Aquaporin 4 and neuromyelitis optica

Abstract

Neuromyelitis optica is an inflammatory demyelinating disorder of the CNS. The discovery of circulating IgG1 antibodies against the astrocyte water channel protein aquaporin 4 (AQP4) and the evidence that AQP4-IgG is involved in the development of neuromyelitis optica revolutionised our understanding of the disease. However, important unanswered questions remain--for example, we do not know the cause of AQP4-IgG-negative disease, how astrocyte damage causes demyelination, the role of T cells, why peripheral AQP4-expressing organs are undamaged, and how circulating AQP4-IgG enters neuromyelitis optica lesions. New drug candidates have emerged, such as aquaporumab (non-pathogenic antibody blocker of AQP4-IgG binding), sivelestat (neutrophil elastase inhibitor), and eculizumab (complement inhibitor). Despite rapid progress, randomised clinical trials to test new drugs will be challenging because of the small number of individuals with the disorder.

Figure 1. The astrocyte water channel AQP4

(A) High-resolution crystal structure of human AQP4 (Protein Data Bank reference 3GD8) showing eight membrane-associated helical segments, labelled M1–M8. (B) Freeze-fracture electron microscopy of AQP4 orthogonal arrays of particles in plasma membranes of Chinese hamster ovary cells transfected with M23-AQP4. (C) Protein sequence of human AQP4, showing Met-1 and Met-23 translation inhibition sites (black), residues that form intermolecular N-terminus associations to produce orthogonal arrays of particles (pink), residues preventing formation of orthogonal arrays of particles by M1-AQP4 (green), cysteine residues involved in palmitolyation-regulated assembly of orthogonal arrays of particles (blue), and the C-terminus PDZ domain (red).

Figure 2. Formation of neuromyelitis optica lesion

(A) Normal CNS with AQP4-IgG in the serum. (B) At the start of lesion formation, AQP4-IgG binds to AQP4 on foot processes of astrocytes, activates complement, and causes deposition of membrane attack complexes. (C) Cytokines (eg, interleukin 17, interleukin 8, and granulocyte colony-stimulating factor) recruit neutrophils and eosinophils into perivascular spaces; neutrophils degranulate to cause astrocyte death. Loss of astrocytes leads to oligodendrocyte death, which causes axon degeneration (D), and neuronal death (E). Infiltrating macrophages (and possibly microglia) phagocytose cellular and myelin debris. (F) Mature lesions are characterised by pan-necrosis (complete tissue necrosis), and widespread infiltration by macrophages; AQP4-positive reactive astrocytes are confined around the lesion.

Figure 3. Potential targets for treatment

OAP=orthogonal array of particles.