A mouse TSH receptor A-subunit transgene expres... - Thyroid UK

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A mouse TSH receptor A-subunit transgene expressed in thyroiditis-prone mice may provide insight into why Graves' only occurs in humans

helvella profile image
helvellaAdministrator
6 Replies

I very recently posted about orangutans and hypothyroidism. But we never see Graves in animals. Hyperthyroid cats are well-known but that isn't Graves.

This paper attempts to explain why Graves is a human-only disorder. Though even then, it is making a suggestion rather than claiming definitive proof.

Tends to question any research whatsoever why relies on similarity between humans and other animals if there are known genetic differences, hence known different chemical structures in elements which are directly involved in thyroid.

Thyroid. 2019 Jun 11. doi: 10.1089/thy.2019.0260. [Epub ahead of print]

A mouse TSH receptor A-subunit transgene expressed in thyroiditis-prone mice may provide insight into why Graves' disease only occurs in humans.

McLachlan SM1, Aliesky H2, Rapoport B3,4.

Author information

1 Cedars-Sinai Research Institute & UCLA, Endocrinology , 8700 Beverly Blvd, B-131 , Los Angeles, California, United States , 90048 ; mclachlansm@gmail.com.

2 Cedars-Sinai, 5149, Medicine, Los Angeles, California, United States ; Holly.Aliesky@gmail.com.

3 Cedars-Sinai Medical Center , 8700 Beverly Blvd, Suite B-131 , Los Angeles, California, United States , 90048-0750.

4 United States ; basil.rapoport@ucla.edu.

Abstract

BACKGROUND:

Graves' disease, caused by autoantibodies that activate the TSH receptor (TSHR), has only been reported in humans. Thyroiditis-prone NOD.H2h4 mice develop autoantibodies to thyroglobulin and thyroid peroxidase but not to the TSHR. Evidence supports the importance of the shed TSHR A-subunit in the initiation and/or amplification of the autoimmune response to the holoreceptor. Cells expressing the gene for the isolated A-subunit secrete A-subunit protein, a surrogate for holoreceptor A-subunit shedding. NOD.H2h4 mice with the human TSHR A-subunit targeted to the thyroid (a 'self' antigen in such transgenic animals), unlike their wild-type siblings, spontaneously develop pathogenic TSHR antibodies to the human-TSH holoreceptor. These autoantibodies do not recognize the endogenous mouse-TSH holoreceptor and do not cause hyperthyroidism.

METHODS:

We have now generated NOD.H2h4 mice with the mouse-TSHR A-subunit transgene targeted to the thyroid. Transgenic mice and wild type littermates were compared for intrathyroidal expression of the mouse A-subunit. Sera from six month old mice were tested for the presence of autoantibodies to thyroglobulin and thyroid peroxidase as well as for pathogenic TSHR antibodies (TSH binding inhibition, bioassay for thyroid stimulating antibodies) and nonpathogenic TSHR antibodies (ELISA).

RESULTS:

Expression of the mouse TSHR A-subunit transgene in the thyroid was confirmed by real-time polymerase chain reaction in the transgenics and had no effect on the spontaneous development of autoantibodies to thyroglobulin or thyroid peroxidase. However, unlike the same NOD.H2h4 strain with the human-TSHR A-subunit target to the thyroid, mice expressing intra-thyroidal mouse-TSHR A subunit failed to develop either pathogenic or non-pathogenic TSHR antibodies. The mouse TSHR A-subunit differs from the human TSHR A-subunit in terms of its amino acid sequence and has one less glycosylation site than the human TSHR A-subunit.

CONCLUSIONS:

Multiple genetic and environmental factors contribute to the pathogenesis of Graves' disease. The present study suggests that the TSHR A-subunit structure (possibly including post-translational modification such as glycosylation) may explain, in part, why Graves' disease only develops in humans.

PMID: 31184281

DOI: 10.1089/thy.2019.0260

ncbi.nlm.nih.gov/pubmed/311...

Being a Mary Ann Liebert paper, the full paper is well and truly behind paywall.

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TSH110 profile image
TSH110

I never knew it was only found in humans you learn something new every day 😊

helvella profile image
helvellaAdministrator in reply toTSH110

Nor did I. Hit me between the eyes as soon as I read it that I had never seen mention of it in animals.

TSH110 profile image
TSH110 in reply tohelvella

Yes my thoughts exactly - they just say hyperthyroid. It is very interesting that only humans get Graves - we drew the short straw there, it is a very awful disorder. I had bouts of overactivity and just went totally crazy I became very aggressive, lacking in empathy, paranoid and flew off the handle in a nanosecond at nothing of any significance whatsoever, then I’d be weeping and eventually become calm and just think “oh that was a bit odd” as I struggled to just keep going. I had got so used to dealing with all sorts of horrible symptoms It never occurred to me that I needed to see a doctor. I had been fobbed off so much in the past, I just assumed I was a hypochondriac as my mental competence deteriorated! I could run 8 miles fast with no effort whatsoever between feeling utterly exhausted. I must have been vacillating between super hypo and hyper. Small wonder I had frequent angina. When I did eventually muster up the courage and energy to demand a thyroid function test, initially they thought I had hyperthyroidism but it soon plunged into eternal hypo. I can’t even begin to imagine how awful it must be to be in constant overdrive. Not to mention the eye disease.

Rapunzel profile image
Rapunzel

Ave Rod. What an egghead 😘

helvella profile image
helvellaAdministrator in reply toRapunzel

Do you mean these:

first-nature.com/fungi/pana... :-)

These papers are available to everyone. I just check through and post the ones that appeal. Doesn't take many grey cells.

Greekchick profile image
Greekchick

You find the coolest papers - what can I say? Thanks for posting! 😀

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