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#Post#: 548--------------------------------------------------
Article about the KIR4.1 debate
DIR By: Matt2
Date: November 10, 2014, 3:34 pm
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The Lancet Neurology, Volume 13, Issue 8, Pages 753 - 755,
August 2014 <Previous Article|Next Article>
doi:10.1016/S1474-4422(14)70149-8Cite or Link Using DOI
This article can be found in the following collections:
Neurology (Multiple sclerosis)
Published Online: 07 July 2014
Copyright © 2014 Elsevier Ltd All rights reserved.
KIR4.1: another misleading expectation in multiple sclerosis?
Massimo Filippi a bEmail Address, Maria A Rocca a b, Hans
Lassmann c
The identification of a biomarker for the diagnosis, prognosis,
and monitoring of patients with multiple sclerosis is needed.
Several biomarkers have been proposed (eg, immunological and
clinical markers) but have had disappointing results.
Pathological changes in the immunological response in patients
with multiple sclerosis affect not only T cells, but also B
cells, and increase immunoglobulin synthesis in the CSF,
oligoclonal bands, and complement deposition; therefore, CNS
antigens have been regarded as potential autoimmune targets.
Such research has been fuelled by the discovery of a pathogenic
antibody against the aquaporin-4 channel in neuromyelitis
optica, which has revolutionised the diagnosis and treatment of
this disorder.1
A serum autoantibody specific for multiple sclerosis would
profoundly affect the diagnostic work-up of people suspected of
having this disease, the monitoring of disease evolution, and
ultimately treatment. In 2012, KIR4.1 (also known as KCNJ10) was
proposed as the target of IgG antibodies in a proportion of
patients with multiple sclerosis.2 Using ELISA, serum antibodies
against KIR4.1 were detected in 47% of 397 patients with
multiple sclerosis, 1% of 329 patients with other neurological
diseases, and none of 59 healthy donors.2 Only two of 19
patients who were serum IgG positive had detectable
concentrations of KIR4.1 antibodies in the CSF, which is not
surprising considering the high expression of the target antigen
on the surface of CSF cells, which might lead to absorption of
antibodies from the extracellular space and CSF.3 Using the same
method, KIR4.1 serum antibodies have been reported in roughly
57% of paediatric patients with acquired demyelinating diseases
and more than 50% of paediatric patients with multiple sclerosis
or clinically isolated syndromes,4 independently of the presence
of antibodies against myelin oligodendrocyte glycoproteins.
According to these data, KIR4.1 would be an excellent candidate
for a pathogenic antibody in multiple sclerosis, since
demyelination associated with complement activation has been
reported in about half of patients in pathological-histological
studies of early multiple sclerosis,5 and a similar incidence of
reactivity to oligodendrocytes by serum IgG from patients with
multiple sclerosis has been reported.6 The prevalence of
anti-KIR4.1 antibodies in patients with multiple sclerosis has
been questioned in a few studies,7, 8 including a study by
Brickshawana and colleagues,8 the results of which are reported
in The Lancet Neurology.
KIR4.1 is an inward rectifying potassium channel expressed on
oligodendrocytes and the endfeet of astrocytes (including
retinal Müller glia and Hensen's and Claudius' cells in the
cochlea). It contributes to the maintenance of electrochemical
gradient by removing potassium from the extracellular space and
to the maintenance of potassium and water balance by acting in
concert with aquaporin-4 to maintain osmotic homoeostasis.
Similar to aquaporin-4, KIR4.1 is not uniquely expressed in CNS
cells—it is present also in the retina, kidney, and parietal
cells of gastric mucosal epithelium.9 Antibodies against
parietal cells have been detected in the sera of patients with
multiple sclerosis, particularly in those with gastrointestinal
disturbances.10 Therefore, the occurrence of antibodies against
KIR4.1 might merely be an epiphenomenon rather than a sign of
causality.
