Immunotherapy of Guillain-Barré syndrome

Abstract

Guillain-Barré syndrome (GBS), the most common cause of acute neuromuscular weakness and paralysis worldwide, encompasses a group of acute immune-mediated disorders restricted to peripheral nerves and roots. Immune-mediated attack of peripheral nervous system myelin, axons or both is presumed to be triggered by molecular mimicry, with both cell- and humoral-dependent mechanisms implicated in disease pathogenesis. Good circumstantial evidence exists for a pathogenic role for molecular mimicry in GBS pathogenesis, especially with its axonal forms, providing insights that could guide future immunotherapy. Intravenous immunoglobulin (IVIg) and plasma exchange (PE) are the most commonly prescribed immunotherapies for GBS with variable efficacy dependent on GBS subtype, severity at initial presentation and other clinical and electrophysiologic prognostic factors. The mechanisms of action of IVIg and PE are not known definitely. Despite recent significant advances in molecular biology that provide insights into GBS pathogenesis, no advances in therapeutics or significant improvements in patient outcomes have occurred over the past three decades. We summarize the clinical aspects of GBS, its current pathogenesis and immunotherapy, and highlight the potential of leukocyte trafficking inhibitors as novel disease-specific immunotherapeutic drugs.

Keywords: Blood-Nerve Barrier; Guillain-Barré syndrome; Immunopathology; Immunotherapy; Leukocyte Trafficking; Peripheral Nerve Inflammation.

Figure 1.

Histopathologic features of Guillain-Barré syndrome. Digital photomicrographs depict essential histopathological features of AIDP, the most common GBS variant in Western countries. Semi-thin plastic embedded axial section of the sural nerve biopsy of an AIDP patient shows thinly myelinated large diameter axons (black arrows), indicative of demyelination (A). Frozen thick axial section of the sural nerve biopsy shows mononuclear cells within the endoneurium with some perivascular foci (black arrows) in an AIDP patient (B). Longitudinal frozen thick section from the same AIDP patient's sural nerve biopsy shows reduction in large diameter axon density with evidence of Wallerian degeneration (black arrow). A node of Ranvier (white arrow) in an intact axon is shown (C). Leukocyte trafficking from endoneurial microvessels (EMV, white arrows) is another characteristic pathological finding in AIDP, as shown in the frozen longitudinal section of the sural nerve biopsy of an untreated AIDP patient stained with Periodic Acid Schiff (PAS) with high affinity for blood vessel walls that are rich in glycogen (D). Multifocal leukocyte infiltration (CD45+, black arrows) is commonly seen in AIDP patient nerve biopsies, as shown by immunohistochemistry (IHC) of a frozen thick axial section of a sural nerve biopsy (E). Macrophages (CD68+, black arrows) are the most prevalent endoneurial leukocyte subpopulation in AIDP (F), followed by CD3+ T-cells (black arrows, G) and CD20+ B-cells (black arrows, H). CD11b+ mononuclear leukocytes (white arrows) infiltrating into peripheral nerve endoneurium associated with demyelination of S100β Schwann cells is shown in a frozen thick section of an untreated AIDP patient sural nerve biopsy using indirect fluorescent immunohistochemistry (FIHC; I). An animal model of GBS, severe murine experimental autoimmune neuritis, recapitulates essential pathological features of AIDP, with diffuse areas of demyelination associated with mononuclear leukocyte infiltration (*) seen in the sciatic nerve endoneurium on a semi-thin, plastic-embedded axial section of an affected mouse at peak severity (J). As seen in AIDP, the most prevalent inflammatory leukocyte subpopulation observed in this murine GBS model is the monocyte/macrophage (F4/80+) and these cells are predominantly CD11b+ (white arrows, K) as shown in a frozen axial FIHC section. Electron microscopy (EM) demonstrates macrophages (Mac), T-cells (TC) and B-cells (BC) in the endoneurium of an AIDP patient sural nerve biopsy close to an endoneurial microvessel (EMV) that forms the blood-nerve barrier, sharing its basement membrane with a pericyte (Pc), as shown in L. In this region of leukocyte infiltration, higher magnification demonstrates intact electron dense interendothelial cell tight junctions (black arrows, M). In another region showing active monocyte transmigration, intact tight junctions persist between endoneurial endothelial cells and the migrating monocyte during paracellular diapedesis (black arrows, N). Unless indicated, the stains or histological technique performed on each section are indicated at the upper left corner of the photomicrograph.

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 [α_M-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.