Neuromyelitis optica: Pathogenicity of patient immunoglobulin in vivo

TLDR

Neuromyelitis optica is characterized by severe inflammation, astrocyte loss, and profound demyelination of the spinal cord and optic nerves, with serum autoantibodies against aquaporin‑4 serving as a diagnostic hallmark. The study induced acute T‑cell–mediated experimental autoimmune encephalomyelitis in Lewis rats and then administered immunoglobulins from AQP‑4 antibody–positive and –negative NMO patients, multiple sclerosis patients, and controls. Immunoglobulins from AQP‑4 antibody–positive NMO patients were pathogenic, amplifying disease and producing NMO‑like lesions in the CNS when serum titers matched those seen in patients, whereas similar antibodies did not induce pathology in naïve or leaky‑BBB rats or after transfer of non‑encephalitogenic T cells; absorption with AQP‑4–transfected cells reduced titers and astrocyte damage. Ann Neurol 2009;66:630–643.

Abstract

Abstract Objective Severe inflammation and astrocyte loss with profound demyelination in spinal cord and optic nerves are typical pathological features of neuromyelitis optica (NMO). A diagnostic hallmark of this disease is the presence of serum autoantibodies against the water channel aquaporin‐4 (AQP‐4) on astrocytes. Methods We induced acute T‐cell–mediated experimental autoimmune encephalomyelitis in Lewis rats and confronted the animals with an additional application of immunoglobulins from AQP‐4 antibody–positive and –negative NMO patients, multiple sclerosis patients, and control subjects. Results The immunoglobulins from AQP‐4 antibody–positive NMO patients are pathogenic. When they reach serum titers in experimental animals comparable with those seen in NMO patients, they augment clinical disease and induce lesions in the central nervous system that are similar in structure and distribution to those seen in NMO patients, consisting of AQP‐4 and astrocyte loss, granulocytic infiltrates, T cells and activated macrophages/microglia cells, and an extensive immunoglobulin and complement deposition on astrocyte processes of the perivascular and superficial glia limitans. AQP‐4 antibody containing NMO immunoglobulin injected into naïve rats, young rats with leaky blood–brain barrier, or after transfer of a nonencephalitogenic T‐cell line did not induce disease or neuropathological alterations in the central nervous system. Absorption of NMO immunoglobulins with AQP‐4–transfected cells, but not with mock‐transfected control cells, reduced the AQP‐4 antibody titers and was associated with a reduction of astrocyte pathology after transfer. Interpretation Human anti–AQP‐4 antibodies are not only important in the diagnosis of NMO but also augment disease and induce NMO‐like lesions in animals with T‐cell–mediated brain inflammation. Ann Neurol 2009;66:630–643