Immunology of neuromyelitis optica: a T cell-B cell collaboration

Abstract

Neuromyelitis optica (NMO) is a debilitating autoimmune inflammatory disease of the central nervous system (CNS) that is distinct from multiple sclerosis (MS). The discovery of NMO-immunoglobulin G (IgG) in the serum of NMO-but not MS-patients was a breakthrough in defining diagnostic criteria for NMO. NMO-IgG is an antibody directed against the astrocytic water channel protein aquaporin-4 (AQP4). While there is evidence that NMO-IgG is also involved in mediating tissue damage in the CNS, many aspects of the pathogenic cascade in NMO remain to be determined. It is clear that antigen-specific T cells contribute to the generation of NMO-IgG in the peripheral immune compartment, as well as to the development of NMO lesions in the CNS. T helper 17 (Th17) cells, equipped both in providing B cell help and inducing tissue inflammation, may be involved in NMO development and pathogenesis. Here, we review immunologic aspects of NMO, placing recent findings in the biology of T-B cell cooperation into perspective with autoimmunity of the CNS.

Figure 1

Longitudinal extensive transverse myelitis is a defining feature of NMO. (A) In the left panel: T2w image of the cervicothoracic spinal cord of a patient with NMO. Note the extension of the centromedullary lesion (arrow) over more than three vertebral segments. Middle panel: Contrast-enhanced T1w image of the same lesion. Right panel: T2w image (transverse section) showing the centromedullary location of the NMO lesion (arrow). (B) Pathogenic process in NMO: in the peripheral immune compartment, B cells bearing an AQP4-specific B cell receptor might serve as antigen presenting cells to prime autoreactive T cells to develop into the Th17 lineage. In turn, Th17 cells have the ability to help B cells become plasma cells, producing antibodies to AQP4 (NMO-IgG). These serum antibodies that are not per se produced intrathecally only cross the blood–brain barrier, including the endothelial basement membrane (BM) under conditions of ongoing inflammation of the endothelium of the CNS vasculature, which might again be driven by Th17 cells. Upon binding of their target antigen (i.e., AQP4 expressed in astrocytic endfeet of the glia limitans), NMO-IgG initiate a downstream pathogenic cascade leading to tissue damage either by complement-dependent cytotoxicity (CDC, upper box) or antibody-dependent cell-mediated cytotoxicity (ADCC, lower box). Here, eosinophils (Eo) recruited into the lesion by C5a, or neutrophils (Neu) recruited into the lesion by ELR chemokines such as CXCL1, are potential effector cells.