Myelin proteolipid protein: An effective autoantigen and target of autoimmunity in multiple sclerosis

Greer, Judith M.; Pender, Michael P.

doi:10.1016/j.jaut.2008.04.018

Cited by 39 publications

(25 citation statements)

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“…The tetraspan protein plays a major role in the structure and function of myelin (Klugmann et al., 1997) and is thought to be a possible immunogen for multiple sclerosis (MS; Pender and Greer, 2007; Greer and Pender, 2008). PLP is important for communication between oligodendrocytes and axons (Gruenenfelder et al., 2011).…”

Section: Introductionmentioning

confidence: 99%

Effects of Intron 1 Sequences on Human PLP1 Expression: Implications for PLP1-Related Disorders

Wight

2017

ASN Neuro

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Alterations in the myelin proteolipid protein gene (PLP1) may result in rare X-linked disorders in humans such as Pelizaeus–Merzbacher disease and spastic paraplegia type 2. PLP1 expression must be tightly regulated since null mutations, as well as elevated PLP1 copy number, both lead to disease. Previous studies with Plp1-lacZ transgenic mice have demonstrated that mouse Plp1 (mPlp1) intron 1 DNA (which accounts for slightly more than half of the gene) is required for the mPlp1 promoter to drive significant levels of reporter gene expression in brain. However not much is known about the mechanisms that control expression of the human PLP1 gene (hPLP1). Therefore this review will focus on sequences in hPLP1 intron 1 DNA deemed important for hPLP1 gene activity as well as a couple of “human-specific” supplementary exons within the first intron which are utilized to generate novel splice variants, and the potential role that these sequences may play in PLP1-linked disorders.

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Section: Introductionmentioning

confidence: 99%

Effects of Intron 1 Sequences on Human PLP1 Expression: Implications for PLP1-Related Disorders

Wight

2017

ASN Neuro

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“…One of the brain's auto-antigens is proteolipid protein (PLP); the most abundant autoantigen in the CNS myelin. It plays an important role in the stability of the structure and the function of the myelinated neurons (11,12). Solely, PLP composes about 50% of the total CNS myelin proteins.…”

Section: Introductionmentioning

confidence: 99%

“…PLP is able to induce autoimmune encephalomyelitis experimentally in the rodents and non-human primates. Its post-translational modifi cation, acylation, makes PLP an eff ective autoantigen (11,15).…”

Section: Introductionmentioning

confidence: 99%

In Silico Perspectives on the Prediction of the PLP’s Epitopes involved in Multiple Sclerosis

Zamanzadeh

Ataei

Nabavi

et al. 2017

Iran. J. Biotechnol.

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Background Multiple sclerosis (MS) is the most common autoimmune disease of the central nervous system (CNS). The main cause of the MS is yet to be revealed, but the most probable theory is based on the molecular mimicry that concludes some infections in the activation of T cells against brain auto-antigens that initiate the disease cascade. Objectives The Purpose of this research is the prediction of the auto-antigen potency of the myelin proteolipid protein (PLP) in multiple sclerosis. Materials and Methods As there wasn’t any tertiary structure of PLP available in the Protein Data Bank (PDB) and in order to characterize the structural properties of the protein, we modeled this protein using prediction servers. Meta prediction method, as a new perspective in silico, was performed to fi nd PLPs epitopes. For this purpose, several T cell epitope prediction web servers were used to predict PLPs epitopes against Human Leukocyte Antigens (HLA). The overlap regions, as were predicted by most web servers were selected as immunogenic epitopes and were subjected to the BLASTP against microorganisms. Results Three common regions, AA58-74, AA161-177, and AA238-254 were detected as immunodominant regions through meta-prediction. Investigating peptides with more than 50% similarity to that of candidate epitope AA58-74 in bacteria showed a similar peptide in bacteria (mainly consistent with that of clostridium and mycobacterium) and spike protein of Alphacoronavirus 1, Canine coronavirus, and Feline coronavirus. These results suggest that cross reaction of the immune system to PLP may have originated from a bacteria or viral infection, and therefore molecular mimicry might have an important role in the progression of MS. Conclusions Through reliable and accurate prediction of the consensus epitopes, it is not necessary to synthesize all PLP fragments and examine their immunogenicity experimentally (in vitro). In this study, the best encephalitogenic antigens were predicted based on bioinformatics tools that may provide reliable results for researches in a shorter time and at a lower cost.

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“…In this respect, it has been suggested that antibodies against PLP, which are abundant in MS patients (Greer and Pender, 2008), might play a role in this, as PLP has been shown to complex with adhesion molecules to facilitate cell migration (Gudz et al, 2006).…”

Section: Other Potential Pathogenic Roles Of Autoantibodiesmentioning

confidence: 99%

“…There are several ways in which the potential pathogenicity of autoantibodies could be explored, and initially the intent of this thesis was to use an animal model utilising C3H/HeJ mice to explore the pathogenic role of antibodies, as work from the lab had previously suggested that these antibodies might play a pathogenic role (Greer and Pender, 2008;Muller et al, 2005). However, following the building of a new animal house shortly after this thesis was commenced, many issues arose with the development of disease in this animal model, and unfortunately the model had to be abandoned, as disease could no longer be reliably induced in the mice.…”

Section: Introductionmentioning

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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Myelin proteolipid protein: An effective autoantigen and target of autoimmunity in multiple sclerosis

Cited by 39 publications

References 70 publications

Effects of Intron 1 Sequences on Human PLP1 Expression: Implications for PLP1-Related Disorders

Effects of Intron 1 Sequences on Human PLP1 Expression: Implications for PLP1-Related Disorders

In Silico Perspectives on the Prediction of the PLP’s Epitopes involved in Multiple Sclerosis

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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