RRC ID 2031
Author Guo J, Pichurin P, Nagayama Y, Rapoport B, McLachlan SM.
Title Insight into antibody responses induced by plasmid or adenoviral vectors encoding thyroid peroxidase, a major thyroid autoantigen.
Journal Clin Exp Immunol
Abstract Plasmid and adenoviral vectors have been used to generate antibodies in mice that resemble human autoantibodies to the thyrotrophin receptor. No such studies, however, have been performed for thyroid peroxidase (TPO), the major autoantigen in human thyroiditis. We constructed plasmid and adenovirus vectors for in vivo expression of TPO. BALB/c mice were immunized directly by intramuscular injection of TPO-plasmid or TPO-adenovirus, as well as by subcutaneous injection of dendritic cells (DC) infected previously with TPO-adenovirus. Intramuscular TPO-adenovirus induced the highest, and TPO-plasmid the lowest, TPO antibody titres. Mice injected with TPO-transfected DC developed intermediate levels. Antibodies generated by all three approaches had similar affinities (Kd approximately 10(-9)M) and recognized TPO expressed on the cell-surface. Their epitopes were analysed in competition assays using monoclonal human autoantibodies that define the TPO immunodominant region (IDR) recognized by patients with thyroid autoimmune disease. Surprisingly, high titre antibodies generated using adenovirus interacted with diverse TPO epitopes largely outside the IDR, whereas low titre antibodies induced by DNA-plasmid recognized restricted epitopes in the IDR. This inverse relationship between antibody titre and restriction to the IDR is likely to be due to epitope spreading following strong antigenic stimulation provided by the adenovirus vector. However, TPO antibody epitope spreading does not occur in Hashimoto's thyroiditis, despite high autoantibody levels. Consequently, these data support the concept that in human thyroid autoimmunity, factors besides titre must play a role in shaping an autoantibody epitopic profile.
Volume 132(3)
Pages 408-15
Published 2003-6-1
DOI 10.1046/j.1365-2249.2003.02170.x
PII 2170
PMID 12780686
PMC PMC1808732
MeSH Adenoviridae / genetics* Animals Antibody Affinity Antibody Specificity / immunology Autoantibodies / biosynthesis* Autoantigens / genetics Autoantigens / immunology Cell Transplantation Dendritic Cells / transplantation Female Genetic Vectors / immunology* Immunization / methods Immunodominant Epitopes / immunology Immunoglobulin G / biosynthesis Injections, Intramuscular Iodide Peroxidase / genetics Iodide Peroxidase / immunology* Mice Mice, Inbred BALB C Plasmids / genetics* Thyroid Gland / immunology
IF 3.532
Times Cited 15
DNA material AxCAmGM-CSF (RDB1419)