Rationale for therapeutic targeting insulin-like growth factor-1 receptor and bone marrow-derived fibrocytes in thyroid-associated ophthalmopathy

Smith, Terry J.

doi:10.1586/17469899.2016.1164598

Cited by 5 publications

(4 citation statements)

References 25 publications

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“…Fibrocytes have recently been implicated in the pathogenesis of several autoimmune diseases, including rheumatoid arthritis (11), type I diabetes mellitus (12), and Graves’ disease (GD) (13, 14). In GD, orbital connective tissues surrounding the eye become infiltrated with T and B cells, mast cells and fibrocytes which appear to participate in the development of thyroid-associated ophthalmopathy (TAO).…”

Section: Introductionmentioning

confidence: 99%

Slit2 Modulates the Inflammatory Phenotype of Orbit-Infiltrating Fibrocytes in Graves’ Disease

Fernando

Grisolia

Lü

et al. 2018

The Journal of Immunology

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Human CD34 fibrocytes, circulating monocyte lineage progenitor cells, have recently been implicated in thyroid-associated ophthalmopathy (TAO), the ocular manifestation of Graves' disease (GD). Fibrocytes express constitutive MHC class II (MHC-2) and, surprisingly, thyroglobulin (Tg) and functional thyrotropin (TSH) receptor (TSHR). Underlying expression of these thyroid proteins is the autoimmune regulator protein (AIRE). Fibrocytes respond robustly to TSH and thyroid-stimulating Igs by generating extremely high levels of inflammatory cytokines, such as IL-6. In TAO, they appear to infiltrate the orbit, where they transition to CD34 orbital fibroblasts (OF). There, they coexist with CD34 OF as a mixed fibroblast population (GD-OF). In contrast to fibrocytes, GD-OF express vanishingly low levels of MHC-2, Tg, TSHR, and AIRE. Further, the amplitude of IL-6 induction by TSH in GD-OF is substantially lower. The molecular basis for this divergence between fibrocytes and CD34 OF remains uncertain. In this article, we report that Slit2, an axon guidance glycoprotein, is constitutively expressed by the CD34 OF subset of GD-OF. Culture conditioned medium (CM) generated by incubating with GD-OF and CD34 OF substantially reduces levels of MHC-2, Tg, TSHR, and AIRE in fibrocytes. Expression can be restored by specifically depleting CM of Slit2. The effects of CD34 OF CM are mimicked by recombinant human Slit2. TSH induces Slit2 levels in GD-OF by enhancing both Slit2 gene transcription and mRNA stability. These findings suggest that Slit2 represents a TSH-inducible factor within the TAO orbit that can modulate the inflammatory phenotype of CD34 OF and therefore may determine the activity and severity of the disease.

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Section: Introductionmentioning

confidence: 99%

Slit2 Modulates the Inflammatory Phenotype of Orbit-Infiltrating Fibrocytes in Graves’ Disease

Fernando

Grisolia

Lü

et al. 2018

The Journal of Immunology

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“…Thus, medical therapy for TAO has largely been aimed at the active phase of the disease. The mechanisms underlying development of TAO are complex and intimately intertwined with the related autoimmunity occurring within the thyroid gland (18). Connectivity between glandular and orbital manifestations of GD remains shrouded in uncertainty, in large part by the historical absence of animal models exhibiting high fidelity with the human disease.…”

Section: Introductionmentioning

confidence: 99%

“…Recent advances in preclinical modeling are encouraging but remain imperfect (19). Another barrier to solving its pathogenesis concerns the wide variability among patients with regard to their clinical presentation of TAO and the relative rarity of the disease (18). At the core of GD is loss of immune tolerance to the TSHR and the generation of autoantibodies directed at the receptor protein (20).…”

Section: Introductionmentioning

confidence: 99%

Will biological agents supplant systemic glucocorticoids as the first-line treatment for thyroid-associated ophthalmopathy?

