Figure 2.

Humoral immunity and biologics. The circulating TRAb and M22 act on TSHR to induce cAMP production, which activates the PI3K cascade reaction and promotes the production of HAS1, HAS2 and HAS3, resulting in increased production of hyaluronan, leading to extraocular muscle hypertrophy. M22 also increases the expression and secretion of IL-6. Subsequently, the increased expression of IL-6 promotes the expression of the autoantigen TSHR by OFs and also drives B-cell immunoglobulin (Ig) production, and plasma cell development. Serum Igs from GO patients bind to IGF-1R and produce IL-16 and RANTES, promoting an inflammatory response. TSHR and IGF-1R can form physical and functional protein complexes that can interact to increase signaling when activated by their respective ligands, resulting in increased hyaluronan (HA) and IL-6 production. The generated HA and IL-6 then repeat the above reaction, aggravating the GO pathological process. New therapeutic drugs are indicated by blue boxes and red lines. By Figdraw (www.figdraw.com).