New immune link to inflammation, scarring in Graves’ disease

Fibrocytes present at higher than normal frequency in patients with Graves’ disease.

A cell type that causes significant scarring in lung disease appears to have a similar effect in Graves’ disease.

In a new Journal of Clinical Endocrinology & Metabolism study, fibrocytes were present at substantially higher frequencies — as much as five times greater — in patients with Graves’ disease. Researchers observed these higher levels in both the bloodstream and orbital tissues of patients who developed thyroid-associated ophthalmopathy.

“We now have a much clearer picture of the disease process, including the pathway by which fibrocytes reach the orbit,” researcher Raymond Douglas, MD, PhD, associate professor of ophthalmology and visual sciences at The University of Michigan Kellogg Eye Center, said in a press release.

“These fibrocytes can be thought of as precursors of fibroblasts that are capable of differentiating into more specialized cells, such as adipocytes and myofibroblasts,” Terry J. Smith, MD, Frederick G.L. Huetwell professor of ophthalmology and visual sciences at The University of Michigan Kellogg Eye Center, told Endocrine Today.

Presence of fibrocytes

The researchers examined fibrocytes from peripheral blood mononuclear cells in samples from 70 patients with Graves’ disease and compared them with 25 healthy controls. They examined orbital tissues and fibroblast culture strains for the presence of fibrocytes. Fibrocytes were characterized by flow cytometry.

CD34⁺, CXCR4⁺, collagen 1⁺ and CD11b⁺ cells expressing insulin-like growth factor I receptor were generated approximately fivefold more from peripheral blood mononuclear cells of patients with Graves’ disease compared with healthy controls (5,268 per 10⁶ PBMCs vs. 954 per 10⁶ PBMCs; P<.001).

The fibrocytes “surprisingly” also expressed thyroid-stimulating hormone receptor at high levels, and TSH induced them to produce interleukin-6 and tumor necrosis factor-alpha.

“These cytokines have established roles in human autoimmunity,” Smith said.

The researchers detected numerous CD34⁺ fibrocytes in orbital tissues in thyroid-associated ophthalmopathy; however, these fibrocytes were absent in healthy orbital tissues.

Tissue-infiltrating fibrocytes expressed TSH receptor in situ, and comprise a subpopulation of thyroid-associated ophthalmopathy-derived orbital fibroblasts.

Role in pathogenesis of Graves’ disease

These data “suggest that fibrocytes may participate in the pathogenesis of thyroid-associated ophthalmopathy because they express relevant autoantigens such as IGF-I receptor and functional TSH receptor and differentially accumulate in orbital tissue in thyroid-associated ophthalmopathy,” the researchers wrote.

Smith added, “Fibrocytes may play important roles in mediating the inflammation, fat expansion and scar formation associated with the disease.”

In an accompanying editorial, George J. Kahaly, MD, PhD, from the department of medicine at Gutenberg-University Medical Center, Mainz, Germany, said the fibrocyte might “immunize” at-risk individuals with TSH receptor, “thereby resulting in the generation of immune reactions against the receptor.

“Thus, the findings might represent insight into a previously unidentified mechanism underlying the pathogenesis of Graves’ disease and Graves’ orbitopathy,” Kahaly wrote.

Both the researchers and Kahaly acknowledged a need for more research.

“Whether the magnitude of increased fibrocyte generation in Graves’ disease changes with disease duration, treatment or development of thyroid-associated ophthalmopathy is currently being assessed in longitudinal studies,” the researchers wrote.

Smith said researchers are currently examining the implications of these findings to other examples of human autoimmunity in which tissue remodeling also plays an important pathogenic role in disease manifestations.

“The knowledge that the complex immunopathogenesis of Graves’ disease is linked to bone marrow stem cells brings us closer to closing the loop between the thyroid gland and the immune system,” Kahaly wrote. - by Katie Kalvaitis

Douglas RS. J Clin Endocrinol Metab. 2010;95:430-438.

Kahaly GJ. J Clin Endocrinol Metab. 2010;95:62-65.