Letter to the Editor: “Elevated Serum Tetrac in Graves Disease: Potential Pathogenic Role in Thyroid-Associated Ophthalmopathy”

The Journal of Clinical Endocrinology & Metabolism, Mar 2019

Neumann, Susanne, Krieger, Christine C, Gershengorn, Marvin C

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Letter to the Editor: “Elevated Serum Tetrac in Graves Disease: Potential Pathogenic Role in Thyroid-Associated Ophthalmopathy”

We are writing in response to an article published in The Journal of Clinical Endocrinology & Metabolism by Fernando et al. (1) in which elevated levels of the thyroid hormone analog tetrac were found in patients with Graves disease (GD). To demonstrate a source of tetrac, thyroxine metabolism was studied in vitro in cells that were termed fibrocytes. The original proposal that these are fibrocytes involved in Graves ophthalmopathy (GO) pathogenesis was also made by Douglas et al. (2). These cells are presumed to originate in the bone marrow, exit into the bloodstream, and home to the retroorbital space. This is a potentially important concept that, if correct, would increase our understanding of GO pathogenesis and identify a new target for GO treatment. However, we think a critical finding regarding whether these cells are fibrocytes is lacking. In the original report (3), a fibrocyte was described as a “circulating cell[s] with fibroblast properties,” “characterized by its distinctive phenotype (collagen+/vimentin+/CD34+)” and “its presence in connective tissue scars.” However, its most important characteristic was that it was formed in and could exit from the bone marrow into the bloodstream and migrate into selective extravascular tissues. Putative fibrocytes from patients with GD, which were “generated from peripheral blood mononuclear cells” and exhibit a fibroblast-like morphology, are CD34+/CXCR4+/Col 1+ (2). Moreover, the number of these cells was shown to be increased in patients with GD. Of note, the authors concluded that these cells were distinguished from “resident fibroblasts” in the retroorbital tissue that were CD34−. Thus, the presence of CD34+ cells in the retroorbital tissue was considered proof that circulating putative fibrocytes migrated into the retroorbital tissue. However, fibroblasts can dedifferentiate into multilineage progenitor cells and express CD34 (4). Thus, CD34+ cells found in retroorbital tissue could be generated from resident fibroblasts (or stem cells). Again, the most important characteristics of true fibrocytes is the sequence of formation in bone marrow, entry into the bloodstream. and homing to specific tissue sites (5). This sequence has not been demonstrated for putative fibrocytes from patients with GD/GO. In the original description of fibrocytes (3), made in a mouse model of tissue injury, bone marrow cells harvested from male mice and implanted into the bone marrow of irradiated female mice were shown to exhibit “rapid entry from the blood into subcutaneously implanted wound chambers.” This type of experiment, which could be performed in immunocompromised mice, has not been performed with putative fibrocytes from patients with GD/GO. We suggest an alternative to the idea that these cells are fibrocytes. We hypothesize that these may be precursor/stem cells (6) released from the thyroid gland. Indeed, the same authors showed that these cells express thyroglobulin, which they agree “is thought to be uniquely expressed by thyroid epithelial cells” (7). It is not surprising that thyroid stem cells could be found in greater numbers in patients with GD in whom thyroid hyperplasia is ongoing, more so than in normal subjects. Therefore, we suggest that the circulating cells in patients with GD may not be fibrocytes and look forward to more definitive experiments demonstrating their site of origin. Abbreviations: Abbreviations:   GD Graves disease   GO Graves ophthalmopathy Acknowledgments Disclosure Summary: The authors have nothing to disclose. References 1. Fernando R , Placzek E , Reese EA , Placzek AT , Schwartz S , Trierweiler A , Niziol LM , Raychaudhuri N , Atkins S , Scanlan TS , Smith TJ . Elevated serum tetrac in Graves disease: potential pathogenic role in thyroid-associated ophthalmopathy . J Clin Endocrinol Metab  . 2017 ; 102 ( 3 ): 776 – 785 . Google Scholar PubMed   2. Douglas RS , Afifiyan NF , Hwang CJ , Chong K , Haider U , Richards P , Gianoukakis AG , Smith TJ . Increased generation of fibrocytes in thyroid-associated ophthalmopathy . J Clin Endocrinol Metab  . 2010 ; 95 ( 1 ): 430 – 438 . Google Scholar Crossref Search ADS PubMed   3. Bucala R , Spiegel LA , Chesney J , Hogan M , Cerami A . Circulating fibrocytes define a new leukocyte subpopulation that mediates tissue repair . Mol Med  . 1994 ; 1 ( 1 ): 71 – 81 . Google Scholar Crossref Search ADS PubMed   4. Szabo E , Rampalli S , Risueño RM , Schnerch A , Mitchell R , Fiebig-Comyn A , Levadoux-Martin M , Bhatia M . Direct conversion of human fibroblasts to multilineage blood progenitors [published correction appears in Nature. 2018;560:E32]. Nature  . 2010 ; 468 ( 7323 ): 521 – 526 . Google Scholar Crossref Search ADS PubMed   5. Reilkoff RA , Bucala R , Herzog EL . Fibrocytes: emerging effector cells in chronic inflammation . Nat Rev Immunol  . 2011 ; 11 ( 6 ): 427 – 435 . Google Scholar Crossref Search ADS PubMed   6. Lin R-Y . New insights into thyroid stem cells . Thyroid  . 2007 ; 17 ( 10 ): 1019 – 1023 . Google Scholar Crossref Search ADS PubMed   7. Fernando R , Atkins S , Raychaudhuri N , Lu Y , Li B , Douglas RS , Smith TJ . Human fibrocytes coexpress thyroglobulin and thyrotropin receptor . Proc Natl Acad Sci USA  . 2012 ; 109 ( 19 ): 7427 – 7432 . Google Scholar Crossref Search ADS PubMed   Published by Oxford University Press on behalf of the Endocrine Society 2019 This article is a U.S. Government work-for-hire and is therefore in the public domain in the U.S.


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Neumann, Susanne, Krieger, Christine C, Gershengorn, Marvin C. Letter to the Editor: “Elevated Serum Tetrac in Graves Disease: Potential Pathogenic Role in Thyroid-Associated Ophthalmopathy”, The Journal of Clinical Endocrinology & Metabolism, 2019, 1075-1076, DOI: 10.1210/jc.2018-02103