Thyrotropin Receptor Epitopes and Their Relation to Histocompatibility Leukocyte Antigen-DR Molecules in Graves’ Disease

Inaba, Hidefumi; Martin, William; Groot, Anne S. De; Qin, Shuwen; Groot, Leslie J. De

doi:10.1210/jc.2005-2537

Cited by 43 publications

(33 citation statements)

References 42 publications

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“…In a recent study we reported the IC50 values for TSH-R-ECD synthetic peptide epitopes binding to several purified HLA molecules, including DR3 (18). We found that peptides 8, 10, and 13, bearing sequences IRNTRNLTYIDPDALKE (109-124), GIFNTGLKMFPDLTKVYST (132-150), and GLKMFPDLTKVYST (137-150) of TSH-R-ECD, bound with very high affinity to HLA-DR-3.…”

Section: Discussionmentioning

confidence: 95%

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Immune Response of Mice Transgenic for Human Histocompatibility Leukocyte Antigen-DR to Human Thyrotropin Receptor-Extracellular Domain

Inaba

Pan

Shin

et al. 2009

Thyroid

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Background: Hyperthyroidism of Graves' disease is caused by auto-antibodies to human thyrotropin receptor (hTSH-R). To elucidate important T-cell epitopes in TSH-R, we studied three models of immunity to TSH-R in mice. Methods: Mice transgenic for histocompatibility leukocyte antigen DR3 or DR2 were immunized with cDNA for hTSH-R-extracellular domain (hTSH-R-ECD), or hTSH-R-ECD protein, or hTSH-R peptide epitopes. Proliferative responses of immunized splenocytes to epitopes derived from the hTSH-ECD sequence, anti-TSH-R antibody responses, serum thyroxine and TSH, and thyroid histology were recorded. Results: DR3 mice responded to genomic immunization with proliferative responses to several epitopes, which increased in intensity and spread to include more epitopes, during a 6-week immunization program. DR2 transgenic mice developed weak proliferative responses. Both types of mice developed anti-TSH-R antibodies measured by enzyme-linked immunosorbent assay or TSH-binding inhibition assay in 16-60% of animals. There was evidence of weak thyroid stimulation in one group of animals. Immunization of DR3 transgenic mice to hTSH-R-ECD protein induced a striking response to an epitope with sequence ISRIYVSIDVTLQQLES (aa78-94). Immunization to peptides derived from the TSH-R-ECD sequence (including aa78-94) caused strong responses to the epitopes, and development of immune responses to several other nonoverlapping epitopes within the hTSH sequence (epitope spreading) and antibodies reacting with hTSH-R. This implies that immunization with hTSH-R epitopes produced immunity to mouse TSH-R. Conclusion: T-cell and B-cell responses to genetic immunization differ in DR3 and DR2 transgenic mice, and there is less genetic control of antibody than of T-cell responses. During both genomic and peptide epitope immunization there was evidence of epitope spreading during the immunization. Several functionally important epitopes are evident, especially aa78-94. However, if similar progressive epitope recruitment occurs in human disease, epitope-based therapy will be difficult to achieve.

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Section: Discussionmentioning

confidence: 95%

“…We also compared responses of T cell immunized in vivo to recent published studies describing in vitro TSH-R-ECD peptide binding to HLA-DR molecules (18).…”

mentioning

confidence: 99%

Immune Response of Mice Transgenic for Human Histocompatibility Leukocyte Antigen-DR to Human Thyrotropin Receptor-Extracellular Domain

Inaba

Pan

Shin

et al. 2009

Thyroid

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“…The common ground between these tools is the ability to quickly screen large datasets, including whole genomes, for prediction of T cell epitopes. These types of predictions have successfully been applied both to vaccine development [37][38][39][40][41] and to the identification of key epitopes triggering autoimmunity [42].…”

Section: In Silico Analysis Toolsmentioning

confidence: 99%

Immunogenicity of Therapeutic Fusion Proteins: Contributory Factors and Clinical Experience

Jawa

Cousens

Groot

2013

Fusion Protein Technologies for Biopharmaceuticals

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“…Thirty-one 16-20 mer peptides covering the entire sequence of TSH-R-ECD with overlaps of five to six amino acids were synthesized as reported (16,17). In addition, 10 TSH-R-ECD peptides, listed as peptide 32-41, were newly synthesized, These peptides were predicted by EpiMatrix (18) to have high binding affinity for HLA-DR3 (peptides 32-36) or multiple DRs (peptides 37-41).…”

Section: Tsh-r-ecd Peptides and Competing Peptidesmentioning

confidence: 99%

The Role of Glutamic or Aspartic Acid in Position Four of the Epitope Binding Motif and Thyrotropin Receptor-Extracellular Domain Epitope Selection in Graves’ Disease

Inaba

Martin

Ardito

et al. 2010

The Journal of Clinical Endocrinology & Metabolism

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Thyrotropin Receptor Epitopes and Their Relation to Histocompatibility Leukocyte Antigen-DR Molecules in Graves’ Disease

Cited by 43 publications

References 42 publications

Immune Response of Mice Transgenic for Human Histocompatibility Leukocyte Antigen-DR to Human Thyrotropin Receptor-Extracellular Domain

Immune Response of Mice Transgenic for Human Histocompatibility Leukocyte Antigen-DR to Human Thyrotropin Receptor-Extracellular Domain

Immunogenicity of Therapeutic Fusion Proteins: Contributory Factors and Clinical Experience

The Role of Glutamic or Aspartic Acid in Position Four of the Epitope Binding Motif and Thyrotropin Receptor-Extracellular Domain Epitope Selection in Graves’ Disease

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