Identification of Outer Membrane Porin F Protein of<i>Yersinia enterocolitica</i>Recognized by Antithyrotopin Receptor Antibodies in Graves’ Disease and Determination of Its Epitope Using Mass Spectrometry and Bioinformatics Tools

Wang, Zhe; Zhang, Qunye; Lu, Jing; Jiang, Fan; Zhang, Haiqing; Gao, Ling; Zhao, Jiajun

doi:10.1210/jc.2009-2184

Cited by 39 publications

(22 citation statements)

References 29 publications

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“…In another recent study using a neutral mAb to TSHR generated in our laboratory, mAb A9 (27), cross-reactivity with Y. enterocolitica OmpF was reported (29). Reactivity of Graves' disease patient serum with Y. enterocolitica OmpF also was demonstrated.…”

Section: Discussionmentioning

confidence: 83%

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Yersinia enterocolitica Provides the Link between Thyroid-Stimulating Antibodies and Their Germline Counterparts in Graves’ Disease

Hargreaves

Grasso

Hampe

et al. 2013

The Journal of Immunology

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Graves’ disease results from thyroid-stimulating Abs (TSAbs) activating the thyrotropin receptor (TSHR). How TSAbs arise from early precursor B cells has not been established. Genetic and environmental factors may contribute to pathogenesis, including the bacterium Yersinia enterocolitica. We developed two pathogenic monoclonal TSAbs from a single experimental mouse undergoing Graves’ disease, which shared the same H and L chain germline gene rearrangements and then diversified by numerous somatic hypermutations. To address the Ag specificity of the shared germline precursor of the monoclonal TSAbs, we prepared rFab germline, which showed negligible binding to TSHR, indicating importance of somatic hypermutation in acquiring TSAb activity. Using rFab chimeras, we demonstrate the dominant role of the H chain V region in TSHR recognition. The role of microbial Ags was tested with Y. enterocolitica proteins. The monoclonal TSAbs recognize 37-kDa envelope proteins, also recognized by rFab germline. MALDI-TOF identified the proteins as outer membrane porin (Omp) A and OmpC. Using recombinant OmpA, OmpC, and related OmpF, we demonstrate cross-reactivity of monoclonal TSAbs with the heterogeneous porins. Importantly, rFab germline binds recombinant OmpA, OmpC, and OmpF confirming reactivity with Y. enterocolitica. A human monoclonal TSAb, M22 with similar properties to murine TSAbs, also binds recombinant porins, showing cross-reactivity of a spontaneously arising pathogenic Ab with Y. enterocolitica. The data provide a mechanistic framework for molecular mimicry in Graves’ disease, where early precursor B cells are expanded by Y. enterocolitica porins to undergo somatic hypermutation to acquire a cross-reactive pathogenic response to TSHR.

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Section: Discussionmentioning

confidence: 83%

“…Bioinformatics searches have reported on regions of sequence homology between Y. enterocolitica outer membrane porin (Omp) M and TSHR (26). Recently, a murine neutral mAb to TSHR (mAb A9) (27), whose linear epitope has been mapped to the TSHR A-subunit (28), was shown to bind Y. enterocolitica OmpF (29).…”

mentioning

confidence: 99%

Yersinia enterocolitica Provides the Link between Thyroid-Stimulating Antibodies and Their Germline Counterparts in Graves’ Disease

Hargreaves

Grasso

Hampe

et al. 2013

The Journal of Immunology

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“…Various studies have hinted at involvement of Yersinia enterocolitica in Graves’ disease, an autoimmune disease, in which thyroid‐stimulating Abs (TSAbs) generated in response to thyroid‐stimulating hormone receptor (TSHR) mimic thyroid‐stimulating hormone (TSH) to activate TSHR and cause hyperthyroidism. One such report by Wang et al depicts that outer membrane porin F protein (ompF) of Y. enterocolitica cross‐reacts with a leucine‐rich domain of human thyrotropin receptor (TSHR). Besides serological evidence, this was also supported by in silico studies by Benvenga et al wherein he successfully established homology between four segments of human TSHR and Yersinia proteins YopM, Ysp, exopolygalacturonase and SpyA …”

Section: Molecular Mimicry: the Conceptmentioning

confidence: 99%

Molecular mimicry: An explanation for autoimmune diseases and infertility

Thaper

Prabha

2018

Scand J Immunol

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Microorganisms execute an enthralling range of adjustments in order to survive in the host. Among the various strategies employed by microorganisms to surmount the host immune response, the phenomenon of molecular mimicry empowers the microorganisms to manoeuvre host physiology and cellular functions for their own advantage by mimicking the host proteins and initiating autoimmunity. This phenomena, by and large, has been studied in context of autoimmune diseases, however, its implications have also been reported in infertility. Hence, in this article, we provide a review of the various instances of molecular mimicry initiated by bacteria, parasites and viruses in the world of autoimmune diseases and infertility. This article is protected by copyright. All rights reserved.

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“…Infection is a trigger even when clinically inapparent-as shown by increased serum antibodies against Yersinia cross-reacting with TRAb because of molecular mimicry in some Graves' disease patients [2,3].…”

Section: To the Editormentioning

confidence: 99%