Immunoinformatic Analysis of Human Thyroglobulin

Abstract The AutoImmune ThyroiDitis (AITD), known as Hashimoto’s disease, is a chronic autoimmune thyroid disease progressively developed to hypothyroidism. The AITD is characterized by the formation of autoantibodies targeting two specific thyroid antigens, Thyroglobulin (Tg) and Thyroid PerOxidase (TPO). Tg is a precursor of the thyroid hormones while TPO catalyses their synthesis. The AITD has a strong genetic predisposition. During the last years, it was found that the susceptibility to AITD is associated with certain Human Leukocyte Antigens (HLA) class II genes of loci DR and DQ. In the present study, we applied in-house immunoinformatic tools to identify peptides originating from Tg and binding to AITD susceptible alleles: HLA-DR3, HLA-DR4, HLA-DR5, HLA-DQ2 and HLA-DQ8. Five peptide fragments containing promiscuous overlapping binders were selected. These were p470, p949, p1948, p2348 and p2583. Only one of them contains a known epitope (p1948). The rest have not been reported yet. The selected peptide fragments will be coupled to monoclonal antibodies specific to inhibitory B cell receptors designed to suppress the production of Tg autoantibodies.

[1]  M. Yasunaga.  Antibody therapeutics and immunoregulation in cancer and autoimmune disease. , 2020, Seminars in cancer biology.

[2]  J. Rappsilber,et al.  The structure of human thyroglobulin , 2020, Nature.

[3]  I. Doytchinova,et al.  Suppression of Disease-Associated B Lymphocytes by GAD65 Epitope-Carrying Protein-Engineered Molecules in a Streptozotocin-Induced Mouse Model of Diabetes. , 2019, Monoclonal antibodies in immunodiagnosis and immunotherapy.

[4]  I. Doytchinova,et al.  Protein‐engineered molecules carrying GAD65 epitopes and targeting CD35 selectively down‐modulate disease‐associated human B lymphocytes , 2019, Clinical and experimental immunology.

[5]  The UniProt Consortium,et al.  UniProt: a worldwide hub of protein knowledge , 2018, Nucleic Acids Res..

[6]  J. Marchesi,et al.  The microbiota and autoimmunity: Their role in thyroid autoimmune diseases. , 2017, Clinical immunology.

[7]  Andrew R. Jones,et al.  Allele frequency net 2015 update: new features for HLA epitopes, KIR and disease and HLA adverse drug reaction associations , 2014, Nucleic Acids Res..

[8]  D. Flower,et al.  EpiDOCK: a molecular docking-based tool for MHC class II binding prediction. , 2013, Protein engineering, design & selection : PEDS.

[9]  Irini Doytchinova,et al.  T-cell epitope vaccine design by immunoinformatics , 2013, Open Biology.

[10]  Irini A. Doytchinova,et al.  EpiTOP - a proteochemometric tool for MHC class II binding prediction , 2010, Bioinform..

[11]  C. Stehouwer,et al.  Coeliac disease in Dutch patients with Hashimoto's thyroiditis and vice versa. , 2007, World journal of gastroenterology.

[12]  R. Osman,et al.  Flexible peptide recognition by HLA-DR triggers specific autoimmune T-cell responses in autoimmune thyroiditis and diabetes. , 2017, Journal of autoimmunity.

[13]  H. Inoko,et al.  Gene Map of the HLA Region, Graves' Disease and Hashimoto Thyroiditis, and Hematopoietic Stem Cell Transplantation. , 2016, Advances in immunology.

[14]  M. Stefanelli,et al.  Journal of Autoimmune Diseases BioMed Central , 2005 .

[15]  P. Unger,et al.  Pregnancy and murine thyroiditis: thyroglobulin immunization leads to fetal loss in specific allogeneic pregnancies. , 2001, Endocrinology.