Figure 3:

Rationale for the development of CD40-targeted therapies. *A T-cell interacts with either a professional APC (i.e., B-cell) or a non-professional APC (i.e., thyroid cell); for illustrative purposes, this figure depicts both types of interactions concurrently with a single T-cell.

(A) CD40 is expressed on thyroid cells and B-cells. CD40-CD40L binding activates CD40 signaling pathways in thyroid cells, such as the canonical and non-canonical NFκB pathways, leading to the secretion of IL-6, IL-8, TNFα, and BAFF. These drive a local inflammatory response in the thyroid and, in genetically susceptible individuals, results in the activation of thyroid-reactive T-cells that have escaped tolerance. Activation of CD40 signaling pathways in B-cells leads to their differentiation into plasma cells. Autoreactive B-cells will secrete antibodies targeting the TSHR. (B) MAb’s targeting either CD40 or CD40L can block these pathways and may have a beneficial clinical effect in GD.