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. 2010 Jul;20(4):720-9.
doi: 10.1111/j.1750-3639.2009.00343.x. Epub 2009 Oct 16.

Upregulation of immunoglobulin-related genes in cortical sections from multiple sclerosis patients

Øivind Torkildsen  1 , Christine Stansberg, Solveig M Angelskår, Evert-Jan Kooi, Jeroen J G Geurts, Paul van der Valk, Kjell-Morten Myhr, Vidar M Steen, Lars Bø
Affiliations

Upregulation of immunoglobulin-related genes in cortical sections from multiple sclerosis patients

Øivind Torkildsen et al. Brain Pathol. 2010 Jul.

Abstract

Multiple sclerosis (MS) is a demyelinating disease of the central nervous system (CNS). Microarray-based global gene expression profiling is a promising method, used to study potential genes involved in the pathogenesis of the disease. In the present study, we have examined global gene expression in normal-appearing gray matter and gray matter lesions from the cortex of MS patients, and compared them with cortical gray matter samples from controls. We observed a massive upregulation of immunoglobulin (Ig)-related genes in cortical sections of MS patients. Using immunohistochemistry, the activation of Ig genes seems to occur within plasma cells in the meninges. As synthesis of oligoclonal IgGs has been hypothesized to be caused by the activation of Epstein-Barr virus (EBV)-infected B-cells, we screened the brain samples for the presence of EBV by real-time quantitative polymerase chain reaction (qPCR) and immunohistochemistry, but no evidence of active or latent EBV infection was detected. This study demonstrates that genes involved in the synthesis of Igs are upregulated in MS patients and that this activation is caused by a small number of meningeal plasma cells that are not infected by EBV. The findings indicate that the Ig-producing B-cells found in the cerebrospinal fluid (CSF) of MS patients could have meningeal origin.

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Figures

Figure 1
Figure 1
Heat map illustrating relative expression levels of the immunoglobulin‐related genes across control‐ and MS patients. Microarray intensity levels were log2 transformed, and high‐level mean was normalized for visualization of contrasts. Red and blue colors indicate expression levels above and below average, respectively. Abbreviations: GML = Grey matter lesions; NGM = Normal‐appearing grey matter.
Figure 2
Figure 2
Relative gene expression as demonstrated by TaqMan quantitative polymerase chain reaction (qPCR) for IGKC, IGHG1, IGKV41, hCG2042707 and VSIG6. The diagrams display mean values for 12 controls and 11 multiple sclerosis (MS) patients (including both NGM and GML samples). Gene expression levels in the samples from the additional patients completely correlated with data from the original patients. A Student's t‐test (P < 0.001) confirmed significant upregulation of IGKC, IGHG1 and IGKV41 in MS patients compared with controls. hCG2042707 was only detected in a fraction of the samples studied, but it indicated a clear upregulation in MS patients. The activation of VSIG6 could not be confirmed by qPCR. Expression of hCG1742442, hCG2038937 and hCG1773456 could not be detected by their respective TaqMan assays. Details on TaqMan assays and statistical results are included in Table 3.
Figure 3
Figure 3
Meninges from one multiple sclerosis (MS) patient (A) and a control (B) stained with immunoglobulin. The pictures show immunoglobulin deposits (arrows) and cellular infiltration in the meningeal tissue from the MS patient compared with the control. All pictures have an original magnification of ×40.
Figure 4
Figure 4
Immunohistochemical staining of CD138 (A), CD20 (B) and CD3 (C) positive cells (arrows) in meninges of multiple sclerosis patients (stainings from controls are not shown). CD20 and CD138 positive cells are only seen occasionally.
See this image and copyright information in PMC

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