylation on mechanisms of action. , 2009, Trends in pharmacological sciences.

[64]  P. Donnelly,et al.  A Flexible and Accurate Genotype Imputation Method for the Next Generation of Genome-Wide Association Studies , 2009, PLoS genetics.

[65]  Inês Barroso,et al.  Meta-Analysis of Genome-Wide Scans for Human Adult Stature Identifies Novel Loci and Associations with Measures of Skeletal Frame Size , 2009, PLoS genetics.

[66]  J. Marth,et al.  Mammalian glycosylation in immunity , 2008, Nature Reviews Immunology.

[67]  Leonard G Presta,et al.  Molecular engineering and design of therapeutic antibodies. , 2008, Current opinion in immunology.

[68]  A Hofman,et al.  Bone mineral density, osteoporosis, and osteoporotic fractures: a genome-wide association study , 2008, The Lancet.

[69]  Lewis L Lanier,et al.  Up on the tightrope: natural killer cell activation and inhibition , 2008, Nature Immunology.

[70]  B. Robert,et al.  Antithyroperoxidase antibody-dependent cytotoxicity in autoimmune thyroid disease. , 2008, The Journal of clinical endocrinology and metabolism.

[71]  A. Kobata.  The N-linked sugar chains of human immunoglobulin G: their unique pattern, and their functional roles. , 2008, Biochimica et biophysica acta.

[72]  A. Hopkins,et al.  Desmoglein-2: a novel regulator of apoptosis in the intestinal epithelium. , 2007, Molecular biology of the cell.

[73]  Pauline M Rudd,et al.  The impact of glycosylation on the biological function and structure of human immunoglobulins. , 2007, Annual review of immunology.

[74]  Akira Okazaki,et al.  Comparison of biological activity among nonfucosylated therapeutic IgG1 antibodies with three different N-linked Fc oligosaccharides: the high-mannose, hybrid, and complex types. , 2007, Glycobiology.

[75]  Tim D Spector,et al.  The UK Adult Twin Registry (TwinsUK) , 2006, Twin Research and Human Genetics.

[76]  J. Li,et al.  Adjusting multiple testing in multilocus analyses using the eigenvalues of a correlation matrix , 2005, Heredity.

[77]  C. Gazzaruso,et al.  Defect of a subpopulation of natural killer immune cells in Graves' disease and Hashimoto's thyroiditis: normalizing effect of dehydroepiandrosterone sulfate. , 2005, European journal of endocrinology.

[78]  K. Shitara,et al.  Enhanced Natural Killer Cell Binding and Activation by Low-Fucose IgG1 Antibody Results in Potent Antibody-Dependent Cellular Cytotoxicity Induction at Lower Antigen Density , 2005, Clinical Cancer Research.

[79]  L. Hegedüs,et al.  The relative importance of genetic and environmental factors in the aetiology of thyroid nodularity: a study of healthy Danish twins , 2005, Clinical endocrinology.

[80]  T. Ottenhoff,et al.  Phenotypic and Functional Characterization of CD4 T Cells Expressing Killer Ig-Like Receptors1 , 2004, The Journal of Immunology.

[81]  Eric Vivier,et al.  Natural Killer Cell Signaling Pathways , 2004, Science.

[82]  K. Shitara,et al.  Enhancement of the Antibody-Dependent Cellular Cytotoxicity of Low-Fucose IgG1 Is Independent of FcγRIIIa Functional Polymorphism , 2004, Clinical Cancer Research.

[83]  Shigeru Iida,et al.  Establishment of FUT8 knockout Chinese hamster ovary cells: An ideal host cell line for producing completely defucosylated antibodies with enhanced antibody‐dependent cellular cytotoxicity , 2004, Biotechnology and bioengineering.

[84]  Kirsten Ohm Kyvik,et al.  Major genetic influence on the regulation of the pituitary-thyroid axis: a study of healthy Danish twins. , 2004, The Journal of clinical endocrinology and metabolism.

[85]  M. Simmonds,et al.  Genetic insights into disease mechanisms of autoimmunity. , 2004, British medical bulletin.

[86]  P. Leibson,et al.  NKG2D-DAP10 triggers human NK cell–mediated killing via a Syk-independent regulatory pathway , 2003, Nature Immunology.

[87]  K. Shitara,et al.  The Absence of Fucose but Not the Presence of Galactose or Bisecting N-Acetylglucosamine of Human IgG1 Complex-type Oligosaccharides Shows the Critical Role of Enhancing Antibody-dependent Cellular Cytotoxicity* , 2003, The Journal of Biological Chemistry.

[88]  L. Presta,et al.  Lack of Fucose on Human IgG1 N-Linked Oligosaccharide Improves Binding to Human FcγRIII and Antibody-dependent Cellular Toxicity* , 2002, The Journal of Biological Chemistry.

[89]  G. Stassi,et al.  Autoimmune thyroid disease: new models of cell death in autoimmunity , 2002, Nature Reviews Immunology.

[90]  M. Juan,et al.  Thyroid autoimmune disease: demonstration of thyroid antigen-specific B cells and recombination-activating gene expression in chemokine-containing active intrathyroidal germinal centers. , 2001, The American journal of pathology.

[91]  L. Hegedüs,et al.  Evidence for a major role of heredity in Graves' disease: a population-based study of two Danish twin cohorts. , 2001, The Journal of clinical endocrinology and metabolism.

[92]  A population-based study of chronic autoimmune hypothyroidism in Danish twins. , 2000, The Journal of clinical endocrinology and metabolism.

[93]  R. Biassoni,et al.  Molecular Cloning of NKp46: A Novel Member of the Immunoglobulin Superfamily Involved in Triggering of Natural Cytotoxicity , 1998, The Journal of experimental medicine.

[94]  L. Ericson,et al.  Cytokines and thyroid epithelial integrity: interleukin-1alpha induces dissociation of the junctional complex and paracellular leakage in filter-cultured human thyrocytes. , 1998, The Journal of clinical endocrinology and metabolism.

[95]  L. Moretta,et al.  p46, a Novel Natural Killer Cell–specific Surface Molecule That Mediates Cell Activation , 1997, The Journal of experimental medicine.

[96]  A. Weetman,et al.  Analysis of antibody-dependent cell-mediated cytotoxicity in autoimmune thyroid disease. , 1997, Autoimmunity.

[97]  A. Madec,et al.  Antibody-dependent cell-mediated cytotoxicity in autoimmune thyroid disease: relationship to antithyroperoxidase antibodies. , 1996, The Journal of clinical endocrinology and metabolism.

[98]  Eric O Long,et al.  Killer cell inhibitory receptors specific for HLA-C and HLA-B identified by direct binding and by functional transfer. , 1995, Immunity.

[99]  M. Nasu,et al.  Increase in peripheral natural killer cell activity in patients with autoimmune thyroid disease. , 1992, Autoimmunity.

[100]  M. Feldmann,et al.  Analysis of intrathyroidal cytokine production in thyroid autoimmune disease: thyroid follicular cells produce interleukin-1 alpha and interleukin-6. , 1989, Clinical and experimental immunology.

[101]  U. Bogner,et al.  Cellular and antibody mediated cytotoxicity in autoimmune thyroid disease. , 1987, Acta endocrinologica. Supplementum.

[102]  E. Barnes,et al.  Lymphocyte-dependent antibody-mediated cytotoxicity in Hashimoto thyroiditis. , 1973, Clinical and experimental immunology.

[103]  R J DUBOS,et al.  Health and disease. , 1960, JAMA.

[104]  C. Aring,et al.  A CRITICAL REVIEW , 1939, Journal of neurology and psychiatry.