Differential loss of KIR4.1 immunoreactivity in multiple sclerosis lesions

Schirmer, Lucas; Srivastava, Rajneesh; Kalluri, Sudhakar Reddy; Böttinger, Susanne; Herwerth, Marina; Carassiti, Daniele; Srivastava, Barkha; Gempt, Jens; Schlegel, Jürgen; Kuhlmann, Tanja; Korn, Thomas; Reynolds, Richard; Hemmer, Bernhard

doi:10.1002/ana.24168

Cited by 43 publications

(39 citation statements)

References 57 publications

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“…Sera from 16 MS patients bound faintly to intracellular components [8] . Our further neuropathological assessment also showed no typical KIR4.1 loss, as has been described in a previous study [17] . Therefore, the occurrence of antibodies against KIR4.1 might be merely an epiphenomenon rather than a sign of causality [20] .…”

Section: Discussionsupporting

confidence: 87%

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Anti-KIR4.1 Antibodies in Chinese Patients with Central Nervous System Inflammatory Demyelinating Disorders

Zhong

Liang²,

Tao³

et al. 2016

Neuroimmunomodulation

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Objectives: The aim of this study was to explore the frequency of KIR4.1 antibodies in patients with multiple sclerosis (MS) and in control groups using a cell-based assay. Materials and Methods: A transfected HEK-293A cell line expressing KIR4.1 was established to test for the presence of KIR4.1 antibodies in blood serum. We tested 904 subjects, including 188 patients with MS, 264 patients with neuromyelitis optica spectrum disorders (NMOSD), 209 patients with other inflammatory neurologic disease (OIND), 203 patients with other noninflammatory neurological disease (OND), and 40 healthy controls. Results: KIR4.1 antibodies were present in 23 of the 188 (12.2%) MS patients, 42 of the 264 (15.9%) NMOSD patients, 32 of the 209 (15.3%) OIND patients, 24 of the 203 (11.8%) OND patients, and 2 of the 40 (5%) healthy controls. There were no significant differences among the MS and control groups (p = 0.279). Conclusions: Anti-KIR4.1 antibody, as determined by a cell-based assay, is not a specific biomarker for MS.

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Section: Discussionsupporting

confidence: 87%

“…Thus, anti-KIR4.1 antibodies are an interesting candidate as a suitable biomarker for MS [5,6,17] . In this study, we successfully established a HEK-293A cell line overexpressing KIR4.1, which was confirmed by quantitative polymerase chain reaction and Western blot analysis.…”

Section: Discussionmentioning

confidence: 99%

Anti-KIR4.1 Antibodies in Chinese Patients with Central Nervous System Inflammatory Demyelinating Disorders

Zhong

Liang²,

Tao³

et al. 2016

Neuroimmunomodulation

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“…Srivastava and colleagues used a proteomic approach focusing on membrane proteins, and they identified the ATP-sensitive inward rectifying potassium channel KIR4.1 as the target of serum IgG of MS patients, but not controls [9]. Serum antibodies to KIR4.1 were also detectable in the majority of children with acquired demyelinating CNS disorders [10], and the same group reported on a differential loss of KIR4.1 immuno-reactivity in multiple sclerosis lesions [11]. The data has not yet been confirmed by independent groups [12].…”

Section: B Cells In Multiple Sclerosismentioning

confidence: 99%

CD19 as a molecular target in CNS autoimmunity

et al. 2014

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Multiple sclerosis (MS) and neuromyelitis optica (NMO) are the most prevalent neuroinflammatory diseases of the central nervous system (CNS). The immunological cascade of these disorders is complex, and the exact spatial and temporal role of different immune cells is not fully understood. Although MS has been considered for many years to be primarily T cell driven, it is well established that B cells and the humoral immune response play an important role in its pathogenesis. This has long been evident from laboratory findings that include the presence of oligoclonal bands in the CSF. In NMO the importance of the humoral immune system appears even more obvious as evidenced by pathogenic antibodies against aquaporin 4 (AQP4). Besides their capacity to mature into antibody-producing plasma cells, B cells are potent antigen presenting cells to T lymphocytes and they can provide soluble factors for cell activation and differentiation to other immune-competent cells. In MS and NMO, there are substantial data from clinical trials that B cell depletion with CD20-directed agents is effective and relatively safe. Plasma cells, which produce antibodies against molecular targets expressed by the host, but which also provide humeral immune responses against pathogens, are not targeted by anti-CD20 therapies. Therefore the depletion of CD19-expressing cells would offer potential advantages with regard to efficacy, but potentially higher risks with regard to infectious complications. This review will outline the rationale for CD19 as a molecular target in CNS autoimmunity. The current stage of drug development is illustrated. Potential safety concerns will be discussed.

