Immune checkpoints: new insights into the pathogenesis of thyroid eye disease

Abstract

Thyroid eye disease (TED) is a disfiguring autoimmune disease characterized by changes in the orbital tissues and is caused by abnormal thyroid function or thyroid-related antibodies. It is the ocular manifestation of Graves' disease. The expression of thyroid-stimulating hormone receptor (TSHR) and the insulin-like growth factor-1 receptor (IGF-1 R) on the cell membrane of orbital fibroblasts (OFs) is responsible for TED pathology. Excessive inflammation is caused when these receptors in the orbit are stimulated by autoantibodies. CD34⁺ fibrocytes, found in the peripheral blood and orbital tissues of patients with TED, express immune checkpoints (ICs) like MHC II, B7, and PD-L1, indicating their potential role in presenting antigens and regulating the immune response in TED pathogenesis. Immune checkpoint inhibitors (ICIs) have significantly transformed cancer treatment. However, it can also lead to the occurrence of TED in some instances, suggesting the abnormality of ICs in TED. This review will examine the overall pathogenic mechanism linked to the immune cells of TED and then discuss the latest research findings on the immunomodulatory role of ICs in the development and pathogenesis of TED. This will offer fresh perspectives on the study of pathogenesis and the identification of potential therapeutic targets.

Keywords: immune cells; immune checkpoints; teprotumumab; therapeutic targets; thyroid eye disease.

Figure 1

The potential mechanism of immune checkpoints in the pathogenesis of TED (By Figdraw). In peripheral blood, CD34⁺ fibrocytes with antigen-presenting function interact with and then activate naive CD4⁺ T cells, with the alteration of the expression of CTLA-4, Tim-3, and PD-1 on the activated T cells. Activated T cells activate B cells through the CD40-CD40L pathway and produce autoantibodies. Autoantibodies bind and activate TSHR and IGF-1R on the orbital fibroblasts, promoting the secretion of chemokines and recruiting T cells to the orbit, exacerbating local inflammation. T cells further activate orbital fibroblasts, causing them to differentiate into adipocytes and myofibroblasts. CD34⁺ fibrocytes also migrate to the orbit and differentiate into CD34^-OFs under the action of Slit2 secreted by orbital fibroblasts in situ, accompanied by downregulation of immune checkpoint molecules such as MHC II, B7, and PD-L1. Teprotumumab can inhibit the interaction between T cells and OFs or fibroblasts by downregulating MHC II, B7, and PD-L1 molecules. Teprotumumab can also reduce inflammation by directly reducing the number of fibrocytes-adherent CD4⁺ T cells in peripheral blood and attenuating the secretion of IFN-γ and IL-17A.