Neuromyelitis optica: Pathogenicity of patient immunoglobulin in vivo

Monika Bradl, Tatsuro Misu, Toshiyuki Takahashi, Mitsutoshi Watanabe, Simone Mader, Markus Reindl, Milena Adzemovic, Jan Bauer, Thomas Berger, Kazuo Fujihara, Yasuto Itoyama, Hans Lassmann

Research output: Contribution to journalArticlepeer-review

415 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)630-643
Number of pages14
JournalAnnals of Neurology
Volume66
Issue number5
DOIs
Publication statusPublished - 2009

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology

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