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“…Despite the presence of these OCB in MS patients, the specificity and functional relevance of these OCB, and of other autoantibodies found in MS patients, remain obscure. The original consensus was that these antibodies would be likely to attack components of CNS myelin (since demyelination is the predominant feature of MS), or the myelin-producing cells (oligodendrocytes); however, it has more recently become clear that autoantibodies may also target other CNS cells, such as neurons and astrocytes (de Bock et al, 2014;Schirmer et al, 2014;Vyshkina and Kalman, 2008). In addition, there does not appear to be a single specific antigen that is targeted in all patients.…”

Section: Multiple Sclerosis (Ms)mentioning

confidence: 99%

“…One point that has been noted with regards to K ir 4.1, which could potentially be relevant to the glutamate transporter molecules, is that the configuration of K ir 4.1 is slightly different in astrocytes and oligodendrocytes: in oligodendrocytes it occurs as a homotetramer, but in astrocytes it can occur in a heterotetramer with K ir 5.1. (Schirmer et al, 2014). Therefore, antibodies recognizing a homotetrameric K ir 4.1 structure on oligodendrocytes may not necessarily recognize the combination of K ir 4.1 and K ir 5.1 as the heterotetramer on astrocytes.…”

Section: Principal Findings Of the Thesismentioning

confidence: 99%

Development of a simple in vitro mature mixed glial model to investigate differential expression of cell markers on glial cells and their potential as targets in multiple sclerosis

Beasley¹

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Autoantibodies are present in many patients with demyelinating diseases and have been shown to have pathogenic potential in the case of people with neuromyelitis optica (NMO). However, it is still debated whether antibodies that are present in people with multiple sclerosis (MS) are pathogenic. There are multiple different mechanisms by which autoantibodies could exert their effects in MS, and they could potentially target any cell/structure within the central nervous system (CNS), although the focus of antibody studies in MS has been almost solely on myelin antigens. Recently, however, some evidence has suggested that astrocytes could also be targeted in MS. Therefore, there is a need for a simple but robust in vitro model to allow the testing of antibodies against oligodendrocytes and astrocytes. The hypothesis tested in this thesis is that a cell culture model containing a mixture of mature glial cells could be a useful model by which to test the pathogenicity of the antibodies from people with MS, and the antigens that they are targeting. In order to test this hypothesis, this thesis set out to develop a mature mixed glial cell culture model, to test whether one cell type could be killed without impacting on the health of the other cells, and to then use this model to test antibodies from people with MS.Chapter 2 describes the development of a rat neonatal-derived mature mixed glial culture. A method was developed that allowed cultures with a mixture of protoplasmic (type 1) and fibrous (type 2) astrocytes to grow alongside mature oligodendrocytes. This method did not rely on addition of extra growth factors, presumably due to the production of all factors required for growth of each cell type by the other cells in the mixed culture. Because of this co-dependence on the other cells in the mixed culture for growth and development, the next step was to test whether specific targeting (killing) of one cell would result in the death of the other cells in culture, as that could potentially interfere with the interpretation of results in later chapters investigating the effects of antibodies in patient sera. In Chapter 3, it was found that oligodendrocytes could be selectively targeted (using a commercially-available antibody against sulfatide) and the astrocytes remained unaffected. It proved to be more difficult to find a cell surface-expressed molecule that could target only astrocytes and not have ii adverse effects on oligodendrocytes. In the literature, one molecule that is generally considered to be expressed on astrocytes, but not oligodendrocytes, is GLAST, a glutamate transporter. Initial studies using an antibody against the intracellular N-terminus of GLAST confirmed that only astrocytes in culture were stained by this antibody. An antibody was therefore generated that was specific for an epitope of GLAST ) that is expressed on the extracellular side of the membrane. However, when this antibody was tested for its ability to kill astrocytes in culture, both oligodendrocytes and astrocytes were ...

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Differential loss of KIR4.1 immunoreactivity in multiple sclerosis lesions

Abstract: The expression profile of KIR4.1 in glial cells and stage-dependent alterations of KIR4.1 IR in MS lesions are compatible with an immune response against KIR4.1 at least in a subset of MS patients.

Cited by 43 publications

References 57 publications

Anti-KIR4.1 Antibodies in Chinese Patients with Central Nervous System Inflammatory Demyelinating Disorders

Anti-KIR4.1 Antibodies in Chinese Patients with Central Nervous System Inflammatory Demyelinating Disorders

CD19 as a molecular target in CNS autoimmunity

Development of a simple in vitro mature mixed glial model to investigate differential expression of cell markers on glial cells and their potential as targets in multiple sclerosis

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