Inhibition of Glyceraldehyde-3-Phosphate Dehydrogenase Activity by Antibodies Present in the Cerebrospinal Fluid of Patients with Multiple Sclerosis

Kölln, Johanna; Zhang, Yiping; Thai, Gaby; Demetriou, Michael A.; Hermanowicz, Neal; Duquette, Pierre; Noort, Stanley van den; Qin, Yingzhi

doi:10.4049/jimmunol.0904083

Cited by 14 publications

(11 citation statements)

References 69 publications

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“…Axonal reactivity was demonstrated to be specific for the glycolytic enzymes triosephosphate ismerase (TPI) and glyceraldehyde-3-phosphate dehydrogenase (GAPDH) (Kolln et al, 2006). In a subsequent study, it was shown that the CSF antibodies were able to inhibit GAPDH, but not TPI, activity, suggesting a mechanism for neurodegeneration (Kolln et al, 2010 ). However, recently, antibody clones isolated from the CSF of MS patients were unable to bind specific myelin proteins, indicating that CSF antibody specificity may be more complex that previously appreciated (Owens et al, 2009).…”

Section: B Cells and Msmentioning

confidence: 99%

A case for regulatory B cells in controlling the severity of autoimmune-mediated inflammation in experimental autoimmune encephalomyelitis and multiple sclerosis

Ray

Mann

Basu

et al. 2011

Journal of Neuroimmunology

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Multiple sclerosis (MS) is considered to be a T cell-mediated autoimmune disease that results in the presence of inflammatory lesions/plaques associated with mononuclear cell infiltrates, demyelination and axonal damage within the central nervous system (CNS). To date, FDA approved therapies in MS are thought to largely function by modulation of the immune response. Since autoimmune responses require many arms of the immune system, the direct cellular mechanisms of action of MS therapeutics are not definitively known. The mouse model of MS, experimental autoimmune encephalomyelitis (EAE), has been instrumental in deciphering the mechanism of action of MS drugs. In addition, EAE has been widely used to study the contribution of individual components of the immune system in CNS autoimmunity. In this regard, the role of B cells in EAE has been studied in mice deficient in B cells due to genetic ablation and following depletion with a B cell-targeted monoclonal antibody (mAb) (anti-CD20). Both strategies have indicated that B cells regulate the extent of EAE clinical disease and in their absence disease is exacerbated. Thus a new population of “regulatory B cells” has emerged. One reoccurring component of regulatory B cell function is the production of IL-10, a pleiotropic cytokine with potent anti-inflammatory properties. B cell depletion has also indicated that B cells, in particular antibody production, play a pathogenic role in EAE. B cell depletion in MS using a mAb to CD20 (rituximab) has shown promising results. In this review, we will discuss the current thinking on the role of B cells in MS drawing from knowledge gained in EAE studies and clinical trials using therapeutics that target B cells.

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Section: B Cells and Msmentioning

confidence: 99%

A case for regulatory B cells in controlling the severity of autoimmune-mediated inflammation in experimental autoimmune encephalomyelitis and multiple sclerosis

Ray

Mann

Basu

et al. 2011

Journal of Neuroimmunology

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“…Both TPI and GAPDH are essential metabolic enzymes involved in ATP production. Another investigation by the same group showed that these antibodies bind with TPI and GADPH, and inhibit the glycolytic activity of GAPDH but not TPI in MS patients (Kölln et al, 2010). …”

Section: Discussionmentioning

confidence: 99%

Bioenergetic Failure in Rat Oligodendrocyte Progenitor Cells Treated with Cerebrospinal Fluid Derived from Multiple Sclerosis Patients

Mathur

Riffo‐Campos

Castillo

et al. 2017

Front. Cell. Neurosci.

