Peripheral blood gene expression signature mirrors central nervous system disease: The model of multiple sclerosis
Introduction
Multiple sclerosis (MS) is a chronic inflammatory demyelinating autoimmune disease affecting the central nervous system (CNS). MS affects mainly young adults with a peak onset between 20 and 40 years of age. The alterations in the immune system initiated by a loss of immunological tolerance to self-antigens, lead to the development of autoreactive phenomena that can be detected in the peripheral blood. Pathologically, the disease is characterized by perivascular infiltration of monocytes and lymphocytes mainly CD4+ T-cells within the brain and spinal cord that lead to myelin destruction [1]. In MS, peripheral blood mononuclear cells (PBMC) are involved in disease pathogenesis and induce active demyelination. Autoreactive activated T-cells invade the blood–brain barrier and initiate an inflammatory response that leads to myelin destruction and significant neurological disability [2], [3]. Gene expression microarray technology is a new tool for comprehensive evaluation of thousands of genes transcripts simultaneously [4]. In recent years, microarray technology has been used for comprehensive analysis to classify diseases, identify effects of different stimuli or treatments in vivo or in vitro, single out genes that may play a role in a specific disease or in a specific biologic process and was shown as a potent technology also to distinguish transcriptional patterns and complex networks that underlie such processes.
The technology is based on hybridization of mRNA to high-density array of immobilized target sequences. Each sequence corresponds to a specific gene of interest. The labeled pool of sample mRNA is subsequently hybridized to the array and the fluorescence at each spot on the array is quantitatively measured in correspondence to the expression level of each particular gene [5].
Section snippets
Gene expression studies in MS—findings in the brain
The first studies using gene expression arrays in MS looked at the brain and explored the differences between active brain lesions of MS patients with normal subjects white matter. Whitney et al. [6] monitored the expression pattern of over 5000 genes and compared the gene expression profile of normal white matter with that found in acute lesions from the brain of a single MS patient. Sixty-two differentially expressed genes were identified, including the Duffy chemokine receptor, interferon
Gene expression studies in MS—findings in peripheral blood
As brain tissue is not readily available and taking into consideration the evidence that in MS autoreactive PBMC initiate the autoimmune inflammatory process against myelin antigens, it was of importance to evaluate whether transcriptional profiling of PBMC could serve to identify a disease specific diagnostic signature. Identification of MS associated gene expression profiles directly from PBMC could highlight important disease-specific pathways and provide a useful tool for clinical studies
PBMC gene expression pharmacogenomics
Another rapidly growing area in the field of gene expression are practical approaches for evaluating pharmacodynamics effects of immunomodulatory therapies in MS by estimation of individual response of patients to a specific treatment. Wandinger et al. [20] performed gene expression analysis of interferon-beta (IFN-b)-treated PBMC by cDNA microarray and demonstrated that IFN-b up-regulates not only TH2 but also numerous TH1-related pro-inflammatory mediators. Sturzebecher et al. [21] assessed
PBMC gene expression pathogenic pathways
Several investigators have looked on specific pathogenic pathways in MS using PBMC gene expression arrays. Iglesias et al. [26] revealed that several E2F1-dependent genes had enhanced expression in MS PBMC, while PBMC from IFNb-1a treated MS patients had lower expression of E2F targets. As the E2F pathway promotes immune cell survival, the authors suggested that its disruption lead to perpetuation of immune cell dysregulation in MS.
We have studied MS gene expression signature of 1109 gene
Conclusions
Gene expression array-based technologies provided new opportunity to illuminate MS disease transcriptional fingerprints. This could enable the re-construction of biological pathways involved in disease evolvement, enable better understanding of the mechanisms of current drug therapies, reveal new potential targets for therapeutic interventions, and evaluate transcription biomarkers for diagnostic and prediction of clinical outcome in MS patients.
Take-home messages
•Peripheral blood mononuclear cells (PBMC) gene expression can be used as a fingerprint of end-organ cerebral neurological disease.
•Variation of PBMC gene expression signatures observed in healthy subjects is markedly smaller than those observed among patients, and thus provide robust support for using gene expression patterns for characterization and diagnosis of disease states.
•PBMC gene expression patterns in MS patients contain information about a remote-target disease process that may by
References (28)
Powerful tools for genetic analysis come of age
Trends Biotechnol
(1999)- et al.
Microarray analysis of gene expression in multiple sclerosis and EAE identifies 5-lipoxygenase as a component of inflammatory lesions
Journal of Neuroimmunology
(2001) - et al.
Gene microarray analysis of multiple sclerosis lesions
Trends Mol Med
(2003) - et al.
Microarray gene expression profiling of chronic active and inactive lesions in multiple sclerosis
Clin Neurol Neurosurg
(2004) - et al.
In vivo gene expression revealed by cDNA arrays: the pattern in relapsing remitting multiple sclerosis patients compared with normal subjects
J Neuroimmunol.
(2001) - et al.
Microarray analysis identifies interferon beta-regulated genes in multiple sclerosis
J Neuroimmunol
(2003) - et al.
Microarray detection of E2F pathway activation and other targets in multiple sclerosis peripheral blood mononuclear cells
J Neuroimmunol
(2004) - et al.
Microarray analysis identifies an aberrant expression of apoptosis and DNA damage-regulatory genes in multiple sclerosis
Neurobiol Dis
(2005) - et al.
The immunopathogenesis of multiple sclerosis
J. Rehabil. Res. Dev.
(2002) - et al.
Migration of multiple sclerosis lymphocytes through brain endothelium
Arch. Neurol.
(2002)