Differential expression of aquaporin-4 isoforms localizes with neuromyelitis optica disease activity

Saini, Harleen; Fernandez, Gregory; Kerr, Douglas A.; Lévy, Michaël

doi:10.1016/j.jneuroim.2010.02.007

Cited by 28 publications

(18 citation statements)

References 19 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Our observation also supports the recent finding of two different missense allelic mutations at Arg19 (R19I and R19T), which enhance susceptibility to NMO and are located within the first 22 residues of the N-terminus of the protein, unique to the AQP4-M 1 [28]. The M 1 isoform of AQP4 seems to be important for NMO, since it is preferentially expressed in the optic nerve and spinal cord, where NMO lesions are usually found [29]. However, in another study, the M 23 isoform has been proposed as a major target of anti-aquaporin-4 antibodies [15].…”

Section: Discussionsupporting

confidence: 90%

Fine specificity of antibodies against AQP4: Epitope mapping reveals intracellular epitopes

Kampylafka

Routsias

Alexopoulos

et al. 2011

Journal of Autoimmunity

View full text Add to dashboard Cite

The autoantibody to aquaporin-4 (AQP4) is a marker and a pathogenetic factor in Neuromyelitis Optica (NMO) (Devic's syndrome). Our aim was to identify B-cell antigenic linear epitopes of the AQP4 protein and investigate similarities with other molecules. To this end, we screened sera from 21 patients positive for anti-AQP4 antibodies (study group), from 23 SLE and 23 pSS patients without neurologic involvement (disease controls) and from 28 healthy individuals (normal controls). Eleven peptides, spanning the entire intracellular and extracellular domains of the AQP4 molecule, were synthesized, and all sera were screened for anti-peptide antibodies by ELISA. Specificity was evaluated by homologous inhibition assays. NMO positive sera exhibited reactivity against 3 different peptides spanning the sequences aa1-22 (AQPpep1) (42.9% of patients), aa88-113 (AQPpep4) (33%) and aa252-275 (AQPpep8) (23.8%). All epitopes were localized in the intracellular domains of AQP4. Homologous inhibition rates were ranging from 71.1% to 84.3%. A 73% sequence homology was observed between AQPpep8' aa257-271, a 15-mer peptide part of the AQPpep8 aa252-275, and the aa219-233 domain of the Tax1-HTLV-1 binding protein (TAX1BP1), a host protein associated with replication of the Human T-Lymphotropic Virus 1 (HTLV-1). Antibodies against the AQP4 and the TAX1BP1 15-mer peptides were detected in 26.3% (N = 5) and 31.6% (N = 6) of NMO positive sera (r(s) = 0.81, P < 0.0001). Healthy controls did not react with these peptides, while homologous and cross-inhibition assays confirmed binding specificity. This first epitope mapping for AQP4 reveals that a significant proportion of anti-AQP4 antibodies target linear epitopes localized in the intracellular domains of the channel. One of the epitopes displays high similarity with a portion of TAX1BP1 protein.

show abstract

Section: Discussionsupporting

confidence: 90%

Fine specificity of antibodies against AQP4: Epitope mapping reveals intracellular epitopes

Kampylafka

Routsias

Alexopoulos

et al. 2011

Journal of Autoimmunity

View full text Add to dashboard Cite

show abstract

“…Optic nerve susceptibility in NMO might also arise from the high AQP4 expression in optic nerve compared to brain (Saini et al, 2010) and the abundance of large OAPs in perivascular astrocytic end-feet of optic nerve (Bäuerle and Wolburg, 1993; Amiry-Moghaddam et al, 2004; Nicchia et al, 2008), which enhance AQP4-IgG binding and CDC, as mentioned above. The presence of plasma blasts in the CSF secreting AQP4-IgG locally (Bennett et al, 2009) and/or regional variations in regulators of complement (CD46 and CD59) may also be involved in the unique susceptibility of the optic nerve in NMO.…”

