Neuromyelitis optica: pathogenicity of patient immunoglobulin in vivo.
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.


CONCLUSIONS
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.
Bradl
Monika
M
Department of Neuroimmunology, Medical University Vienna, Center for Brain Research, Vienna, Austria.
Misu
Tatsuro
T
Takahashi
Toshiyuki
T
Watanabe
Mitsutoshi
M
Mader
Simone
S
Reindl
Markus
M
Adzemovic
Milena
M
Bauer
Jan
J
Berger
Thomas
T
Fujihara
Kazuo
K
Itoyama
Yasuto
Y
Lassmann
Hans
H
D000328:Adult; D000368:Aged; D000818:Animals; D051401:Aquaporin 4 / Q000008:administration & dosage / Q000134:cerebrospinal fluid; D001323:Autoantibodies / Q000008:administration & dosage / Q000009:adverse effects* / Q000134:cerebrospinal fluid; D002460:Cell Line; D005260:Female; D006801:Humans; D007074:Immunoglobulin G / Q000009:adverse effects / Q000134:cerebrospinal fluid*; D008297:Male; D008875:Middle Aged; D009471:Neuromyelitis Optica / Q000134:cerebrospinal fluid* / Q000209:etiology / Q000473:pathology*; D051381:Rats; D011917:Rats, Inbred Lew; D055815:Young Adult
D051401:Aquaporin 4; D001323:Autoantibodies; D007074:Immunoglobulin G