Identification of Epstein-Barr virus proteins as putative targets of the immune response in multiple sclerosis
Sabine Cepok, … , Norbert Sommer, Bernhard Hemmer
Sabine Cepok, … , Norbert Sommer, Bernhard Hemmer
Published May 2, 2005
Citation Information: J Clin Invest. 2005;115(5):1352-1360. https://doi.org/10.1172/JCI23661.
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Identification of Epstein-Barr virus proteins as putative targets of the immune response in multiple sclerosis

Abstract

MS is a chronic inflammatory and demyelinating disease of the CNS with as yet unknown etiology. A hallmark of this disease is the occurrence of oligoclonal IgG antibodies in the cerebrospinal fluid (CSF). To assess the specificity of these antibodies, we screened protein expression arrays containing 37,000 tagged proteins. The 2 most frequent MS-specific reactivities were further mapped to identify the underlying high-affinity epitopes. In both cases, we identified peptide sequences derived from EBV proteins expressed in latently infected cells. Immunoreactivities to these EBV proteins, BRRF2 and EBNA-1, were significantly higher in the serum and CSF of MS patients than in those of control donors. Oligoclonal CSF IgG from MS patients specifically bound both EBV proteins. Also, CD8+ T cell responses to latent EBV proteins were higher in MS patients than in controls. In summary, these findings demonstrate an increased immune response to EBV in MS patients, which suggests that the virus plays an important role in the pathogenesis of disease.

Authors

Sabine Cepok, Dun Zhou, Rajneesh Srivastava, Stefan Nessler, Susanne Stei, Konrad Büssow, Norbert Sommer, Bernhard Hemmer

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Figure 1

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Analysis of CSF IgG immunoreactivity in MS patients by protein expressio...
Analysis of CSF IgG immunoreactivity in MS patients by protein expression arrays. (A) Incubation of the protein expression array with CSF from a representative MS patient (left) and a control donor (right). A 3 cm × 3 cm section of the 24 cm × 24 cm array is shown. IgG immunoreacitivity of the MS CSF to the expression clone B3 (spotted in duplicate) is marked by a circle. IgG concentration was adjusted to 1 mg/l IgG in MS and control CSF. (B) Western blot with purified protein B3. Immunoractivity was observed in the CSF of a representative MS patient (left) but not the NIND (middle) or OIND (right) control donors. All CSF samples were adjusted to 10 mg/l IgG. IgG binding was developed with ECL. M, molecular weight marker. (C) Analysis of immunoreactivity to B3 protein (left) and control protein GAPDH (right) with CSF (1:5 diluted) of 132 MS patients and 125 NIND patients by ELISA. Antibody titers were significantly higher in MS patients. Dot points represent the OD of a single CSF sample. Cut-off point, OD > 0.3 (mean ± 6 SEM). (D) CSF from a patient with high immunoreacitivty to patterns I and II proteins was separated by IEF and blotted against proteins B3, C6, C5, F4, and G4 as well as the control protein GAPDH. Binding of proteins from both patterns was similar with little overlap between the patterns. Similar results were obtained with CSF from another patient (data not shown). (E) IEF immunoblot with CSF (C) and serum (S) from 3 MS patients (adjusted to 10 mg IgG/l) was performed to compare IgG binding patterns to proteins B3, C5, and G4. A stronger and more focused immune response to the proteins was observed in the CSF of 10 patients analyzed in total. *P < 0.001, Fisher’s exact test.