Findings support a pathogenic role for an autoantibody of AQP4 specificity in neuromyelitis optica.
SAN FRANCISCO—A complement activating aquaporin-4 (AQP4)-specific autoantibody has a pathogenic role in initiating neuromyelitis optica (NMO) lesions and distinguishes NMO from multiple sclerosis (MS), according to research presented at the 135th Annual Meeting of the American Neurological Association.
Clinical presentation of NMO differs from MS in a number of ways, explained Claudia Lucchinetti, MD, of the Mayo Clinic Rochester in Minnesota, and member of the Mayo Clinic NMO Consortium. NMO onset tends to occur at an older age, affects more females than males, and is more common in non-Caucasians. NMO is typically a relapsing disease, and unlike MS, a progressive course is distinctly unusual. In contrast to MS, brain MRI scans are often normal early in the disease, while spinal cord MRIs typically show long lesions spanning three or more intervertebral segments, which are not typically seen in adult MS. Oligoclonal bands in the spinal fluid are rare in NMO, whereas pleocytosis is common. NMO can be associated with other autoimmune disorders, including myasthenia gravis. Patients with active NMO respond favorably to antibody-depleting therapies.
In 2002, Dr. Lucchinetti and colleagues described the presence of deposits of immunoglobulin G (IgG) and immunoglobulin M (IgM) co-localizing with products of complement activation in a vasculocentric pattern around thickened hyalinized blood vessels in active NMO lesions, suggesting a pathogenic role for humoral immunity targeting an antigen in the perivascular space. In 2004, Vanda Lennon, MD, PhD, and colleagues at the Mayo Clinic reported a specific serum autoantibody marker that was 73% sensitive and more than 90% specific for clinically defined NMO. Its selective binding to the abluminal face of microvessels, pia, subpia and Virchow-Robin sheaths was reminiscent of the localization of immune complexes in NMO patients’ spinal cord tissues described by Lucchinetti and colleagues.
“With the discovery of the biomarker, a spectrum of neurologic disorders has been identified associated with the presence of NMO-IgG, including not only NMO, but also isolated or recurrent longitudinally extensive transverse myelitis, or optic neuritis, encephalopathy, intractable nausea and vomiting, a posterior reversible leukoencephalopathy (PRES)-like syndrome, endocrinopathies, and even narcolepsy,” she said.
Aquaporin-4
Subsequent studies led by Dr. Lennon identified AQP4 as the target auto-antigen in NMO. AQP4 is the dominant CNS water channel, which regulates bidirectional water flux between the blood and brain, and the brain and spinal fluid, and is concentrated at the astrocytic end-feet. It is expressed in two isoforms, M1 and M23, and consists of six membranes that determine the channel’s selectivity for water molecules, Dr. Lucchinetti said.
AQP4 is found on the surfaces of astrocytes, concentrated in periventricular regions, circumventricular organs, and spinal cord gray matter in healthy controls. Normal AQP4 expression parallels the classic ring and rosette staining pattern of immune complex deposition observed in active NMO lesions. In contrast to active MS lesions, which show an increase in AQP4 immunoreactivity, NMO lesions show a striking loss of AQP4, she explained. “Interestingly, myelin may be relatively preserved in some of these lesions, despite the profound loss of AQP4,” said Dr. Lucchinetti.
Brain Lesions in NMO
MRI detects brain lesions in 60% of NMO patients, which include NMO-specific brain lesions in regions of high AQP4 expression (eg, area postrema, hypothalamus), as well as supratentorial lesions that are either nonspecific or MS-like in appearance. The presence of these supratentorial brain lesions has suggested a possible pathologic overlap of NMO and MS. However, comparison of supratentorial (ST) NMO lesions with opticospinal (OS) NMO lesions, as well as supratentorial MS lesions, confirmed that the pathology of NMO ST lesions is similar to NMO OS lesions with respect to type of inflammation, presence of perivascular immune complex deposits and AQP4 loss. Dr. Lucchinetti suggests these findings indicate that NMO ST and OS lesions have a shared pathogenesis.
Clinical reports have also described intractable hiccups, nausea, and vomiting in NMO. NMO specific medullary lesions have been observed in the area postrema, which are characterized by a selective and targeted loss of AQP4, and likely reflect the pathologic substrate of intractable nausea and vomiting reported in some NMO patients. A study in press by members of the Mayo Clinic NMO consortium suggests that the area postrema may even be the first point of attack in NMO in at least 12% of NMO cases, Dr. Lucchinetti reported.
The Role of NMO IgG
In vitro studies demonstrate that NMO-IgG binds selectively to the surface of living target cell membranes expressing AQP4, a prerequisite for IgG to affect organ-specific pathogenicity. This binding initiates two potentially competing outcomes: 1) rapid downregulation of AQP4 via endocytosis/degradation; and 2) activation of the lytic complement cascade. The relative predominance of antigenic modulation and complement activation that represent competing sequelae of IgG binding to the surface AQP4 may determine an individual’s clinical presentation, response to therapy, and disease course. The rapid endocytosis and degradation of surface AQP4 initiated by IgG binding coupled with the rapid replenishment of newly synthesized AQP4 also supports a potentially reversible insult, at least during early disease stages.
A recent study further demonstrated that exposure to NMO patient serum and active complement compromised the membrane integrity of CNS-derived astrocytes. Without complement, astrocyte membranes remained intact, but AQP4 was endocytosed with concomitant loss of sodium-dependent glutamate transport and loss of the excitatory transporter, EAAT2. These findings suggest that EAAT2 and AQP4 exist in astrocytic membranes as a macromolecular complex. Furthermore, Dr. Lucchinetti reported that NMO lesions demonstrated marked reduction in EAAT2 in regions of AQP4 loss. In summary, binding of NMO-IgG to astrocytic AQP4 initiates not only complement activation, but AQP4 and EAAT2 downregulation, which would be expected to disrupt glutamate homeostasis. This could lead to injury of oligodendrocytes that express calcium-permeable glutamate receptors.
Dr. Lucchinetti discussed several possible mechanisms that might initiate demyelination in NMO. First, oligodendrocyte are more susceptible than astrocytes to lethal injury by noxious stimuli, and would be expected to be injured at the paranode where they directly contact AQP4 containing astrocytic foot processes. Second, demyelination could be secondary as a result of axonal injury due to alterations in the ionic microenvironment at the internode. Third, glutamate toxicity may contribute to demyelination.
“NMO IgG can produce three potentially pathogenic outcomes—AQP4 and EAAT2 modulation, complement activation, and reduced glutamate uptake,” she said. “Treatment strategies targeting complement activation and glutamate excitotoxicity may prove effective."