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In relapsing-remitting multiple sclerosis (RRMS) subtype, the patient’s brain itself is capable of repairing the damage, remyelinating the axon and recovering the neurological function. Cerebrospinal fluid (CSF) is in close proximity with brain parenchyma and contains a host of proteins and other molecules, which influence the cellular physiology, that may balance damage and repair of neurons and glial cells. The purpose of this study was to determine the pathophysiological mechanisms underpinning myelin repair in distinct clinical forms of MS and neuromyelitis optica (NMO) patients by studying the effect of diseased CSF on glucose metabolism and ATP synthesis. A cellular model with primary cultures of oligodendrocyte progenitor cells (OPCs) from rat cerebrum was employed, and cells were treated with CSF from distinct clinical forms of MS, NMO patients and neurological controls. Prior to comprehending mechanisms underlying myelin repair, we determine the best stably expressed reference genes in our experimental condition to accurately normalize our target mRNA transcripts. The GeNorm and NormFinder algorithms showed that mitochondrial ribosomal protein (Mrpl19), hypoxanthine guanine phosphoribosyl transferase (Hprt), microglobulin β2 (B2m), and transferrin receptor (Tfrc) were identified as the best reference genes in OPCs treated with MS subjects and were used for normalizing gene transcripts. The main findings on microarray gene expression profiling analysis on CSF treated OPCs cells revealed a disturbed carbohydrate metabolism and ATP synthesis in MS and NMO derived CSF treated OPCs. In addition, using STRING program, we investigate whether gene–gene interaction affected the whole network in our experimental conditions. Our findings revealed downregulated expression of genes involved in carbohydrate metabolism, and that glucose metabolism impairment and reduced ATP availability for cellular damage repair clearly differentiate more benign forms from the most aggressive forms and worst prognosis in MS patients.

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“…In MS patients, the percentage of anti-GAPDH AAbs in the CSF was significantly higher than in patients with other neurologic diseases (61). Such AAbs strongly inhibited the catalytic function of GADPH, which could be reversed by their pre-adsorption with immobilized enzyme (112). Thus, an increased intrathecal production of anti-GAPDH AAbs may lead to their binding of GAPDH present in axons and neurons, inhibition of GAPDH glycolytic activity, neuro-axonal apoptosis, and cytotoxicity.…”

Section: Pathogenic Aabsmentioning

confidence: 99%

Impact of Autoantibodies against Glycolytic Enzymes on Pathogenicity of Autoimmune Retinopathy and Other Autoimmune Disorders

Adamus

2017

Front. Immunol.

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Autoantibodies (AAbs) against glycolytic enzymes: aldolase, α-enolase, glyceraldehyde-3-phosphate dehydrogenase, and pyruvate kinase are prevalent in sera of patients with blinding retinal diseases, such as paraneoplastic [cancer-associated retinopathy (CAR)] and non-paraneoplastic autoimmune retinopathies, as well as in many other autoimmune diseases. CAR is a degenerative disease of the retina characterized by sudden vision loss in patients with cancer and serum anti-retinal AAbs. In this review, we discuss the widespread serum presence of anti-glycolytic enzyme AAbs and their significance in autoimmune diseases. There are multiple mechanisms responsible for antibody generation, including the innate anti-microbial response, anti-tumor response, or autoimmune response against released self-antigens from damaged, inflamed tissue. AAbs against enolase, GADPH, and aldolase exist in a single patient in elevated titers, suggesting their participation in pathogenicity. The lack of restriction of AAbs to one disease may be related to an increased expression of glycolytic enzymes in various metabolically active tissues that triggers an autoimmune response and generation of AAbs with the same specificity in several chronic and autoimmune conditions. In CAR, the importance of serum anti-glycolytic enzyme AAbs had been previously dismissed, but the retina may be without pathological consequence until a failure of the blood–retinal barrier function, which would then allow pathogenic AAbs access to their retinal targets, ultimately leading to damaging effects.

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Inhibition of Glyceraldehyde-3-Phosphate Dehydrogenase Activity by Antibodies Present in the Cerebrospinal Fluid of Patients with Multiple Sclerosis

Cited by 14 publications

References 69 publications

A case for regulatory B cells in controlling the severity of autoimmune-mediated inflammation in experimental autoimmune encephalomyelitis and multiple sclerosis

A case for regulatory B cells in controlling the severity of autoimmune-mediated inflammation in experimental autoimmune encephalomyelitis and multiple sclerosis

Bioenergetic Failure in Rat Oligodendrocyte Progenitor Cells Treated with Cerebrospinal Fluid Derived from Multiple Sclerosis Patients

Impact of Autoantibodies against Glycolytic Enzymes on Pathogenicity of Autoimmune Retinopathy and Other Autoimmune Disorders

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