Autoantibodies and their potential roles in diseases of the nervous system

Beasley, Shannon J.; Greer, Judith M.

doi:10.1111/cen3.12269

Cited by 8 publications

(9 citation statements)

References 157 publications

(291 reference statements)

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“…There are many ways in which anti-PLP antibodies, particularly those targeting epitopes on the extracellular surfaces of oligodendrocytes or myelin, could potentially have an impact in MS, including mechanisms such as complement-mediated lysis, antibody mediated cell cytotoxicity, modulation of cell architecture, opsonization of myelin or myelin debris leading to increased activation of phagocytic cells ( 19 ). In a C3H/HeJ mouse model in which demyelinating disease can be induced by immunization with PLP 190−209 , we have previously reported that mice that can make a T cell response, but not an antibody response, develop lesions in the brainstem, but not in the cerebellum, whereas in the presence of both T cells and antibodies specific for PLP 190−209 there is development of lesions in both the brainstem and the cerebellum ( 23 , 25 ).…”

Section: Discussionmentioning

confidence: 99%

“…Numerous published studies have reported antibodies directed against myelin proteins (2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12) or other CNS antigens (13)(14)(15)(16)(17)(18) in CSF or serum of MS patients, but only a small number of these studies have attempted to determine whether these antibodies are potentially pathogenic (3,7,15,18). In some cases, antibodies in MS patients may be merely an epiphenomenon; however, there are multiple examples in the non-MS literature of how antibodies targeting CNS tissues can be directly pathogenic (reviewed in (19)), and the chance that antibodies present in at least some patients with MS are pathogenic is relatively high.…”

Section: Introductionmentioning

confidence: 99%

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Correlation Between Anti-Myelin Proteolipid Protein (PLP) Antibodies and Disease Severity in Multiple Sclerosis Patients With PLP Response-Permissive HLA Types

2020

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The most prominent pathological features of multiple sclerosis (MS) are demyelination and neurodegeneration. The exact pathogenesis of MS is unknown, but it is generally regarded as a T cell-mediated autoimmune disease. Increasing evidence, however, suggests that other components of the immune system, particularly B cells and antibodies, contribute to the cumulative CNS damage and worsening disability that characterize the disease course in many patients. We have previously described strongly elevated T cell reactivity to an extracellular domain of the most abundant CNS myelin protein, myelin proteolipid protein (PLP) in people with MS. The current paper addresses the question of whether this region of PLP is also a target of autoantibodies in MS. Here we show that serum levels of isotype-switched anti-PLP 181−230 specific antibodies are significantly elevated in patients with MS compared to healthy individuals and patients with other neurological diseases. These anti-PLP 181−230 antibodies can also live-label PLP-transfected cells, confirming that they can recognize native PLP expressed at the cell surface. Importantly, the antibodies are only elevated in patients who carry HLA molecules that allow strong T cell responses to PLP. In that subgroup of patients, there is a positive correlation between the levels of anti-PLP 181−230 antibodies and the severity of MS. These results demonstrate that anti-PLP antibodies have potentially important roles to play in the pathogenesis of MS.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Correlation Between Anti-Myelin Proteolipid Protein (PLP) Antibodies and Disease Severity in Multiple Sclerosis Patients With PLP Response-Permissive HLA Types

2020

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“…In disorders affecting the nervous system, autoantibodies can exert pathogenic effects via a wide range of mechanisms, including antibody-mediated cell lysis, opsonisation of target proteins for attack by macrophages, crosslinking of Fc receptors, blocking or removing receptors involved in neurotransmission or cellular homeostasis or blocking of repair mechanisms (Beasley and Greer, 2015). It is possible for more than one of these mechanisms to be active in the same disease.…”

Section: Potential Functional (Pathogenic) Effects Of Antibodies Targmentioning

confidence: 99%

Is there a role for antibodies targeting muscarinic acetylcholine receptors in the pathogenesis of schizophrenia?

Ryan

Mowry

Kesby

et al. 2019

Aust N Z J Psychiatry

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Objective: Muscarinic receptor dysfunction has been suggested to play an important role in the pathophysiology of schizophrenia. Recently, it has also become clear that immune reactivity directed against neurotransmitter receptors may play a pathogenic role in some cases of schizophrenia. The aim of this review is to summarize the case for muscarinic receptor dysfunction in schizophrenia and the evidence supporting the hypothesis that this dysfunction is related to the development of muscarinic receptor–targeting antibodies. Method: The article reviews studies of muscarinic receptors and the presence and potential role(s) of anti-muscarinic acetylcholine receptor antibodies in people with schizophrenia. Results: There is accumulating evidence that altered or deficient muscarinic signalling underlies some of the key clinical features of schizophrenia. Although the number of studies investigating anti-muscarinic acetylcholine receptor antibodies in schizophrenia is relatively small, they consistently demonstrate that such antibodies are present in a proportion of patients. This evidence suggests that these antibodies could have pathogenic effects or exist as a biomarker to an unknown pathophysiological process in schizophrenia. Conclusion: The presence of elevated levels of anti-muscarinic acetylcholine receptor antibodies may identify a subgroup of people with schizophrenia, potentially informing aetiopathogenesis, clinical presentation and treatment. To date, all studies have examined antibodies in participants with chronic schizophrenia, who have likely received antipsychotic medication for many years. As these medications modulate immune functions and regulate receptor densities, it is recommended that future studies screen for the presence of anti-muscarinic antibodies in people experiencing their first episode of psychosis.

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“…Given the findings in the current chapter, another potential future direction would be to transfect cells with the glutamate transporter molecules against which some patient sera appear to show strong antibody reactivity, and screen much larger panels of sera. Finally, it has to be remembered that the potential functional roles of autoantibodies in MS and other autoimmune demyelinating diseases don't necessarily stop at complement-mediated ADCC or opsonization: there are many other ways in which antibodies could act (recently reviewed in Beasley and Greer, 2015), and it may be necessary to investigate those before we gain a full understanding of the role of autoantibodies in diseases such as MS.…”

Section: 4mentioning

confidence: 99%

“…Therefore, even though an antibody might be directed against an epitope that has the correct specificity, it will not be able to induce complement-mediated lysis if it is not of an isotype that can bind complement. However, such antibodies might be able to act in other ways, for example by opsonization of target proteins for attack by macrophages, crosslinking of Fc receptors, blocking or destroying receptors involved in cellular homeostasis, and blocking of repair mechanisms such as remyelination (recently reviewed in Beasley and Greer, 2015).…”

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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Autoantibodies and their potential roles in diseases of the nervous system

Cited by 8 publications

References 157 publications

Correlation Between Anti-Myelin Proteolipid Protein (PLP) Antibodies and Disease Severity in Multiple Sclerosis Patients With PLP Response-Permissive HLA Types

Correlation Between Anti-Myelin Proteolipid Protein (PLP) Antibodies and Disease Severity in Multiple Sclerosis Patients With PLP Response-Permissive HLA Types

Is there a role for antibodies targeting muscarinic acetylcholine receptors in the pathogenesis of schizophrenia?

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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