Triosephosphate Isomerase- and Glyceraldehyde-3-Phosphate Dehydrogenase-Reactive Autoantibodies in the Cerebrospinal Fluid of Patients with Multiple Sclerosis

Govarts

The Journal of Immunology

et al. 2008

An important contribution of B cells and autoantibodies has been demonstrated in the pathogenesis of multiple sclerosis (MS), leading to interest in the use of such autoantibodies as diagnostic or prognostic biomarkers. The objective of this study was to identify novel Ab biomarkers for MS using “serological Ag selection”. Using a phage display library derived from MS brain plaques, we applied serological Ag selection to identify antigenic targets specifically interacting with Abs present in the cerebrospinal fluid (CSF) of 10 relapsing-remitting MS patients. These antigenic targets were further evaluated on a large panel of CSF from 63 other MS patients, 30 patients with other inflammatory disorders, and 64 patients with noninflammatory neurological disorders. A panel of eight antigenic targets was identified that showed a 86% specificity and 45% sensitivity in discriminating MS patients and controls. Four of the antigenic targets showed exclusive reactivity (100% specificity; 23% sensitivity) in the MS group as compared with the control group. Detailed bio-informatic analyses revealed a novel Ag, SPAG16. Among the novel phage peptides identified, novel epitopes were generated from untranslated sequences and out-of-frame sequences. Of 10 relapsing-remitting patients used for serological Ag selection, Ab reactivity toward one of the eight antigenic targets was also demonstrated in serum of 38% CSF-positive patients. Autoantibody profiles against epitopes derived from MS brain tissue could serve as diagnostic markers or form the basis for the identification of a subgroup of MS patients.

Section: Ultiple Sclerosis (Ms)mentioning

confidence: 99%

Autoantibody Profiling in Multiple Sclerosis Reveals Novel Antigenic Candidates

Govarts

The Journal of Immunology

et al. 2008

Journal of Neuroimmunology

“…However, no additional bands (especially at 30 kDa) could be detected in the IP components resolved separately. Recently, another group has reported that CSF antibodies from some MS patients are reactive to triosephosphate isomerase (TPI), which is 27 kDa and glyceraldehyde-3-phosphate dehydrogenase (GAPDH), which is 37 kDa (Kolln et al, 2006). However, it is not possible that the identity of the ~30 kDa bands we observed in the immunoprecipitates could be TPI or GAPDH, because these proteins were not included in the IP components, and in the subsequent western blots, the primary antibody recognizes MBP specifically, and the secondary antibody recognizes antibody constant regions.…”

Section: The Mbp Reactive Fabs Precipitate Mbp In Solutionmentioning

confidence: 99%

Antigen specificity of clonally expanded and receptor edited cerebrospinal fluid B cells from patients with relapsing remitting MS

Lambracht-Washington

O’Connor

Cameron

et al. 2007

We re-engineered the immunoglobulin rearrangements from clonally expanded CSF B cells of three Multiple Sclerosis patients as Fab fragments, and used three methods to test for their Ag-specificity. Nine out of ten Fab fragments were reactive to Myelin Basic Protein (MBP). The one Fab that did not react to MBP was a product of receptor editing. Two of the nine MBP-reactive Fabs were also reactive to GFAP and CNPase, indicating that these clones were polyreactive. Targeting the mechanisms that allows these self-reactive B cells to reside in the CSF of MS patients may prove to be a potent immunotherapeutic strategy.

Molecular & Cellular Proteomics

“…Therefore, it is not surprising that any events that may impair the function of molecules involved in glucose metabolism could lead to significant damage in the integrity and function of neurons or their supporting cells. In this context, it is noteworthy that antibodies to AE, TPI, and GAPDH have been shown to be present in the CSF from MS patients (15,51,52). Besides their glycolytic roles, these enzymes also have other functions.…”

Section: Discussionmentioning

confidence: 99%

A Novel Unbiased Proteomic Approach to Detect the Reactivity of Cerebrospinal Fluid in Neurological Diseases

Menon

Steer

Short

et al. 2011

Neurodegenerative diseases, such as multiple sclerosis represent global health issues. Accordingly, there is an urgent need to understand the pathogenesis of this and other central nervous system disorders, so that more effective therapeutics can be developed. Cerebrospinal fluid is a potential source of important reporter molecules released from various cell types as a result of central nervous system pathology. Here, we report the development of an unbiased approach for the detection of reactive cerebrospinal fluid molecules and target brain proteins from patients with multiple sclerosis. To help identify molecules that may serve as clinical biomarkers for multiple sclerosis, we have biotinylated proteins present in the cerebrospinal fluid and tested their reactivity against brain homogenate as well as myelin and myelin-axolemmal complexes. Proteins were separated by two-dimensional gel electrophoresis, blotted onto membranes and probed separately with biotinylated unprocessed cerebrospinal fluid samples. Protein spots that reacted to two or more multiple sclerosis-cerebrospinal fluids were further analyzed by matrix assisted laser desorption ionization-time-of-flight time-of-flight mass spectrometry. In addition to previously reported proteins found in multiple sclerosis cerebrospinal fluid, such as ␣␤ crystallin, enolase, and 14 -3-3-protein, we have identified several additional molecules involved in mitochondrial and energy metabolism, myelin gene expression and/or cytoskeletal organization. These include aspartate aminotransferase, cyclophilin-A, quaking protein, collapsin response mediator protein-2, ubiquitin carboxy-terminal hydrolase L1, and cofilin. To further validate these findings, the cellular expression pattern of collapsin response mediator protein-2 and ubiquitin carboxy-terminal hydrolase L1 were investigated in human chronic-active MS lesions by immunohistochemistry. The observation that in multiple sclerosis lesions phosphorylated collapsin response mediator protein-2 was increased, whereas Ubiquitin carboxy-terminal hydrolase L1 was down-regulated, not only highlights the importance of these molecules in the pathology of this disease, but also illustrates the use of our approach in attempting to decipher the complex pathological processes leading to multiple sclerosis and other neurodegenerative diseases.