Author Topic: Article about the KIR4.1 debate  (Read 128 times)

0 Members and 1 Guest are viewing this topic.

Offline Matt2

  • Trailblazer - Rest In Peace
  • *
  • Posts: 975
Article about the KIR4.1 debate
« on: November 10, 2014, 11:34:01 am »
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
Click to toggle image size
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. 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

Offline agate

  • Administrator
  • *****
  • Posts: 9822
  • MS diagnosed 1980
  • Location: Pacific Northwest
Re: Article about the KIR4.1 debate
« Reply #1 on: November 10, 2014, 11:39:47 am »
Matt, thanks so much for posting this!
MS Speaks--online for 17 years

SPMS, diagnosed 1980. Avonex 2001-2004. Copaxone 2007-2010. Glatopa (glatiramer acetate 40mg 3 times/week) since 12/16/20.