A study by Nerrant and colleagues,7 using ELISA, reported that
only 7·5% of 268 patients with multiple sclerosis had
anti-KIR4.1 antibodies, and that this proportion did not
significantly differ to those of healthy controls or patients
with other neurological diseases; immunofluorescence analysis
did not detect any specific staining. Brickshawana and
colleagues8 detect reactivity to KIR4.1 in sera of three (<1%)
of 268 people with multiple sclerosis and two (<1%) of 208
controls.
Click to toggle image size
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Full-size image (91K) Animated Healthcare Ltd/Science Photo
Library
The discrepancies between the results of Srivastava and
colleagues' study2 and those reported by others (Nerrant and
colleagues7 and Brickshawana and colleagues8) are difficult to
explain, since very similar techniques were used for the
detection of KIR4.1 antibodies. However, in a subsequent study
from the Munich group (Schirmer and colleagues11), tetramers or
high-order polymers of KIR4.1 were used for antibody detection
in the ELISA assay. This approach might be important, since such
human channel antibodies might be directed against
conformational epitopes, which might be detected with higher
affinity in clustered proteins within the cell membrane, but
binding of the antibodies might still be blocked by a specific
competing peptide as shown by Srivastava and colleagues.2 Thus,
whether subtle differences in the detection assays between the
studies2, 7, 8, 11 might explain the divergent results awaits
further clarification.
When KIR4.1 antibodies, which are directed against epitopes
expressed on the surface of oligodendrocytes or astrocytes, are
present in patients with multiple sclerosis, the cells
recognised by these antibodies are thought to be destroyed in a
complement-dependent manner in early stages of the development
of multiple sclerosis lesions. Furthermore, a selective loss of
KIR4.1 from the remaining glia is expected. Studies by the
Munich group2, 11 suggest that both complement activation and
selective loss of KIR4.1 occur in active multiple sclerosis
lesions; Brickshawana and colleagues8 report no KIR4.1 loss from
glia in early active demyelinating lesions, but rather an
apparent increase in astrocytic and oligodendrocytic KIR4.1
immunoreactivity in early active and remyelinated plaques and in
periplaque white matter. The interpretation of these findings is
challenging, since KIR4.1 might occur as homotetramers in
oligodendrocytes and as heterotetramers with KIR5.1 in
astrocytes.11 Furthermore, KIR4.1 loss will also occur when
oligodendrocytes are lost in the demyelinating process or
astrocyte processes are damaged by mechanisms independent of
antibody-mediated and complement-mediated immune reactions.12
Finally, technical issues of immunocytochemistry (eg, use of
frozen vs paraffin sections) and exact staging of lesions might
partly differ between the studies.
Do these findings, from independent research groups, mean that
research into KIR4.1 in multiple sclerosis should end? We hope
not. The reasons for the discrepancies between the
investigations might be at least partly technical and call for
additional work. Pathological studies using different analytical
approaches are also warranted to deepen the understanding of
this potentially revolutionary aspect of multiple sclerosis
research. Many unanswered questions related to KIR4.1 function
still remain. The coexpression of KIR4.1 and aquaporin-4
channels in endfeet of astrocytes and their synergistic effect
in maintaining osmotic homoeostasis is intriguing, especially
when considering that most retinal pathological changes
characterised by Müller cell damage are accompanied by changes
of the amount or spatial distribution of both channels. Finally,
the potential relation between anti-KIR4.1 antibodies and a more
general dysfunction of immune-mediated mechanisms in patients
with multiple sclerosis deserves further investigation.
MF serves on the scientific advisory board for Teva
Pharmaceutical Industries; has received compensation for
consulting services or speaking activities from Bayer Schering
Pharma, Biogen Idec, Merck Serono, and Teva Pharmaceutical
Industries; and receives research support from Bayer Schering
Pharma, Biogen Idec, Merck Serono, Teva Pharmaceutical
Industries, Italian Ministry of Health, Fondazione Italiana
Sclerosi Multipla, Cure PSP, and the Jacques and Gloria
Gossweiler Foundation (Switzerland). MAR has received speakers'
honoraria from Novartis, Biogen Idec, and Serono Symposia
International Foundation and receives research support from the
Italian Ministry of Health and Fondazione Italiana Sclerosi
Multipla. HL has received honoraria for lectures from Teva,
Novartis, and Biogen and served as a consultant for Amgen and
Baxter.
