Identification of outer membrane porin f protein of Yersinia enterocolitica recognized by antithyrotopin receptor antibodies in Graves' disease and determination of its epitope using mass spectrometry and bioinformatics tools.
BACKGROUND
In addition to genetic susceptibility, Yersinia enterocolitica (YE) infection played an important causative role in the pathogenesis of Graves' disease (GD) through molecular mimicry. However, the specific YE proteins and epitopes recognized by anti-TSH receptor (TSHR) autoantibodies (TRAb) have not been fully clarified, resulting in conflicting results from clinical research.


OBJECTIVE
Our aim was to explore the roles of YE in the pathogenesis of GD and identify the YE proteins and epitopes that are similar to the TSHR and are recognized by TRAb.


METHODS
Assays of YE antibodies, TRAb, thyroglobulin antibodies, and thyroid microsomal antibodies as well as cross-absorption and two-way immunodiffusion were performed in patients with GD. Using mass spectrometry and the bioinformatics tools of protein structure modeling and epitope prediction, we identified the YE protein and its epitope, which was recognized by TRAb and was similar to TSHR.


RESULTS
Our study demonstrated for the first time that the YE protein outer membrane porin F protein (ompF) shared cross-immunogenicity with a leucine-rich domain of TSHR. The epitope recognized by antihuman TSHR antibody is located within the ompF region of amino acids 190-197, and the polyantibody against ompF protein showed TSAb activity.


CONCLUSIONS
Our results suggest that YE ompF is involved in the production of TRAb and the pathogenesis of GD through molecular mimicry. These findings are potentially important for understanding the role molecular mimicry plays in the disturbance of immune tolerance and the induction of autoimmunity to the TSHR.
Wang
Zhe
Z
Division of Endocrinology and Metabolism, Provincial Hospital, Shandong University, 324 Jing Wu Road, Jinan 250021, China.
Zhang
Qunye
Q
Lu
Jing
J
Jiang
Fan
F
Zhang
Haiqing
H
Gao
Ling
L
Zhao
Jiajun
J
D000293:Adolescent; D000328:Adult; D000368:Aged; D001323:Autoantibodies / Q000276:immunology / Q000378:metabolism; D015153:Blotting, Western; D019295:Computational Biology; D004797:Enzyme-Linked Immunosorbent Assay; D000939:Epitopes / Q000276:immunology / Q000378:metabolism; D005260:Female; D006111:Graves Disease / Q000209:etiology / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D018828:Immunoglobulins, Thyroid-Stimulating / Q000276:immunology / Q000378:metabolism; D008297:Male; D013058:Mass Spectrometry; D008875:Middle Aged; D018272:Porins / Q000276:immunology* / Q000378:metabolism; D011989:Receptors, Thyrotropin / Q000276:immunology* / Q000378:metabolism; D015009:Yersinia Infections / Q000150:complications / Q000276:immunology* / Q000378:metabolism; D015008:Yersinia enterocolitica / Q000276:immunology* / Q000378:metabolism
D001323:Autoantibodies; D000939:Epitopes; D018828:Immunoglobulins, Thyroid-Stimulating; C109237:OmpF protein; D018272:Porins; D011989:Receptors, Thyrotropin; C094372:thyrotropin-binding inhibitory immunoglobulin