Restoring immune tolerance in neuromyelitis optica: Part I

Abstract

Neuromyelitis optica (NMO) and spectrum disorder (NMO/SD) represent a vexing process and its clinical variants appear to have at their pathogenic core the loss of immune tolerance to the aquaporin-4 water channel protein. This process results in a characteristic pattern of astrocyte dysfunction, loss, and demyelination that predominantly affects the spinal cord and optic nerves. Although several empirical therapies are currently used in the treatment of NMO/SD, none has been proven effective in prospective, adequately powered, randomized trials. Furthermore, most of the current therapies subject patients to long-term immunologic suppression that can cause serious infections and development of cancers. The following is the first of a 2-part description of several key immune mechanisms in NMO/SD that might be amenable to therapeutic restoration of immune tolerance. It is intended to provide a roadmap for how potential immune tolerance restorative techniques might be applied to patients with NMO/SD. This initial installment provides a background rationale underlying attempts at immune tolerization. It provides specific examples of innovative approaches that have emerged recently as a consequence of technical advances. In several autoimmune diseases, these strategies have been reduced to practice. Therefore, in theory, the identification of aquaporin-4 as the dominant autoantigen makes NMO/SD an ideal candidate for the development of tolerizing therapies or cures for this increasingly recognized disease.

Figure 1. Integrative model of NMO/SD pathogenesis

Distinct stages of disease are illustrated as relative temporal and spatial comparators in NMO/SD progression. Note that over the course of disease progression and demyelination, additional autoantigens may be revealed and/or recognized, potentially resulting in antigen spreading and expansion/compounding of autoreactivity. A = astrocyte (AQP4-expressing cells that support neuronal viability and function); AQP4 = aquaporin 4; B = B lymphocyte; BBB = blood-brain barrier; E = eosinophil; M = monocyte/macrophage; N = neuron; NK = natural killer cell; NMO/SD = neuromyelitis optica/spectrum disorder; P = polymorphonuclear leukocyte (neutrophil); PER = periphery; T = T lymphocyte.

Figure 2. Comparative milestones in T and B lymphocyte maturation

(A) T cell development. (B) B cell development. Each lineage is represented with distinguishing markers for corresponding stages, and where cell commitment occurs. Arrows indicate potential points along the development pathway where immune tolerizing interventions might be targeted in neuromyelitis optica/spectrum disorder. CAR = chimeric antigen receptor; CD = class designation marker; CLP = common lymphoid precursor; DN = double-negative thymocyte; DP = double-positive CD4⁺/CD8⁺ thymocyte; Ig = immunoglobulin; ImmB = immature B cell; ISP = immature single-positive CD8⁺ thymocyte; LPreB = large PreB; MatB = mature B cell; PreB = pre-B cell receptor B cell; ProB = progenitor B cell; SP = single positive CD4⁺ or CD8⁺ thymocyte; SPreB = small PreB; TcR = T cell receptor; Treg = regulatory T cell.

Figure 3. Hypothesized cellular and molecular crosstalk influencing NMO/SD

(A) Theoretical proinflammatory interactions that arise from loss of immune tolerance, which may promote the onset or progression of neuromyelitis optica/spectrum disorder (NMO/SD). (B) Theoretical anti-inflammatory interactions that arise and could be amenable to therapeutic intervention in restoring immune tolerance in NMO/SD. (Cellular) APC = antigen-presenting cell; Bc = B cell; Tc = T cell; (cell surface determinants) CD = class designation; MHC = major histocompatibility complex; (soluble) BAFF = B cell activating factor; IL = interleukin; IL-18BP = IL-18 binding protein; sIL-1R = soluble IL-1 receptor; sTNFR = soluble tumor necrosis factor α receptor.