Figure 2.
Potential Targets for GBS Immunotherapy Development. Pathogenic leukocyte trafficking across tight junction-forming endoneurial microvessels that form the blood-nerve barrier is pathogenically relevant to AIDP and other demyelinating GBS variants based on human in situ and in vitro data, as well as in vivo data from representative animal models. Taking into account the coordinated process of leukocyte trafficking (multi-step paradigm), leukocyte trafficking antagonists that block pathogenic leukocyte chemoattraction, haptotaxis and firm arrest on activated endoneurial endothelial cells (e.g. Chemokine receptor CCR2 antagonists), firm leukocyte adhesion (e.g. CD11b [αM-integrin] antagonists) or diapedesis (undetermined; with platelet-endothelial cell adhesion molecule-1, CD99, CD99L2 and junctional adhesion molecules-A, -B and –C being potential candidates for antagonism) could result in targeted molecular immunotherapies for GBS. Another unexplored possibility involves modulating pathogenic polyclonal IgG antibody transport from the blood circulation into peripheral nerves and nerve roots across the blood-nerve barrier by Fc gamma receptor and transporter (FCGRT) antagonists. These therapeutic approaches target GBS pathogenesis after systemic immune activation at the critical interphase between the immune system and peripheral nerves/ nerve roots at a time period when patients are symptomatic, with the goal being to limit demyelination and axonal injury/ degeneration. It is envisioned that drugs targeting pathogenic leukocyte trafficking or polyclonal IgG antibody transport can be administered systemically with therapeutic modulation occurring in circulation without need for significant drug blood-nerve barrier permeability to treat GBS. The challenge is elucidating biologically relevant molecules and signaling pathways preferentially activated in GBS at the blood-nerve barrier that are amenable to pharmacologic antagonism to limit potential adverse systemic effects associated with non-specific immune modulation or immunosuppression during the active phase of the disorder.