Section: Pathogenesis Mechanismsmentioning

confidence: 99%

Optic neuritis in neuromyelitis optica

Levin

Bennett

Verkman

2013

Progress in Retinal and Eye Research

View full text Add to dashboard Cite

Neuromyelitis optica (NMO) is an autoimmune demyelinating disease associated with recurrent episodes of optic neuritis and transverse myelitis, often resulting in permanent blindness and/or paralysis. The discovery of autoantibodies (AQP4-IgG) that target aquaporin-4 (AQP4) has accelerated our understanding of the cellular mechanisms driving NMO pathogenesis. AQP4 is a bidirectional water channel expressed on the plasma membranes of astrocytes, retinal Müller cells, skeletal muscle, and some epithelial cells in kidney, lung and the gastrointestinal tract. AQP4 tetramers form regular supramolecular assemblies at the cell plasma membrane called orthogonal arrays of particles. The pathological features of NMO include perivascular deposition of immunoglobulin and activated complement, loss of astrocytic AQP4, inflammatory infiltration with granulocyte and macrophage accumulation, and demyelination with axon loss. Current evidence supports a causative role of AQP4-IgG in NMO, in which binding of AQP4-IgG to AQP4 orthogonal arrays on astrocytes initiates complement-dependent and antibody-dependent cell-mediated cytotoxicity and inflammation. Immunosuppression and plasma exchange are the mainstays of therapy for NMO optic neuritis. Novel therapeutics targeting specific steps in NMO pathogenesis are entering the development pipeline, including blockers of AQP4-IgG binding to AQP4 and inhibitors of granulocyte function. However, much work remains in understanding the unique susceptibility of the optic nerves in NMO, in developing animal models of NMO optic neuritis, and in improving therapies to preserve vision.

show abstract

“…Only the CNS is damaged by NMO disease, but NMO-IgG has access to peripheral AQP4-bearing tissues (Lennon, Kryzer et al 2005; Pohl, Fischer et al 2011). It has been proposed that a specific conformation or isoform may be enriched in the optic nerve and spinal cord to account for the distribution of lesions in NMO, while other brain regions or peripheral organs are spared (Saini, Fernandez et al 2010). However, adsorption of NMO-IgG to AQP4-expressing cells before infusion can dampen its pathogenic potency (Bradl, Misu et al 2009), arguing against this mechanism.…”

Section: Pathological Potential Of Nmo-igg By Passive Transfermentioning

confidence: 99%

“…NMO is unique among inflammatory diseases of the central nervous system (CNS) in that 33–91% of patients worldwide test positive for the NMO-IgG biomarker (Jarius and Wildemann 2010), an antibody that targets the aquaporin-4 (AQP4) water channel on the endfeet of astrocytes (Lennon, Kryzer et al 2005). The discovery of the NMO-IgG in 2004 (Lennon, Wingerchuk et al 2004) created a surge of research publications on the prospect that the NMO-IgG may be pathogenic in inducing or exacerbating the disease by binding to AQP4 in susceptible CNS tissues (Roemer, Parisi et al 2007; Saini, Fernandez et al 2010). Building on decades of research on rodent models of multiple sclerosis, several groups have turned to rats and mice to understand the pathogenesis of NMO with specific questions about the roles of the NMO-IgG and AQP4.…”

Section: Introductionmentioning

confidence: 99%

Review of animal models of neuromyelitis optica

Jones

Collongues

Seze

et al. 2012

Multiple Sclerosis and Related Disorders

Self Cite

View full text Add to dashboard Cite

Neuromyelitis optica (NMO) is a recurrent neuroinflammatory disease of the optic nerves and spinal cord associated with the anti-aquaporin-4 (AQP4) antibody biomarker, NMO-IgG. As clinical and scientific research interest in NMO grows, the need for an animal model becomes more urgent. Over the past few years, several groups have developed rodent models that partially represent human NMO disease. Passive transfer of the NMO-IgG is not pathogenic alone, but in certain contexts can recruit granulocytes and lead to increased inflammation. Studies of the cellular immune response against AQP4 have also shed light on the roles of B and T cells in NMO, especially focusing on the role of Th17 T helper cells. This review discusses the contribution of the available NMO animal models to the understanding of NMO disease pathogenesis.

show abstract

Differential expression of aquaporin-4 isoforms localizes with neuromyelitis optica disease activity

Cited by 28 publications

References 19 publications

Fine specificity of antibodies against AQP4: Epitope mapping reveals intracellular epitopes

Fine specificity of antibodies against AQP4: Epitope mapping reveals intracellular epitopes

Optic neuritis in neuromyelitis optica

Review of animal models of neuromyelitis optica

Contact Info

Product

Resources

About