Fig. 1

Pathogenesis of TAO. In TAO, T cells, B cells, and CD34⁺ fibrocytes infiltrate the orbit. Antigen- presenting cells present self-antigens to T cells and activate T cells. Activated T cells differentiate into subsets including T helper (Th) 1, Th2, and Th17 cells, producing cytokines like IFN-γ, TNF-α, IL(interleukin)-4, IL-13, IL-17A, and IL-22, which exacerbate immune inflammatory responses, activate OFs and stimulate proliferation and differentiation of orbital fibroblasts (OFs). The self-antigen is the first signal to activate B cells and the second signal is provided by activated T cells. Activated B cells differentiate into plasma cells that secrete autoantibodies. Fibrocytes can recruit Th17 cells in a macrophage inflammatory protein 3/C-C chemokine receptor type 6-dependent manner, and can also differentiate into CD34⁺ fibroblasts, which coexist with the resident CD34⁻ OFs in orbit. Both CD34⁺ and CD34⁻ OFs express the thyroid stimulating hormone receptor and insulin-like growth factor 1 receptor. Activated OFs that secrete chemokines including intercellular adhesion molecule-1, macrophage inflammatory protein 1, C-X-C motif ligand (CXCL) 9/10/11, and regulated on activation, normal T cell expressed and secreted (RANTES) can recruit more lymphocytes. They also secrete proinflammatory factors such as IL-1β, IL-6, IL-8, and prostaglandin E₂, maintaining and amplifying immune responses. Activated OFs differentiate into adipocytes, myofibroblasts, and promote the synthesis of hyaluronic acid, all of which contribute to the increase in the volume of the orbital tissues and remodeling of the orbit, ultimately leading to the clinical manifestations of TAO.