References
1 Lennon VA, Wingerchuk DM, Kryzer TJ, et al. A serum
autoantibody marker of neuromyelitis optica: distinction from
multiple sclerosis. Lancet 2004; 364: 2106-2112. Summary | Full
Text | PDF(1049KB) | CrossRef | PubMed
2 Srivastava R, Aslam M, Kalluri SR, et al. Potassium channel
KIR4.1 as an immune target in multiple sclerosis. N Engl J Med
2012; 367: 115-123. CrossRef | PubMed
3 Bradl M, Misu T, Takahashi T, et al. Neuromyelitis optica:
pathogenicity of patient immunoglobulin in vivo. Ann Neurol
2009; 66: 630-643. CrossRef | PubMed
4 Kraus V, Srivastava R, Kalluri SR, et al. Potassium channel
KIR4.1-specific antibodies in children with acquired
demyelinating CNS disease. Neurology 2014; 82: 470-473. CrossRef
| PubMed
5 Lucchinetti C, Bruck W, Parisi J, Scheithauer B, Rodriguez M,
Lassmann H. Heterogeneity of multiple sclerosis lesions:
implications for the pathogenesis of demyelination. Ann Neurol
2000; 47: 707-717. CrossRef | PubMed
6 Lily O, Palace J, Vincent A. Serum autoantibodies to cell
surface determinants in multiple sclerosis: a flow cytometric
study. Brain 2004; 127: 269-279. CrossRef | PubMed
7 Nerrant E, Salsac C, Charif M, et al. Lack of confirmation of
anti-inward rectifying potassium channel 4.1 antibodies as
reliable markers of multiple sclerosis. Mult Scler
201410.1177/1352458514531086. published online April 22. PubMed
8 Brickshawana A, Hinson SR, Romero MF, et al. Investigation of
the KIR4.1 potassium channel as a putative antigen in patients
with multiple sclerosis: a comparative study. Lancet Neurol
2014. published online July 7.
HTML http://dx.doi.org/10.1016/S1474-4422(14)70141-3.
9 Jin X, Yu L, Wu Y, et al. S-Glutathionylation underscores the
modulation of the heteromeric Kir4.1-Kir5.1 channel in oxidative
stress. J Physiol 2012; 590: 5335-5348. CrossRef | PubMed
10 Banati M, Csecsei P, Koszegi E, et al. Antibody response
against gastrointestinal antigens in demyelinating diseases of
the central nervous system. Eur J Neurol 2013; 20: 1492-1495.
PubMed
11 Schirmer L, Srivastava R, Kalluri SR, et al. Differential
loss of KIR4.1 immunoreactivity in multiple sclerosis lesions.
Ann Neurol 201410.1002/ana.24168. published online April 29.
PubMed
12 Sharma R, Fischer MT, Bauer J, et al. Inflammation induced by
innate immunity in the central nervous system leads to primary
astrocyte dysfunction followed by demyelination. Acta
Neuropathol 2010; 120: 223-236. CrossRef | PubMed
a Neuroimaging Research Unit, Institute of Experimental
Neurology, Division of Neuroscience, Scientific Institute and
University Ospedale San Raffaele, 20132 Milan, Italy
b Department of Neurology, Scientific Institute and University
Ospedale San Raffaele, 20132 Milan, Italy
c Center for Brain Research, Medical University of Vienna,
Austria
#Post#: 550--------------------------------------------------
Re: Article about the KIR4.1 debate
DIR By: agate
Date: November 10, 2014, 3:39 pm
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Matt, thanks so much for posting this!
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