Smith

Bartalena

2019

European Journal of Endocrinology

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In this article, the two authors present their opposing points of view concerning the likelihood that glucocorticoids will be replaced by newly developed biological agents in the treatment of active, moderate-to-severe thyroid-associated ophthalmopathy (TAO). TAO is a vexing, disfiguring and potentially blinding autoimmune manifestation of thyroid autoimmunity. One author expresses the opinion that steroids are nonspecific, frequently fail to improve the disease and can cause sometimes serious side effects. He suggests that glucocorticoids should be replaced as soon as possible by more specific and safer drugs, once they become available. The most promising of these are biological agents. The other author argues that glucocorticoids are proven effective and are unlikely to be replaced by biologicals. He reasons that while they may not uniformly result in optimal benefit, they have been proven effective in many reports. He remains open minded about alternative therapies such as biologicals but remains skeptical that they will replace steroids as the first-line therapy for active, moderate-to-severe TAO without head-to-head comparative clinical trials demonstrating superiority. Despite these very different points of view, both authors are optimistic about the availability of improved medical therapies for TAO, either as single agents or in combination. Further, both agree that better treatment options are needed to improve the care of our patients with active moderate-to-severe TAO.

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“…TSHR, the disease-specific, pathogenic autoantigen, is uniquely targeted in GD by activating autoantibodies, known as thyroid-stimulating Igs (TSI) (37). These Abs underlie the hyperthyroidism frequently associated with GD but their role in TAO remains uncertain (38).…”

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confidence: 99%

Slit2 May Underlie Divergent Induction by Thyrotropin of IL-23 and IL-12 in Human Fibrocytes

Fernando

Atkins

Smith

2020

The Journal of Immunology

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IL-23 and IL-12, two structurally related heterodimeric cytokines sharing a common subunit, divergently promote Th cell development and expansion. Both cytokines have been implicated in the pathogenesis of thyroid-associated ophthalmopathy (TAO), an autoimmune component of Graves disease. In TAO, CD34+ fibrocytes, putatively derived from bone marrow, can be identified in the orbit. There they masquerade as CD34+ orbital fibroblasts (OF) (CD34+ OF) and cohabitate with CD34− OF in a mixed fibroblast population (GD-OF). Slit2, a neural axon repellent, is expressed and released by CD34− OF and dampens the inflammatory phenotype of fibrocytes and CD34+ OF. In this study we report that thyrotropin (TSH) and the pathogenic, GD-specific monoclonal autoantibody, M22, robustly induce IL-23 in human fibrocytes; however, IL-12 expression is essentially undetectable in these cells under basal conditions or following TSH-stimulation. In contrast, IL-12 is considerably more inducible in GD-OF, cells failing to express IL-23. This divergent expression and induction of cytokines appears to result from cell type–specific regulation of both gene transcription and mRNA stabilities. It appears that the JNK pathway activity divergently attenuates IL-23p19 expression while enhancing that of IL-12p35. The shift from IL-23p19 expression in fibrocytes to that of IL-12p35 in their derivative CD34+ OF results from the actions of Slit2. Thus, Slit2 might represent a molecular determinant of balance between IL-23 and IL-12 expression, potentially governing immune responses in TAO.

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Rationale for therapeutic targeting insulin-like growth factor-1 receptor and bone marrow-derived fibrocytes in thyroid-associated ophthalmopathy

Cited by 5 publications

References 25 publications

Slit2 Modulates the Inflammatory Phenotype of Orbit-Infiltrating Fibrocytes in Graves’ Disease

Slit2 Modulates the Inflammatory Phenotype of Orbit-Infiltrating Fibrocytes in Graves’ Disease

Will biological agents supplant systemic glucocorticoids as the first-line treatment for thyroid-associated ophthalmopathy?

Slit2 May Underlie Divergent Induction by Thyrotropin of IL-23 and IL-12 in Human Fibrocytes

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